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1.  Associations between Nonalcoholic Fatty Liver Disease and Subclinical Atherosclerosis in Middle-Aged Adults: The Coronary Artery Risk Development in Young Adults Study 
Atherosclerosis  2014;235(2):599-605.
Non-alcoholic fatty liver disease (NAFLD) is an obesity-related condition associated with cardiovascular mortality. Yet, whether or not NAFLD is independently related to atherosclerosis is unclear. In a population-based cross-sectional sample of middle-aged adults free from liver or heart disease, we tested the hypothesis that NAFLD is associated with subclinical atherosclerosis (coronary artery (CAC) and abdominal aortic calcification (AAC)) independent of obesity.
Participants from the Coronary Artery Risk Development in Young Adults study with CT quantification of liver fat, CAC and AAC were included (n=2,424). NAFLD was defined as liver attenuation ≤ 40 Hounsfield Units after exclusion of other causes of liver fat. CAC and AAC presence was defined as Agatston score > 0.
Mean participant age was 50.1±3.6 years, (42.7% men, 50.0% black) and BMI was 30.6±7.2 kg/m2. The prevalence of NAFLD, CAC, and AAC was 9.6%, 27.1%, and 51.4%. NAFLD participants had increased prevalence of CAC (37.9% vs. 26.0%, p<0.001) and AAC (65.1% vs. 49.9%, p<0.001). NAFLD remained associated with CAC (OR, 1.33; 95% CI, 1.001–1.82) and AAC (OR, 1.74; 95% CI, 1.29–2.35) after adjustment for demographics and health behaviors. However, these associations were attenuated after additional adjustment for visceral adipose tissue (CAC OR, 1.05; 95% CI, 0.74–1.48, AAC OR=1.20; 95% CI, 0.86–1.67). There was no interaction by race or sex.
In contrast to prior research, these findings suggest that obesity attenuates the relationship between NAFLD and subclinical atherosclerosis. Further studies evaluating the role of NAFLD duration on atherosclerotic progression and cardiovascular events are needed.
PMCID: PMC4124046  PMID: 24956534
calcium; cardiovascular diseases; epidemiology; imaging; liver; obesity; risk factors
2.  Association of Neighborhood Characteristics with Cardiovascular Health in the Multi-Ethnic Study of Atherosclerosis (MESA) 
The concept of ‘cardiovascular health’ (CVH) was introduced as a global measure of one’s cardiovascular health. Previous studies established the relationship between neighborhood characteristics and individual cardiovascular risk factors. However, the relationship between neighborhood environment and overall CVH remains unknown.
Methods and Results
We analyzed data from the MESA baseline exam (2000–2002). Mean age was 61.6 years and 52% were female. Ideal, intermediate and poor categories of cholesterol, body mass index, diet, physical activity, fasting glucose, blood pressure and smoking were defined according to the AHA 2020 Strategic Goals, assigned an individual score and summed to create an overall score. CVH scores were categorized into ideal (11–14 points), intermediate (9–10) and poor (0–8). Neighborhood exposures included favorable food store and physical activity resources densities (by 1-mile buffer), reported healthy food availability, walking/physical activity environment, safety and social cohesion (by census tract). Multinomial logistic regression was used to determine the association of each characteristic with ideal and intermediate CVH, adjusted for demographics and neighborhood socioeconomic status (SES). Over 20% of MESA participants had an ideal CVH score at baseline. In fully adjusted models, favorable food stores (OR= 1.22, 1.06–1.40), physical activity resources (OR=1.19, 1.08–1.31), walking/physical activity environment (OR=1.20, 1.05–1.37) and neighborhood SES (OR=1.22, 1.11–1.33) were associated with higher odds of having an ideal CVH score.
Neighborhood environment including favorable food stores, physical activity resources, walking/physical activity environment and neighborhood SES are associated with ideal CVH. Further research is needed to investigate the longitudinal associations between neighborhood environment and CVH.
PMCID: PMC4172357  PMID: 25006187
risk factors; blood pressure; cholesterol; diet; exercise; prevention
3.  Clinical Characteristics and Outcomes Associated with the Natural History of Early Repolarization in a Young, Biracial Cohort Followed to Middle Age: The Coronary Artery Risk Development in Young Adults (CARDIA) Study 
Early repolarization (ER), a common electrocardiographic phenotype, has been associated with increased mortality risk in middle-aged adults. Data are sparse on long-term follow-up and outcomes associated with ER in younger adults.
Methods and Results
We prospectively examined 5,039 participants (mean age 25 years at baseline, 40% black) from the CARDIA cohort over 23 years. Twelve-lead electrocardiograms were recorded and analyzed at Years 0, 7 and 20 and coded as definite or probable ER using a standardized algorithm. Cox regression was used, and models were adjusted for important baseline and clinical covariates. Kaplan-Meier curves were created for presence of ER and total mortality and cardiovascular (CV) mortality. Participants with ER were more likely to be black, male, smoke, have higher systolic blood pressure, lower heart rate, and BMI, and also higher exercise duration, and longer PR, QRS and QT intervals. ER was associated with total mortality (HR1.77, 1.38–2.28, p<0.01), and CV mortality (HR 1.59, 1.01–2.50, p=0.04) in unadjusted analyses, but adjustment for age, sex, and race attenuated associations almost completely. Sex-race stratified analyses showed no significant associations between ER and outcome for any of the subgroups except blacks.
