Longitudinal changes in diet quality and food intake before and after diabetes awareness in American adults: the Coronary Artery Risk Development in Young Adults (CARDIA) study.

INTRODUCTION: Limited longitudinal research is available examining how American adults make dietary changes after learning they have diabetes. We examined the associations between diabetes awareness and changes in dietary quality and food intake in a prospective cohort from the Coronary Artery Risk Development in Young Adults (CARDIA) study. RESEARCH DESIGN AND METHODS: A nested case-control design was used. In the original CARDIA study, black and white participants were recruited from four US urban areas and partitioned into one control group (no diabetes over 30-year follow-up) and three case groups (early-onset, intermediate-onset, later-onset diabetes groups) based on timing of diagnosis and first awareness of diabetes. Estimated mean A Priori Diet Quality Score (APDQS), and food subgroup intake were examined at three CARDIA examinations (year (Y)0, Y7, and Y20). The mean APDQS with 95% CIs and food intake (servings/day) were compared across the one control group and three case groups using exam-specific and repeated measures linear regression. RESULTS: Among 4576 participants (mean age: 25±4 years; 55% female; 49% black race), 653 incident cases (14.3%) of diabetes were observed over 30 years. APDQS was lowest at Y0 when the diabetes-free participants were aged 18-30 years (61.5-62.8), but increased over 20 years with advancing age across all groups (64.6-73.3). Lower APDQS in young adulthood was associated with a higher incidence of diabetes later in life. Diabetes awareness was associated with a net increase of 2.95 points in APDQS. The greatest increase of APDQS was when people learned of their diabetes for the first time (an increase of 5.71 in early-onset and 6.64 in intermediate-onset diabetes groups, respectively). CONCLUSIONS: Advancing age and diabetes awareness were associated with more favorable dietary changes leading to improved diet quality. Optimal diet quality and healthy food intake in young adulthood seem important to prevent diabetes later in life.

Trajectory modeling of cannabis use over 30 years identifies five unique longitudinal patterns.

Cannabis is the most prevalently used psychoactive substance in the United States. Cannabis has conflicting federal and state legal status in the US, however medical and recreational cannabis use are increasing. When assessing health outcomes, cannabis use classification has been modeled largely as current use status (never/former/current) or cumulative use (joint-years). These methods do not describe longitudinal patterns of use which may have unique relationships with health outcomes. We used cannabis use data spanning 30 years from the Coronary Artery Risk Development in Young Adults Cohort (CARDIA) to create trajectories of current cannabis use during young and middle adulthood. We identified 5 unique patterns of the probability of cannabis use during young and middle adulthood in the CARDIA Cohort. To support the cannabis probability trajectories, we qualitatively examined cumulative cannabis use as joint-years for each trajectory group. Trajectory group 5 had high probability of consistent cannabis use (0.8-0.9% probability of use) and had the highest number of joint-years (0.6 +/- 0.4). Trajectory group 1 who had a lower probability of cannabis use (0.05-0% probability of use) with the lowest number of joint-years (0.1 +/- 0.1).

Effect of Dietary Sodium on Blood Pressure: A Crossover Trial.