The presence of ER at any time point over 23 years of follow-up was not associated with adverse outcomes. Black race and male sex confound the unadjusted association of ER and outcomes, with no race-sex interactions noted. Further studies are necessary to understand the factors associated with heightened risk of death in those who maintain ER into and beyond middle age.
PMCID: PMC4136505  PMID: 24759868
ECG; ECG criteria; outcome; mortality; early repolarization
4.  Prognostic Value of Frontal QRS-T Angle in Patients without Clinical Evidence of Cardiovascular Disease (From the Multi-Ethnic Study of Atherosclerosis [MESA]) 
The American journal of cardiology  2013;112(12):10.1016/j.amjcard.2013.08.017.
Abnormal frontal QRS-T angle on a 12 lead electrocardiogram (ECG) is associated with incident coronary heart disease and total mortality in a biracial cohort but there have been no studies to date examining QRS-T angle’s prognostic value across multiple ethnicities. We studied 6,814 participants (52.7% women, mean age 62) from MESA; a multi-ethnic cohort aged 45–84 free of clinical cardiovascular disease (CVD) at enrollment. Baseline examination included measurement of traditional risk factors and 12-lead ECG’s. Frontal QRS-T axis was defined as normal (<75th percentile), borderline (75–95th percentile) or abnormal (≥ 95th percentile) and participants were followed for the composite endpoint of incident CVD events: cardiovascular death, myocardial infarction, angina pectoris or heart failure. After 7.6 years of follow up there were 444 total events. Borderline ((HR 1.37 95% Confidence Interval (CI) (1.10,1.70)) and abnormal QRS-T angle (HR 2.2 95% CI (1.63, 2.97)) was associated with incident CVD events in multivariable-adjusted models. However, after adjusting for T wave abnormalities there was no statistically significant association of either borderline (HR 1.12 95% CI (0.90, 1.41)) or abnormal (HR 1.31 95% CI (0.93, 1.84)) QRS-T angle with incident CVD events. Abnormal frontal QRS-T angle predicts incident CVD events in a multiethnic population and this increased risk is primarily mediated through T wave abnormalities. QRS-T angle provides an easily interpretable, continuous marker of abnormal ventricular repolarization that can aid the everyday clinician in risk prediction.
PMCID: PMC3863114  PMID: 24063831
Electrocardiography; risk assessment; cardiovascular disease
Exposure to arsenic (As) has been associated with cancers, CVD, and neurological disorder. To explore the possible underlying epigenetic mechanisms, a genome-wide study was conducted in low exposed healthy individuals. This study was nested within a prospective study of Coronary Artery Risk Development in Young Adults (CARDIA) by randomly selecting 46 non-smoker and non-diabetic White participants with low (N=23) and high (N=23) As exposure. based on toenail total As measures at examination year 2. We conducted methylomic profiling of white blood cell DNA collected at examination year 15 using the Illumina HumanMethylation450 BeadChip. Multivariate linear regression models were fitted to evaluate the associations between As exposure status and DNA methylation levels at each CpG site. We identified 29 CpG sites with methylation levels associated with As exposure status at a nominal p-value less than 0.0001. Some genes are known to be involved in cancers, CVD, and neurological disorder. Pathway analyses further revealed several canonical pathways relevant to the etiology of As-associated diseases. We demonstrated that As exposure is prospectively associated with DNA methylation levels in a number of genes implicated in As-associated diseases. Further studies are required for elucidating the role of epigenetic alterations in the pathogenesis of these diseases.
PMCID: PMC4167014  PMID: 24368509
arsenic exposure; methylomic profiling; prospective association
6.  Status of Cardiovascular Health in US Adults: Prevalence Estimates from the National Health and Nutrition Examination Surveys (NHANES) 2003-2008 
Circulation  2011;125(1):45-56.
The American Heart Association's 2020 Strategic Impact Goals define a new concept, “cardiovascular (CV) health”; however, current prevalence estimates of the status of CV health in U.S. adults according to age, sex and race/ethnicity have not been published.
Methods and Results
We included 14,515 adults (≥20 years) from the 2003-2008 National Health and Nutrition Examination Surveys. Participants were stratified by young (20-39 years), middle (40-64 years), and older ages (65+ years). CV health behaviors (diet, physical activity, body mass index, smoking) and CV health factors (blood pressure, total cholesterol, fasting blood glucose, smoking) were defined as poor, intermediate, or ideal. Less than 1% of adults exhibited ideal CV health for all 7 metrics. For CV health behaviors, non-smoking was most prevalent (range:60.2-90.4%) while ideal Healthy Diet Score was least prevalent (range:0.2-2.6%) across groups. Prevalence of ideal BMI (range:36.5-45.3%) and ideal physical activity levels (range:50.2-58.8%) were higher in young adults compared to middle or older ages. Ideal total cholesterol (range:23.7-36.2%), blood pressure (range:11.9-16.3%) and fasting blood glucose (range:31.2-42.9%) were lower in older adults compared with young and middle age adults.Prevalence of poor CV health factors was lowest in young age but higher at middle and older ages. Prevalence estimates by age and sex were consistent across race/ethnic groups.
These prevalence estimates of CV health represent a starting point from which effectiveness of efforts to promote CV health and prevent CV disease can be monitored and compared in U.S. adult populations.
PMCID: PMC4077723  PMID: 22095826
Cardiovascular Diseases; Diet; Epidemiology; Obesity; Risk Factors
7.  Quantifying Options for Reducing Coronary Heart Disease Mortality By 2020 
Circulation  2013;127(25):2477-2484.
The AHA 2020 Strategic Impact Goal proposes a 20% improvement in cardiovascular health of all Americans. We aimed to estimate the potential reduction in coronary heart disease (CHD) deaths.
Methods and Results
We used data on 40,373 CVD-free adults from NHANES (1988–2010). We quantified recent trends for six metrics (total cholesterol [TC]; systolic blood pressure [SBP]; physical inactivity; smoking; diabetes; obesity) and generated linear projections to 2020. We projected the expected number of CHD deaths in 2020 if 2006 age- and sex-specific CHD death rates remained constant, which would result in approximately 480,000 CHD deaths in 2020 (12% increase). We used the previously validated IMPACT CHD model to project numbers of CHD deaths in 2020 under two different scenarios.
A) Assuming a 20% improvement in each CVH metric, we project 365,000 CHD deaths in 2020, (range 327,000–403,000) a 24% decrease reflecting modest reductions in TC (−41,000), SBP (−36,000), physical inactivity (−12,000), smoking (−10,000), diabetes (−10,000), and obesity (−5,000). B) Assuming that recent risk factor trends continue to 2020, we project 335,000 CHD deaths (range 274,000–386,000), a 30% decrease reflecting improvements in TC, SBP, smoking and physical activity (~167,000 fewer deaths), offset by increases in diabetes and BMI (~24,000 more deaths).
Two contrasting scenarios of change in CVH metrics could prevent 24–30% of the CHD deaths expected in 2020, though with differing impacts by age. Unfavorable continuing trends in obesity and diabetes would have substantial adverse effects. This analysis demonstrates the utility of modelling to inform health policy.
PMCID: PMC3795417  PMID: 23661723
heart disease; American Heart Association; epidemiology; risk factor
8.  Competing Cardiovascular Outcomes Associated with Subclinical Atherosclerosis (From the Multi-Ethnic Study of Atherosclerosis) 
The American journal of cardiology  2013;111(11):1541-1546.
Subclinical atherosclerosis measured by coronary artery calcium (CAC) is associated with increased risk for multiple cardiovascular disease (CVD) outcomes and non-CVD death simultaneously, and we sought to determine the competing risks of specific cardiovascular disease (CVD) events and non-CVD death associated with varying burdens of subclinical atherosclerosis. We included 3095 men and 3486 women from the Multi-Ethnic Study of Atherosclerosis, aged 45–84 years, and from 4 ethnic groups. Participants were stratified by CAC scores: 0, 1–99, and ≥ 100. We used competing Cox models to determine competing cumulative incidences and hazards ratios within a group (e.g., among those with CAC ≥ 100) and hazards ratios for specific events between groups (e.g., CAC ≥ 100 vs. CAC = 0). We compared risks for specific CVD events and also compared against non-CVD death. In women, during a mean follow up of 7.1 years, the hazards ratios (HR) for any CVD event compared with a non-CVD death occurring first for CAC = 0 and CAC ≥ 100 were 1.40 (95% CI, 0.97–2.04) and 3.07 (2.02–4.67), respectively. CHD was the most common first CVD event type at all levels of CAC, and CHD rates were 9.5% vs. 1.6% (HR 6.24; 3.99–9.75) for women with CAC ≥100 compared with CAC = 0. We observed similar results in men. In conclusion, at all levels of CAC, CHD was the most common first CVD event and this analysis represents a novel approach to understanding the temporal sequence of cardiovascular events associated with atherosclerosis.
PMCID: PMC3657323  PMID: 23499272
coronary artery calcium; competing risks
9.  Associations Between a Parental History of Premature Cardiovascular Disease and Coronary Calcium and Carotid Intima-Media Thickness: The Coronary Artery Risk Development In Young Adults (CARDIA) Study 
It is unclear if associations between a parental history of premature CVD (pCVD) and subclinical atherosclerosis are attenuated by adjustment for long-term risk factors levels through middle adulthood.
Prospective community-based cohort study
CARDIA participants who attended the year 20 exam (N=2283, mean age 45 years) were grouped by pCVD status: maternal only, paternal only, any parental, and no parental history (referent). We used separate logistic regression models, adjusted for average risk factor levels over 20 years' follow-up to assess associations of parental pCVD and subclinical atherosclerosis in offspring.
White participants with any parental history of pCVD had a higher odds of CAC>0 than participants with no parental history (OR 1.55; 95% CI, 1.01-2.37). This was largely driven by the association of a paternal history of pCVD with CAC>0 (OR 2.15; 95% CI, 1.42-3.23), which was minimally attenuated by multivariable adjustment (OR 2.09; 95% CI, 1.31-3.32). Similarly, adjusted associations between parental pCVD and IMT > 90%tile were observed in white participants with a paternal history of pCVD (OR=1.93; 95% CI, 1.10-3.39) and any parental history pCVD (OR 1.67; 95% CI, 1.02-2.74). No significant associations between a parental history of pCVD and the odds of subclinical atherosclerosis were observed in black participants.
Parental pCVD is independently associated with early development of subclinical atherosclerosis; these associations may be race-specific for participants in their 5th decade of life.
PMCID: PMC3779512  PMID: 23027592
Family History of Premature Cardiovascular Disease; Coronary Artery Calcium; Carotid Intima-Media Thickness
10.  Lifetime Risk for Heart Failure Among White and Black Americans: Cardiovascular Lifetime Risk Pooling Project 
To estimate lifetime risk for HF by sex and race.