Importance: Dietary sodium recommendations are debated partly due to variable blood pressure (BP) response to sodium intake. Furthermore, the BP effect of dietary sodium among individuals taking antihypertensive medications is understudied. Objectives: To examine the distribution of within-individual BP response to dietary sodium, the difference in BP between individuals allocated to consume a high- or low-sodium diet first, and whether these varied according to baseline BP and antihypertensive medication use. Design, Setting, and Participants: Prospectively allocated diet order with crossover in community-based participants enrolled between April 2021 and February 2023 in 2 US cities. A total of 213 individuals aged 50 to 75 years, including those with normotension (25%), controlled hypertension (20%), uncontrolled hypertension (31%), and untreated hypertension (25%), attended a baseline visit while consuming their usual diet, then completed 1-week high- and low-sodium diets. Intervention: High-sodium (approximately 2200 mg sodium added daily to usual diet) and low-sodium (approximately 500 mg daily total) diets. Main Outcomes and Measures: Average 24-hour ambulatory systolic and diastolic BP, mean arterial pressure, and pulse pressure. Results: Among the 213 participants who completed both high- and low-sodium diet visits, the median age was 61 years, 65% were female and 64% were Black. While consuming usual, high-sodium, and low-sodium diets, participants' median systolic BP measures were 125, 126, and 119 mm Hg, respectively. The median within-individual change in mean arterial pressure between high- and low-sodium diets was 4 mm Hg (IQR, 0-8 mm Hg; P < .001), which did not significantly differ by hypertension status. Compared with the high-sodium diet, the low-sodium diet induced a decline in mean arterial pressure in 73.4% of individuals. The commonly used threshold of a 5 mm Hg or greater decline in mean arterial pressure between a high-sodium and a low-sodium diet classified 46% of individuals as "salt sensitive." At the end of the first dietary intervention week, the mean systolic BP difference between individuals allocated to a high-sodium vs a low-sodium diet was 8 mm Hg (95% CI, 4-11 mm Hg; P < .001), which was mostly similar across subgroups of age, sex, race, hypertension, baseline BP, diabetes, and body mass index. Adverse events were mild, reported by 9.9% and 8.0% of individuals while consuming the high- and low-sodium diets, respectively. Conclusions and Relevance: Dietary sodium reduction significantly lowered BP in the majority of middle-aged to elderly adults. The decline in BP from a high- to low-sodium diet was independent of hypertension status and antihypertensive medication use, was generally consistent across subgroups, and did not result in excess adverse events. Trial Registration: ClinicalTrials.gov Identifier: NCT04258332.

Aerobic and Muscle-Strengthening Physical Activity, Television Viewing, and Nonalcoholic Fatty Liver Disease: The CARDIA Study.

BACKGROUND: The prevalence of non-alcoholic fatty liver disease (NAFLD) in U.S. adults is over 30%, yet the role of lifestyle factors in the etiology of NAFLD remains understudied. We examined the associations of physical activity, by intensity and type, and television viewing with prevalent NAFLD. METHODS: Cross-sectional analysis of a population-based sample of 2726 Black (49%) and White (51%) adults (Mean (SD) age, 50 (3.6) years; 57.3% female) from the CARDIA study. Exposures were aerobic activity by intensity (moderate, vigorous; hours/week); activity type (aerobic, muscle-strengthening; hours/week); and television viewing (hours/week), examined concurrently in all models and assessed by validated questionnaires. Our outcome was NAFLD (liver attenuation < 51 Hounsfield Units), measured by non-contrast computed tomography, after exclusions for other causes of liver fat. Covariates were sex, age, race, study center, education, diet quality, smoking status, alcohol consumption, and body mass index or waist circumference. RESULTS: 648 participants had NAFLD. In the fully adjusted modified Poisson regression model, the risk ratios per interquartile range of each exposure were moderate-intensity aerobic activity, 1.10 (95% CI, 0.97-1.26); vigorous-intensity aerobic activity, 0.72 (0.63-0.82); muscle-strengthening activity, 0.89 (0.80-1.01); and television viewing, 1.20 (1.10-1.32). Relative to less active participants with higher levels of television viewing, those who participated in ≥2 h/week of both vigorous-intensity aerobic and muscle-strengthening activity and <7 h/week of television viewing had 65% lower risk of NAFLD (risk ratio = 0.35, 95% CI = 0.23-0.51). CONCLUSION: Adults who follow public health recommendations for vigorous-aerobic and muscle-strengthening activity, as well as minimize television viewing, are considerably less likely to have NAFLD than those who do not follow the recommendations and who have relatively high levels of television viewing.

Cumulative BMI and incident prediabetes over 30 years of follow-up: The CARDIA study.