Prior estimates of lifetime risk for developing heart failure (HF) range from 20% to 33% in predominantly white cohorts. Short-term risks for HF appear higher for blacks than whites, but only limited comparisons of lifetime risk for HF have been made.
Using public-release and internal datasets from NHLBI-sponsored cohorts, we estimated lifetime risks for developing HF to age 95, with death free of HF as the competing event, among participants in Chicago Heart Association Detection Project in Industry (CHA), Atherosclerosis Risk in Communities (ARIC), and Cardiovascular Health Study (CHS) cohorts.
There were 39,578 participants (33,652 [85%] white; 5,926 [15%] black) followed for 716,976 person-years; 5,983 participants developed HF. At age 45 years, lifetime risks for HF through age 95 years in CHA and CHS were 30-42% in white men, 20-29% in black men, 32-39% in white women, and 24-46% in black women. Results for ARIC demonstrated similar lifetime risks for HF in blacks and whites through age 75 years (limit of follow-up). Lifetime risk for HF was higher with higher BP and BMI at all ages in both blacks and whites and did not diminish substantially with advancing index age.
These are among the first data to compare lifetime risks for HF between blacks and whites. Lifetime risks for HF are high and appear similar for black and white women, yet are somewhat lower for black compared with white men due to competing risks.
PMCID: PMC3618527  PMID: 23500287
lifetime risk; heart failure; epidemiology
11.  Coronary Heart Disease Risks Associated with High Levels of HDL Cholesterol 
The association between high‐density lipoprotein cholesterol (HDL‐C) and coronary heart disease (CHD) events is not well described in individuals with very high levels of HDL‐C (>80 mg/dL).
Methods and Results
Using pooled data from 6 community‐based cohorts we examined CHD and total mortality risks across a broad range of HDL‐C, including values in excess of 80 mg/dL. We used Cox proportional hazards models with penalized splines to assess multivariable, adjusted, sex‐stratified associations of HDL‐C with the hazard for CHD events and total mortality, using HDL‐C 45 mg/dL and 55 mg/dL as the referent in men and women, respectively. Analyses included 11 515 men and 12 925 women yielding 307 245 person‐years of follow‐up. In men, the association between HDL‐C and CHD events was inverse and linear across most HDL‐C values; however at HDL‐C values >90 mg/dL there was a plateau effect in the pattern of association. In women, the association between HDL‐C and CHD events was inverse and linear across lower values of HDL‐C, however at HDL‐C values >75 mg/dL there were no further reductions in the hazard ratio point estimates for CHD. In unadjusted models there were increased total mortality risks in men with very high HDL‐C, however mortality risks observed in participants with very high HDL‐C were attenuated after adjustment for traditional risk factors.
We did not observe further reductions in CHD risk with HDL‐C values higher than 90 mg/dL in men and 75 mg/dL in women.
PMCID: PMC4187512  PMID: 24627418
CHD events; total mortality; very‐high HDL‐C
12.  Association of Electrocardiographically Determined Left Ventricular Mass With Incident Diabetes, 1985–1986 to 2010–2011 
Diabetes Care  2013;36(3):645-647.
Electrocardiographic indices reflecting left ventricular hypertrophy are associated with incident diabetes in clinical populations at risk for coronary heart disease. We tested whether electrocardiographically determined left ventricular mass was positively associated with incident diabetes in a population sample.
Coronary Artery Risk Development in Young Adults (CARDIA) study participants (n = 4,739) were followed from 1985–1986 to 2010–2011 for incident diabetes. Validated sex- and race-specific formulas were applied to standard electrocardiograms to determine left ventricular mass.
Over 25 years, 444 participants developed diabetes (9.4%). After adjustment for demographic, behavioral, and clinical covariates, participants in the highest quartile of left ventricular mass index (LVMI) were twice as likely to develop diabetes than participants in the lower three quartiles (hazard ratio 2.61 [95% CI 2.16–3.17]). Neither Cornell voltage nor Cornell voltage product was associated with incident diabetes in fully adjusted models.
Electrocardiographically determined LVMI may be a useful noninvasive marker for identifying adults at risk for diabetes.
PMCID: PMC3579342  PMID: 23160723
13.  Natural History of the Early Repolarization Pattern in a Biracial Cohort: CARDIA (Coronary Artery Risk Development in Young Adults) Study 
The objective of this analysis was to determine the natural history and prospective association of cardiovascular risk factors with early repolarization (ER).
ER is common and has been suggested to increase risk for cardiovascular mortality in middle-aged adults. Data are sparse regarding the natural history of ER from young adulthood to middle age.
We examined 5,069 participants (mean age 25 years at baseline; 40% black) from the CARDIA (Coronary Artery Risk Development in Young Adults) cohort over 20 years. Electrocardiograms were recorded at years 0 (Y0), 7 (Y7), and 20 (Y20) and coded as either definite, probable, possible, or no ER. Logistic regression was used to determine the association of cardiovascular risk factors with the presence of ER cross-sectionally and prospectively.