OBJECTIVE: This study examined how cumulative BMI (cBMI) is associated with incident prediabetes in a biracial observational cohort study followed from young adulthood to middle age. METHODS: Black and White men and women (n = 4190) from the Coronary Artery Risk Development in Young Adults (CARDIA) study, ages 18 to 30 years in 1985 to 1986 and free of prediabetes or diabetes at baseline, were followed for 30 years. Cox regression was used to determine how cBMI was associated with incident prediabetes after controlling for traditional cardiovascular risk factors. RESULTS: Over 30 years of follow-up, 46.2% of the sample developed prediabetes. Mean cBMI was 801.4 BMI-years for those with prediabetes and 658.3 BMI-years for those without (p < 0.0001). After multivariable adjustment, the hazard rate ratio for the highest cBMI quartile was 2.064 (95% CI: 1.793-2.377) relative to the lowest quartile. The second and third quartiles did not differ from the first quartile, consistent with a nonlinear trend. CONCLUSIONS: The cumulative burden of higher weight and longer duration was associated with incident prediabetes, but this association was statistically significant only after a higher threshold was reached. Strategies for prevention of prediabetes in middle age may focus on avoiding overweight in young adulthood to limit duration.

Association of Incident Cardiovascular Disease With Time Course and Cumulative Exposure to Multiple Risk Factors.

BACKGROUND: The quantitative relationship of incident cardiovascular disease (CVD) to lifetime cumulative risk factor exposure is not well understood. OBJECTIVES: Using CARDIA (Coronary Artery Risk Development in Young Adults) study data, we examined the quantitative associations of cumulative exposure over time to multiple, simultaneously operating risk factors with CVD incidence and the incidence of its components. METHODS: Regression models were developed quantifying the influence of the time course and severity of multiple CVD risk factors, operating simultaneously, on risk of incident CVD. The outcomes were incident CVD and the incidence of its components: coronary heart disease, stroke, and congestive heart failure. RESULTS: Our study included 4,958 asymptomatic adults enrolled in CARDIA from 1985 to 1986 (ages 18 to 30 years) who were followed for 30 years. Risk of incident CVD depends on the time course and severity of a series of independent risk factors, the impact of which is mediated by their effects on individual CVD components after age 40 years. Cumulative exposure (AUC vs time) to low-density lipoprotein cholesterol and triglycerides was independently associated with risk of incident CVD. Of the blood pressure variables, areas under the mean arterial pressure vs time curve and the pulse pressure vs time curve were strongly and independently associated with incident CVD risk. CONCLUSIONS: The quantitative description of the link between risk factors and CVD informs the construction of individualized CVD mitigation strategies, design of primary prevention trials, and assessment of public health impact of risk factor-based interventions.

Oxidative Stress and Cardiovascular Risk Factors: The Coronary Artery Risk Development in Young Adults (CARDIA) Study.

Introduction-Oxidative stress is linked to cardiovascular diseases (CVD) and is suggested to vary by sex. However, few population-level studies have explored these associations and the majority comprise populations with advanced CVD. We assessed urinary isoprostane concentrations, a standard measure of oxidative stress, in a relatively young and healthy cohort, hypothesizing that higher oxidative stress is associated with an adverse cardiometabolic profile and female sex. Methods-Oxidative stress was measured in 475 women and 266 men, aged 48-55 years, from the Coronary Artery Risk Development in Young Adults (CARDIA) study using urinary 8-isoprostane (IsoP) and 2,3-dinor-8-isoprostane (IsoP-M). Multivariable-adjusted regression was used to evaluate cross-sectional associations. As secondary analysis, previously measured plasma F2-isoprostanes (plasma IsoP) from another CARDIA subset was similarly analyzed. Results-Mean (SD) ages for men and women were 52.1(2.3) and 52.2(2.2) years, respectively (p = 0.46), and 39% of the participants self-identified as Black (vs. White). Before adjustments, female sex was associated with higher median urinary IsoP (880 vs. 704 ng/g creatinine in men; p < 0.01) and IsoP m (1675 vs. 1284 ng/g creatinine in men; p < 0.01). Higher body mass index (BMI), high-density cholesterol (HDL-C), and triglycerides, current smoking, and less physical activity were associated with higher oxidative stress. Diabetes was not associated with urinary IsoP but was associated with lower IsoP m and plasma IsoP. Higher serum creatinine showed diverging associations with higher plasma and lower urinary isoprostane concentrations. Conclusions-Different isoprostane entities exhibit varying association patterns with CVD risk factors, and therefore are complementary, rather than interchangeable, in assessment of oxidative stress. Still, consistently higher isoprostanes among women, smokers, less active persons, and those with higher BMI and plasma triglycerides could reflect higher oxidative stress among these groups. While urinary isoprostanes are indexed to urinary creatinine due to variations in concentration, caution should be exercised when comparing groups with differing serum creatinine.