A total of 941 of the 5,069 participants (18.6%) had definite ER at baseline, and only 119 of 2,505 participants (4.8%) at the Y20 examination still demonstrated the presence of ER. Younger age, black race, male sex, longer exercise duration and QRS duration, and lower body mass index (BMI), heart rate, QT index, and Cornell voltage were associated cross-sectionally with the presence of ER. Predictors of maintenance of ER from Y0 to Y20 were black race (odds ratio [OR]: 2.62; 95% CI; 1.61 to 4.25), BMI (OR: 0.62 per 1 SD; 95% CI: 0.40 to 0.94), serum triglyceride levels (OR: 0.66 per 1 SD; 95% CI: 0.45 to 0.98), and QRS duration (OR: 1.68 per 1 SD; 95% CI: 1.37 to 2.06) at baseline.
The prevalence of ER was significantly higher than previous estimates among asymptomatic young adults, and the majority of ER regressed by middle age. Black race, lower BMI, lower serum triglyceride levels, and longer QRS duration were independently associated with maintenance of ER over time.
PMCID: PMC3748821  PMID: 23428218
early repolarization; electrocardiography; epidemiology
14.  Cardiovascular Health Behavior and Health Factor Changes (1988 –2008) and Projections to 2020 
Circulation  2012;125(21):2595-2602.
The American Heart Association’s 2020 Strategic Impact Goals target a 20% relative improvement in overall cardiovascular health with the use of 4 health behavior (smoking, diet, physical activity, body mass) and 3 health factor (plasma glucose, cholesterol, blood pressure) metrics. We sought to define current trends and forward projections to 2020 in cardiovascular health.
Methods and Results
We included 35 059 cardiovascular disease–free adults (aged ≥20 years) from the National Health and Nutrition Examination Survey 1988–1994 and subsequent 2-year cycles during 1999–2008. We calculated population prevalence of poor, intermediate, and ideal health behaviors and factors and also computed a composite, individual-level Cardiovascular Health Score for all 7 metrics (poor=0 points; intermediate=1 point; ideal=2 points; total range, 0–14 points). Prevalence of current and former smoking, hypercholesterolemia, and hypertension declined, whereas prevalence of obesity and dysglycemia increased through 2008. Physical activity levels and low diet quality scores changed minimally. Projections to 2020 suggest that obesity and impaired fasting glucose/diabetes mellitus could increase to affect 43% and 77% of US men and 42% and 53% of US women, respectively. Overall, population-level cardiovascular health is projected to improve by 6% overall by 2020 if current trends continue. Individual-level Cardiovascular Health Score projections to 2020 (men=7.4 [95% confidence interval, 5.7–9.1]; women=8.8 [95% confidence interval, 7.6–9.9]) fall well below the level needed to achieve a 20% improvement (men=9.4; women=10.1).
The American Heart Association 2020 target of improving cardiovascular health by 20% by 2020 will not be reached if current trends continue.
PMCID: PMC3914399  PMID: 22547667
cardiovascular disease risk factors; epidemiology; risk factors; trends
15.  Association of QRS duration with left ventricular structure and function and risk of heart failure in middle-aged and older adults: the Multi-Ethnic Study of Atherosclerosis (MESA) 
European Journal of Heart Failure  2012;14(11):1285-1292.
Prolonged QRS duration (QRSd) on the electrocardiogram (ECG) has been associated with cardiac structural and functional abnormalities by echocardiography and an increased risk of heart failure (HF). Data are sparse on these relationships in middle-aged and elderly individuals free of baseline cardiovascular disease with respect to cardiac magnetic resonance imaging (MRI). We sought to determine whether QRSd is associated with incident HF and measures of cardiac structure and function by cardiac MRI.
Methods and results
We analysed baseline ECGs in the Multi-Ethnic Study of Atherosclerosis (MESA) to determine whether QRSd >100 ms was associated with incident HF. We adjusted for demographic and clinical risk factors, as well as MRI measures of left ventricular (LV) structure and function. Among 4591 eligible participants (51% women; 39% white; mean age 61 years), 75 developed incident HF over a mean follow-up of 7.1 years. QRSd >100 ms was significantly associated with MRI measures of cardiac structure and function, as well as incident HF, even after adjustment for demographic covariates [hazard ratio (HR) 2.10, 95% confidence interval (CI) 1.29–3.42; P = 0.003] and clinical risk factors (HR 1.86, 95% CI 1.14–3.03; P = 0.01). With further adjustment for individual LV structural measures, findings were attenuated to non-significance. Separate adjustment for LV functional measures yielded only mild attenuation.
In middle-aged and older adults without cardiovascular disease, a QRSd >100 ms was significantly associated with incident HF. After adjustment for LV structural measures, the association was attenuated to non-significance, suggesting that prolonged QRSd is potentially a useful marker of LV structure that may predispose to HF risk.
PMCID: PMC3530347  PMID: 22791081
Electrocardiogram; Heart failure; Magnetic resonance imaging; QRS duration
16.  Remaining Lifetime Risk for Cancer Death at Selected Ages by Sex and Smoking status: The Lifetime Risk Pooling Project 
Cancer causes & control : CCC  2012;23(10):1729-1737.
Understanding how sex and tobacco exposure may modify lifetime risks for cancer mortality is important for effective communication of risk in targeted public health messages.
To determine lifetime risk estimates for cancer death associated with sex and smoking status in the United States.
A pooled cohort design using ten well-defined epidemiologic cohorts including middle-aged and older individuals was used to estimate the lifetime risk for cancer death at selected index ages, with death from non-cancer causes as the competing risk, by sex and smoking status.