Analysis of Cardiorespiratory Fitness in Early Adulthood and Midlife With All-Cause Mortality and Fatal or Nonfatal Cardiovascular Disease.

Importance: Optimizing cardiovascular fitness is a prevention strategy against premature death and cardiovascular disease (CVD) events. Since this evidence has largely been established in older populations, the importance of cardiorespiratory fitness during earlier periods of adulthood remains unclear. Objective: To examine the association of early-adulthood cardiorespiratory fitness and percentage of early-adulthood cardiorespiratory fitness retained during midlife with subsequent risk of all-cause mortality and CVD-related morbidity and mortality overall as well as by sex and race. Design, Setting, and Participants: This retrospective population-based cohort study analyzed data from the Coronary Artery Risk Development in Young Adults (CARDIA) study, an ongoing prospective cohort study conducted at field center clinics in Birmingham, Alabama; Chicago, Illinois; Minneapolis, Minnesota; and Oakland, California. Participants in the CARDIA study were aged 18 to 30 years when they completed the baseline graded exercise test protocol in 1985 to 1986 and have since undergone follow-up examinations biannually and every 2 to 5 years. Data were collected through August 31, 2020, and were analyzed in October 2022. Exposures: Cardiorespiratory fitness was estimated from a symptom-limited, maximal graded exercise test protocol conducted at baseline and at year 7 and year 20 follow-up examinations. Main Outcomes and Measures: All-cause mortality and combined fatal and nonfatal CVD events were obtained since year 20 of follow-up examinations through August 31, 2020. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) for each primary exposure with each outcome. Results: A total of 4808 participants (mean [SD] age at baseline, 24.8 [3.7] years; 2670 females [56%]; 2438 Black individuals [51%]) were included in the sample. During 68 751 person-years of follow-up, there were 302 deaths (6.3%) and 274 CVD events (5.7%) since year 20. Every 1-minute increment in cardiorespiratory fitness at baseline was associated with a lower risk of all-cause mortality in females (HR, 0.73; 95% CI, 0.64-0.82) and males (HR, 0.87; 95% CI, 0.80-0.96). Every 5% increment in cardiorespiratory fitness retained through year 20 was associated with a lower risk of all-cause mortality (HR, 0.89; 95% CI, 0.79-0.99), but no evidence of effect modification by race or sex was found. Every 1-minute increment in cardiorespiratory fitness at baseline was associated with a lower risk of fatal or nonfatal CVD (HR, 0.89; 95% CI, 0.82-0.96), and the estimated HR per 5% increment in cardiorespiratory fitness retained throughout midlife was 0.89 (95% CI, 0.78-1.00), with no evidence for interaction by race or sex. Conclusions and Relevance: This cohort study found that higher early-adulthood cardiorespiratory fitness and greater retention of early-adulthood cardiorespiratory fitness throughout midlife were associated with a lower risk of premature death and CVD events. Additional research is needed to clarify the association of cardiorespiratory fitness timing across the life course with risk of clinical outcomes.

Multivariate longitudinal data for survival analysis of cardiovascular event prediction in young adults: insights from a comparative explainable study.

BACKGROUND: Multivariate longitudinal data are under-utilized for survival analysis compared to cross-sectional data (CS - data collected once across cohort). Particularly in cardiovascular risk prediction, despite available methods of longitudinal data analysis, the value of longitudinal information has not been established in terms of improved predictive accuracy and clinical applicability. METHODS: We investigated the value of longitudinal data over and above the use of cross-sectional data via 6 distinct modeling strategies from statistics, machine learning, and deep learning that incorporate repeated measures for survival analysis of the time-to-cardiovascular event in the Coronary Artery Risk Development in Young Adults (CARDIA) cohort. We then examined and compared the use of model-specific interpretability methods (Random Survival Forest Variable Importance) and model-agnostic methods (SHapley Additive exPlanation (SHAP) and Temporal Importance Model Explanation (TIME)) in cardiovascular risk prediction using the top-performing models. RESULTS: In a cohort of 3539 participants, longitudinal information from 35 variables that were repeatedly collected in 6 exam visits over 15 years improved subsequent long-term (17 years after) risk prediction by up to 8.3% in C-index compared to using baseline data (0.78 vs. 0.72), and up to approximately 4% compared to using the last observed CS data (0.75). Time-varying AUC was also higher in models using longitudinal data (0.86-0.87 at 5 years, 0.79-0.81 at 10 years) than using baseline or last observed CS data (0.80-0.86 at 5 years, 0.73-0.77 at 10 years). Comparative model interpretability analysis revealed the impact of longitudinal variables on model prediction on both the individual and global scales among different modeling strategies, as well as identifying the best time windows and best timing within that window for event prediction. The best strategy to incorporate longitudinal data for accuracy was time series massive feature extraction, and the easiest interpretable strategy was trajectory clustering. CONCLUSION: Our analysis demonstrates the added value of longitudinal data in predictive accuracy and epidemiological utility in cardiovascular risk survival analysis in young adults via a unified, scalable framework that compares model performance and explainability. The framework can be extended to a larger number of variables and other longitudinal modeling methods. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00005130, Registration Date: 26/05/2000.

Dietary metabolic signatures and cardiometabolic risk.

AIMS: Observational studies of diet in cardiometabolic-cardiovascular disease (CM-CVD) focus on self-reported consumption of food or dietary pattern, with limited information on individual metabolic responses to dietary intake linked to CM-CVD. Here, machine learning approaches were used to identify individual metabolic patterns related to diet and relation to long-term CM-CVD in early adulthood. METHODS AND RESULTS: In 2259 White and Black adults (age 32.1 ± 3.6 years, 45% women, 44% Black) in the Coronary Artery Risk Development in Young Adults (CARDIA) study, multivariate models were employed to identify metabolite signatures of food group and composite dietary intake across 17 food groups, 2 nutrient groups, and healthy eating index-2015 (HEI2015) diet quality score. A broad array of metabolites associated with diet were uncovered, reflecting food-related components/catabolites (e.g. fish and long-chain unsaturated triacylglycerols), interactions with host features (microbiome), or pathways broadly implicated in CM-CVD (e.g. ceramide/sphingomyelin lipid metabolism). To integrate diet with metabolism, penalized machine learning models were used to define a metabolite signature linked to a putative CM-CVD-adverse diet (e.g. high in red/processed meat, refined grains), which was subsequently associated with long-term diabetes and CVD risk numerically more strongly than HEI2015 in CARDIA [e.g. diabetes: standardized hazard ratio (HR): 1.62, 95% confidence interval (CI): 1.32-1.97, P < 0.0001; CVD: HR: 1.55, 95% CI: 1.12-2.14, P = 0.008], with associations replicated for diabetes (P < 0.0001) in the Framingham Heart Study. CONCLUSION: Metabolic signatures of diet are associated with long-term CM-CVD independent of lifestyle and traditional risk factors. Metabolomics improves precision to identify adverse consequences and pathways of diet-related CM-CVD.