There were a total of 11,317 cancer-related deaths. At age 45 years, the lifetime risk of cancer death for male smokers is 27.7% (95% CI 24.0% to 31.4%) compared to 15.8% (95% CI 12.7% to 18.9%) for male non-smokers. At age 45 years, the lifetime risk of cancer death for female smokers is 21.7% (95% CI 18.8% to 24.6%) compared to 13.2% (95% CI 11.0% to 15.4%) for female non-smokers. Remaining lifetime risk for cancer death declined with age, and men have a greater risk for cancer death compared to women. Adjustment for competing risk of death, particularly representing cardiovascular mortality, yielded a greater change in lifetime risk estimates for men and smokers compared to women and non-smokers.
At the population level the lifetime risk for cancer death remains significantly higher for smokers compared to non-smokers, regardless of sex. These estimates may provide clinicians with useful information for counseling individual patients and highlight the need for continued public health efforts related to smoking cessation.
PMCID: PMC3542389  PMID: 22825072
Tobacco; Smoking; Cancer; Lifetime Risk; Cancer mortality; Sex
17.  Yield of Screening for Coronary Artery Calcium in Early Middle-Age Adults Based on the 10-Year Framingham Risk Score 
JACC. Cardiovascular imaging  2012;5(9):923-930.
The purpose of this study was to assess the prevalence and distribution of coronary artery calcium (CAC) across Framingham Risk Score (FRS) strata and therefore determine FRS levels at which asymptomatic, young to early middle-age individuals could potentially benefit from CAC screening.
High CAC burden is associated with increased risk of coronary events beyond the FRS. Expert panel recommendations for CAC screening are based on data obtained in middle-age and older individuals.
We included 2,831 CARDIA (Coronary Artery Risk Development in Young Adults) study participants with an age range of 33 to 45 years. The number needed to screen ([NNS] number of people in each FRS stratum who need to be screened to detect 1 person with a CAC score above the specified cut point) was used to assess the yield of screening for CAC. CAC prevalence was compared across FRS strata using a chi-square test.
CAC scores >0 and ≥100 were present in 9.9% and 1.8% of participants, respectively. CAC prevalence and amount increased across higher FRS strata. A CAC score >0 was observed in 7.3%, 20.2%, 19.1%, and 44.8% of individuals with FRSs of 0 to 2.5%, 2.6% to 5%, 5.1% to 10%, and >10%, respectively (NNS = 14, 5, 5, and 2, respectively). A CAC score of ≥100 was observed in 1.3%, 2.4%, and 3.5% of those with FRSs of 0 to 2.5%, 2.6% to 5%, and 5.1% to 10%, respectively (NNS = 79, 41, and 29, respectively), but in 17.2% of those with an FRS >10% (NNS = 6). Similar trends were observed when findings were stratified by sex and race.
In this young to early middle-age cohort, we observed concordance between CAC prevalence/amount and FRS strata. Within this group, the yield of screening and possibility of identifying those with a high CAC burden (CAC score of ≥100) is low in those with an FRS of ≤10%, but considerable in those with an FRS >10%.
PMCID: PMC3664953  PMID: 22974805
coronary artery calcium; coronary heart disease; Framingham Risk Score; number needed to screen; risk factors
18.  Lifetime Risk and Years Lived Free of Total Cardiovascular Disease 
Estimates of lifetime risk (LTR) for total cardiovascular disease (tCVD) may provide projections of the future population burden of cardiovascular disease and may assist in clinician-patient risk communication. To date, no LTR estimates of tCVD have been reported.
To calculate LTR estimates of tCVD by index age [45, 55, 65, 75 years(y)] and risk factor strata and to estimate years lived free of CVD across risk factor strata.
Design, Setting, and Participants
Pooled survival analysis of up to 905,115 person-years of data from 1964 through 2008 from 5 NHLBI-funded community-based cohorts: Framingham Heart Study, Framingham Offspring Study, Atherosclerosis Risk in Communities Study, Chicago Heart Association Detection Project in Industry Study and Cardiovascular Health Study.
All participants free of CVD at baseline with risk factor data (blood pressure (BP), total cholesterol (TC), diabetes and smoking status) and tCVD outcome data
Outcome Measures
Any tCVD event (including fatal and non-fatal coronary heart disease, all forms of stroke, congestive heart failure and other CVD deaths)
At an index age of 45y, overall LTR for tCVD was 60.3% (95% CI, 59.3 to 61.2) for men and 55.6% (95% CI, 54.5 to 56.7) for women. Men had higher LTR estimates than women across all index ages. At index ages 55 and 65y, men and women with ≥1 elevated risk factor (BP 140-149/90-99 mmHg or TC 200-239 mg/dL but no diabetes or smoking), or 1, or ≥ 2 major risk factors (BP ≥ 160/100mmHg or on treatment; TC ≥ 240mg/dL or on treatment, diabetes mellitus, or current smoking) had LTR estimates to age 95y that exceeded 50%. Despite an optimal risk factor profile (BP < 120/80 mmHg, TC < 180 mg/dL, and no smoking or diabetes) men and women at an index age of 55y had LTR for total CVD to age 85y > 40% and 30% respectively. Compared with participants with ≥ 2 major risk factors, those with an optimal risk factor profile lived up to 14y longer free of tCVD.
LTR estimates for tCVD are high (>30%) for all individuals, even those with optimal risk factors in middle age. However, maintenance of optimal risk factor levels in middle age is associated with substantially longer morbidity-free survival.