Physical activity from young adulthood to middle age and premature cardiovascular disease events: a 30-year population-based cohort study.

BACKGROUND: Although physical activity is generally protective of cardiovascular disease (CVD), less is known about how young adult physical activity relates to premature CVD events. The objective of this study was to determine the association between level and change in physical activity from young adulthood to middle age and incidence of premature CVD events before age 60. METHODS: We analyzed data collected across four urban sites from nine visits over 30 years of follow-up (1985-2016) from the Coronary Artery Risk Development in Young Adults (CARDIA) study, a prospective community-based cohort study of 5115 Black and White women and men aged 18-30 years at baseline (1985-1986). Linear mixed models were used to develop individualized moderate-to-vigorous intensity self-reported physical activity trajectories per participant. Fatal and nonfatal coronary heart disease (CHD), heart failure, and stroke outcomes were analyzed separately and as a combined CVD event outcome. RESULTS: Overall, physical activity declined in young adults as they progressed through middle age. Lower physical activity scores (per 100 exercise units) in 18 year-olds were associated with higher odds of premature CHD (AOR 1.14, 95% CI 1.02-1.28), heart failure (AOR 1.21, 95% CI 1.05-1.38), stroke (AOR 1.20, 95% CI 1.04-1.39), and any CVD (AOR 1.15, 95% CI 1.06-1.24) events. Each additional annual 1-unit reduction in the physical activity score was associated with a higher annual odds of incident heart failure (1.07, 95% CI 1.02-1.13), stroke (1.06, 95% CI 1.00-1.13), and CVD (1.04, 95% CI 1.01-1.07) events. Meeting the minimum (AOR 0.74, 95% CI 0.0.57-0.96) and twice the minimum (AOR 0.55, 95% CI 0.34-0.91) Department of Health and Human Services physical activity guidelines through follow up was protective of premature CVD events. CONCLUSIONS: Given recent trends in declining physical activity with age and associated premature CVD events, the transition from young adult to midlife is an important time period to promote physical activity.

Blood-Based Fingerprint of Cardiorespiratory Fitness and Long-Term Health Outcomes in Young Adulthood.

Background Cardiorespiratory fitness is a powerful predictor of health outcomes that is currently underused in primary prevention, especially in young adults. We sought to develop a blood-based biomarker of cardiorespiratory fitness that is easily translatable across populations. Methods and Results Maximal effort cardiopulmonary exercise testing for quantification of cardiorespiratory fitness (by peak oxygen uptake) and profiling of >200 metabolites at rest were performed in the FHS (Framingham Heart Study; 2016-2019). A metabolomic fitness score was derived/validated in the FHS and was associated with long-term outcomes in the younger CARDIA (Coronary Artery Risk Development in Young Adults) study. In the FHS (derivation, N=451; validation, N=914; age 54±8 years, 53% women, body mass index 27.7±5.3 kg/m2), we used LASSO (least absolute shrinkage and selection operator) regression to develop a multimetabolite score to predict peak oxygen uptake (correlation with peak oxygen uptake r=0.77 in derivation, 0.61 in validation; both P<0.0001). In a linear model including clinical risk factors, a ≈1-SD higher metabolomic fitness score had equivalent magnitude of association with peak oxygen uptake as a 9.2-year age increment. In the CARDIA study (N=2300, median follow-up 26.9 years, age 32±4 years, 44% women, 44% Black individuals), a 1-SD higher metabolomic fitness score was associated with a 44% lower risk for mortality (hazard ratio [HR], 0.56 [95% CI, 0.47-0.68]; P<0.0001) and 32% lower risk for cardiovascular disease (HR, 0.68 [95% CI, 0.55-0.84]; P=0.0003) in models adjusted for age, sex, and race, which remained robust with adjustment for clinical risk factors. Conclusions A blood-based biomarker of cardiorespiratory fitness largely independent of traditional risk factors is associated with long-term risk of cardiovascular disease and mortality in young adults.