PMCID: PMC3748966  PMID: 23117780
Lifetime Risk; Cardiovascular Disease; Compression of Morbidity
19.  African American Adolescent Girls' Initiation of Sexual Activity: Survival Analysis 
African American adolescent females tend to initiate participation in sexual activity at an earlier age than Caucasian adolescent females. Early initial participation in sexual activity is associated with increased HIV risk. However, limited prospective data are available on the rate at which African American adolescent females delay their initial participation in sexual activity. The purpose is to determine low-income inner city African American adolescent females' survival or continued non-participation in sexual activity over a 20-month period and to determine predictors associated with survival.
A longitudinal quasi-experimental research design with multiple data collection points was used. The convenience sample consisted of 396 African American females with a mean age of 12.4 years (SD = 1.1 years) and their mothers. The adolescents completed questionnaires assessing perceptions of maternal monitoring, HIV transmission knowledge, self-efficacy to refuse sex, intention to refuse sex, and age. Their mothers completed questionnaires assessing perception of maternal monitoring, safer sex self-efficacy, marital status, and educational level. At baseline, the adolescents reported non-participation in sexual activity. Survival analysis was conducted to determine the timing and predictors of sexual activity initiation for these adolescents.
Of the 396 adolescents, 28.5% did not survive; they participated in sexual activity within the 20-month period. Predictors of non-survival were the adolescents' age, perception of maternal monitoring, and intention to refuse sex.
Findings suggest interventions that increase maternal monitoring and adolescents' intentions to refuse sex could be beneficial in delaying sexual activity.
PMCID: PMC3718845  PMID: 20144551
20.  Racial Differences in Risks for First Cardiovascular Events and Non-Cardiovascular Death: the Atherosclerosis Risk in Communities Study (ARIC), the Cardiovascular Health Study (CHS), and the Multi-Ethnic Study of Atherosclerosis (MESA) 
Circulation  2012;126(1):50-59.
No studies have compared first CVD events and non-CVD death between races in a competing risks framework, which examines risks for numerous events simultaneously.
Methods and Results
We used competing Cox models to estimate hazards for first CVD events and non-CVD death within and between races in three multi-center, NHLBI-sponsored cohorts. Of 14569 ARIC study participants aged 45–64y with mean follow up of 10.5y, 11.6% had CVD and 5.0% had non-CVD death as first events; among 4237 CHS study participants aged 65–84y and followed for 8.5y, these figures were 43.2% and 15.7%, respectively. Middle-aged blacks were significantly more likely than whites to experience any CVD as a first event; this disparity disappeared by older adulthood and after adjustment for CVD risk factors. The pattern of results was similar for MESA participants. Traditional Cox and competing risks models yielded different results for CHD risk. Black men appeared somewhat more likely than white men to experience CHD using a standard Cox model (HR 1.06; 95% CI 0.90, 1.26) whereas they appeared less likely than white men to have a first CHD event using a competing risks model (HR 0.77; 95% CI 0.60, 1.00).
CVD affects blacks at an earlier age than whites; this may be partially attributable to elevated CVD risk factor levels among blacks. Racial disparities in first CVD incidence disappear by older adulthood. Competing risks analyses may yield somewhat different results than traditional Cox models and provide a complementary approach to examining risks for first CVD events.
PMCID: PMC3437934  PMID: 22693351
cardiovascular diseases; epidemiology; prevention; risk factors; survival
21.  Association of number of live births with left ventricular structure and function. The Multi-Ethnic Study of Atherosclerosis (MESA) 
American heart journal  2012;163(3):470-476.
Pregnancy is associated with marked maternal cardiovascular/hemodynamic changes. A greater number of pregnancies may be associated with long-term subclinical changes in left ventricular (LV) remodeling.
Among 2,234 white, black, Hispanic, and Chinese women (mean age 62 years) in the MESA, we used linear regression to relate live births and cardiac magnetic resonance imaging LV measures. Covariates included age, ethnicity, height, income, education, birth country, smoking, menopause, and oral contraceptive duration. Models were additionally adjusted for potential mediators: systolic blood pressure, antihypertensive use, total/high-density lipoprotein cholesterol, triglycerides, diabetes, and body mass index. We performed sensitivity analyses excluding 763 women in the lowest socioeconomic group: annual income <$25,000 and lower high school level of education.
With each live birth, LV mass increased 1.26 g; LV end-diastolic volume, 0.74 mL; and LV end-systolic volume, 0.45 mL; LV ejection fraction decreased 0.18% (P trend <0.05). Changes were most notable for the category of women with ≥5 pregnancies. Upon adjustment for potential biologic mediators, live births remained positively associated with LV mass and end-systolic volume. Live births remained significantly associated with LV end-systolic, end-diastolic volumes, and LV mass (P trend ≤0.02) after excluding women in the lowest socioeconomic group.
Number of live births is associated with key LV structural and functional measures in middle to older ages, even after adjustment for sociodemographic factors and cardiovascular disease risk factors. Hemodynamic changes during pregnancy may be associated with cardiac structure/function beyond childbearing years.
PMCID: PMC3656723  PMID: 22424019
22.  Education, Income, and Incident Heart Failure in Post Menopausal Women: The Women’s Health Initiative Hormone Therapy trials 
To estimate the effect of education and income on incident heart failure (HF) hospitalization among post-menopausal women.
Investigations of socioeconomic status (SES) have focused on outcomes after HF diagnosis, not associations with incident HF. We used data from the Women’s Health Initiative Hormone Trials to examine the association between SES levels and incident HF hospitalization.
We included 26,160 healthy, post-menopausal women. Education and income were self-reported. ANOVA, Chi-square tests, and proportional hazards models were used for statistical analysis, with adjustment for demographics, co-morbid conditions, behavioral factors, and hormone and dietary modification assignments.
Women with household incomes <$20,000/year had higher HF hospitalization incidence (57.3/10,000 person-years) than women with household incomes >$50,000/year (16.7/10,000 person-years; p<0.01). Women with less than a high school education had higher HF hospitalization incidence (51.2/10,000 person-years) than college graduates and above (25.5/10,000 person-years; p<0.01). In multivariable analyses, women with the lowest income levels had 56% higher risk (HR 1.56, 95% CI 1.19 to 2.04) than the highest income women; women with the least amount of education had 21% higher risk for incident HF hospitalization (HR 1.21, 95% CI 0.90 to 1.62) than the most educated women.
Lower income is associated with an increased incidence of HF hospitalization among healthy, post-menopausal women, whereas multivariable adjustment attenuated the association of education with incident HF.
PMCID: PMC3635103  PMID: 21939829
heart failure; socioeconomic status; women
23.  Factors Associated with Development of Prolonged QRS Duration over 20 Years in Healthy Young Adults: The Coronary Artery Risk Development in Young Adults (CARDIA) Study 
Journal of electrocardiology  2011;45(2):178-184.
Data are sparse describing factors associated with development of prolonged QRS duration (QRSd) from young adulthood to middle age.
We analyzed 12-lead electrocardiograms (ECGs) from the Coronary Artery Risk Development in Young Adults (CARDIA) study over 20 years. We performed logistic regression to examine associations of baseline (Year 0) or average (Year 0 to Year 20) risk factors with incident prolonged QRSd (QRS > 100 msec).
We included 2,537 participants (57.2% women, 44.7% black, mean age 25 years); 292 (11.5%) developed incident QRSd >100 msec by Year 20. In univariate analyses, baseline covariates associated with incident QRSd prolongation included white race, male sex, ECG-LVMI, and baseline QRSd. Similar results were observed after multivariable adjustment.
We found no long-term associations of modifiable risk factors with incident QRSd >100 msec. Men, whites, and those with higher ECG-LVMI and QRSd in young adulthood are at increased risk for incident prolonged QRSd by middle age.
PMCID: PMC3542388  PMID: 22197105
24.  Prevalence of Electrocardiographic Abnormalities in a Middle-Aged, Biracial Population: Coronary Artery Risk Development in Young Adults (CARDIA) Study 
Journal of electrocardiology  2010;43(5):385.e1-385.e9.
Few studies to date have described the prevalence of electrocardiographic (ECG) abnormalities in a biracial middle-aged cohort.
Methods and Results
Participants underwent measurement of traditional risk factors and 12-lead ECGs coded using both Minnesota Code (MC) and Novacode (NC) criteria. Among 2585 participants, of whom 57% were women and 44% were black (mean age 45 years), the prevalence of major and minor abnormalities were significantly higher (all P<0.001) among black men and women compared to whites. These differences were primarily due to higher QRS voltage and ST/T wave abnormalities among blacks. There was also a higher prevalence of Q waves (MC 1-1, 1-2, 1-3) than described by previous studies. These racial differences remained after multivariate adjustment for traditional cardiovascular (CV) risk factors.
Black men and women have a significantly higher prevalence of ECG abnormalities, independent of traditional CV risk factors, than whites in a contemporary cohort middle-aged participants.
PMCID: PMC3569004  PMID: 20374967
25.  Competing cardiovascular outcomes associated with electrocardiographic left ventricular hypertrophy: the Atherosclerosis Risk in Communities study 
Heart (British Cardiac Society)  2011;98(4):330-334.
Individuals with electrocardiographically-determined left ventricular hypertrophy (ECG LVH) are at risk for multiple cardiovascular disease (CVD) outcomes simultaneously. We sought to characterize the competing incidences for subtypes of first CVD events or non-CVD death in those with and without ECG LVH.
We included participants in the Atherosclerosis Risk in Communities (ARIC) study. ECG LVH was defined according to Sokolow-Lyon criteria. We used competing Cox models to compare hazards for diverse outcomes within groups (e.g., among those with ECG LVH) and for a given event between groups (ECG LVH versus no ECG LVH).
After 15 years, men with ECG LVH at baseline (N = 383) had cumulative incidence of first CVD events and non-CVD deaths of 29.2% and 6.1%, respectively (hazard ratio 4.86; 95% CI, 3.04–7.77). In men without ECG LVH (N = 6576) the incidence of any first CVD event and non-CVD death was 18.9% and 6.9%, respectively (hazard ratio 2.67; 2.39–2.98). Similar associations were observed in women (N = 381 with and N = 8187 without ECG LVH). Coronary heart disease (CHD) was the most common first event in men with ECG LVH (15.0%) and heart failure (HF) was the most common first event in women with ECG LVH (10.5%). After adjustment for risk factors including systolic blood pressure, any CVD event remained the most likely first event.
Among middle-aged individuals with ECG LVH, the most likely first events are CHD in men and HF in women; these results may have implications for preventive approaches.
PMCID: PMC3569012  PMID: 22139711
left ventricular hypertrophy; cardiovascular disease; coronary heart disease; stroke; heart failure

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