Oxidative Stress and Menopausal Status: The Coronary Artery Risk Development in Young Adults Cohort Study.

Background: Low endogenous estrogen concentrations after menopause may contribute to higher oxidative stress and greater cardiovascular disease (CVD) risk. However, differences in oxidative stress between similarly aged premenopausal and postmenopausal women are not well-characterized on a population level. We hypothesized that urinary isoprostane concentrations, a standard measure of systemic oxidative stress, are higher in women who have undergone menopause compared to premenopausal women. Methods and Results: We examined differences in urinary 8-isoprostane (iPF2α-III) and 2,3-dinor-8-isoprostane (iPF2α-III-M) indexed to urinary creatinine between 279 postmenopausal and 196 premenopausal women in the Coronary Artery Risk Development in Young Adults (CARDIA) study, using linear regression with progressive adjustment for sociodemographic factors and traditional CVD risk factors. Unadjusted iPF2α-III-M concentrations were higher among postmenopausal compared to premenopausal women (Median [25th, 75th percentile]: 1762 [1178, 2974] vs. 1535 [1067, 2462] ng/g creatinine; p = 0.01). Menopause was associated with 25.5% higher iPF2α-III-M (95% confidence interval [6.5-47.9]) adjusted for age, race, college education, and field center. Further adjustments for tobacco use (21.2% [2.9-42.6]) and then CVD risk factors (18.8% [0.1-39.6]) led to additional partial attenuation. Menopause was associated with higher iPF2α-III in Black but not White women. Conclusions: We conclude that postmenopausal women had higher oxidative stress, which may contribute to greater CVD risk. ClinicalTrials.gov Identifier: NCT00005130.

Factors Associated with Age-Related Declines in Cardiorespiratory Fitness from Early Adulthood Through Midlife: CARDIA.

PURPOSE: This study aimed to describe maximal and submaximal cardiorespiratory fitness from early adulthood to midlife and examine differences in maximal fitness at age 20 yr and changes in fitness overtime by subcategories of sociodemographic, behavioral, and health-related factors. METHODS: Data include 5018 Coronary Artery Risk Development in Young Adults participants (mean (SD) age, 24.8 (3.7) yr; 53.3% female; and 51.4% Black participants) who completed at least one maximal graded exercise test at baseline and/or the year 7 and 20 exams. Maximal and submaximal fitness were estimated by exercise duration and heart rate at the end of stage 2. Multivariable adjusted linear-mixed models were used to estimate fitness trajectories using age as the mechanism for time after adjustment for covariates. Fitness trajectories from ages 20 to 50 yr in 5-yr increments were estimated overall and by subgroups determined by each factor after adjustment for duration within the less favorable category. RESULTS: Mean (95% confidence interval) maximal fitness at age 20 and 50 yr was 613 (607-616) and 357 (350-362) s; submaximal heart rate during this period also reflected age-related fitness declines (126 (125-127) and 138 (137-138) bpm). Compared with men, women had lower maximal fitness at age 20 yr (P < 0.001), which persisted over follow-up (P < 0.001); differences were also found by race within sex strata (all P < 0.001). Differences in maximal fitness at age 20 yr were noted by socioeconomic, behavioral, and health-related status in young adulthood (all P < 0.05), which persisted over follow-up (all P < 0.001) and were generally consistent in sex-stratified analyses. CONCLUSIONS: Targeting individuals experiencing accelerated fitness declines with tailored intervention strategies may provide an opportunity to preserve fitness throughout midlife to reduce lifetime cardiovascular disease risk.

Associations of Clinical and Social Risk Factors With Racial Differences in Premature Cardiovascular Disease.

BACKGROUND: Racial differences in cardiovascular disease (CVD) are likely related to differences in clinical and social factors. The relative contributions of these factors to Black-White differences in premature CVD have not been investigated. METHODS: In Black and White adults aged 18 to 30 years at baseline in the CARDIA study (Coronary Artery Risk Development in Young Adults), the associations of clinical, lifestyle, depression, socioeconomic, and neighborhood factors across young adulthood with racial differences in incident premature CVD were evaluated in sex-stratified, multivariable-adjusted Cox proportional hazards models using multiply imputed data assuming missing at random. Percent reduction in the ß estimate (log-hazard ratio [HR]) for race quantified the contribution of each factor group to racial differences in incident CVD. RESULTS: Among 2785 Black and 2327 White participants followed for a median 33.9 years (25th-75th percentile, 33.7-34.0), Black (versus White) adults had a higher risk of incident premature CVD (Black women: HR, 2.44 [95% CI, 1.71-3.49], Black men: HR, 1.59 [1.20-2.10] adjusted for age and center). Racial differences were not statistically significant after full adjustment (Black women: HR, 0.91 [0.55-1.52], Black men: HR 1.02 [0.70-1.49]). In women, the largest magnitude percent reduction in the ß estimate for race occurred with adjustment for clinical (87%), neighborhood (32%), and socioeconomic (23%) factors. In men, the largest magnitude percent reduction in the ß estimate for race occurred with an adjustment for clinical (64%), socioeconomic (50%), and lifestyle (34%) factors. CONCLUSIONS: In CARDIA, the significantly higher risk for premature CVD in Black versus White adults was statistically explained by adjustment for antecedent multilevel factors. The largest contributions to racial differences were from clinical and neighborhood factors in women, and clinical and socioeconomic factors in men.

Circulating metabolite profile in young adulthood identifies long-term diabetes susceptibility: the Coronary Artery Risk Development in Young Adults (CARDIA) study.

AIMS/HYPOTHESIS: The aim of this work was to define metabolic correlates and pathways of diabetes pathogenesis in young adults during a subclinical latent phase of diabetes development. METHODS: We studied 2083 young adults of Black and White ethnicity in the prospective observational cohort Coronary Artery Risk Development in Young Adults (CARDIA) study (mean ± SD age 32.1 ± 3.6 years; 43.9% women; 42.7% Black; mean ± SD BMI 25.6 ± 4.9 kg/m2) and 1797 Framingham Heart Study (FHS) participants (mean ± SD age 54.7 ± 9.7 years; 52.1% women; mean ± SD BMI 27.4 ± 4.8 kg/m2), examining the association of comprehensive metabolite profiles with endophenotypes of diabetes susceptibility (adipose and muscle tissue phenotypes and systemic inflammation). Statistical learning techniques and Cox regression were used to identify metabolite signatures of incident diabetes over a median of nearly two decades of follow-up across both cohorts. RESULTS: We identified known and novel metabolites associated with endophenotypes that delineate the complex pathophysiological architecture of diabetes, spanning mechanisms of muscle insulin resistance, inflammatory lipid signalling and beta cell metabolism (e.g. bioactive lipids, amino acids and microbe- and diet-derived metabolites). Integrating endophenotypes of diabetes susceptibility with the metabolome generated two multi-parametric metabolite scores, one of which (a proinflammatory adiposity score) was associated with incident diabetes across the life course in participants from both the CARDIA study (young adults; HR in a fully adjusted model 2.10 [95% CI 1.72, 2.55], p<0.0001) and FHS (middle-aged and older adults; HR 1.33 [95% CI 1.14, 1.56], p=0.0004). A metabolite score based on the outcome of diabetes was strongly related to diabetes in CARDIA study participants (fully adjusted HR 3.41 [95% CI 2.85, 4.07], p<0.0001) but not in the older FHS population (HR 1.15 [95% CI 0.99, 1.33], p=0.07). CONCLUSIONS/INTERPRETATION: Selected metabolic abnormalities in young adulthood identify individuals with heightened diabetes risk independent of race, sex and traditional diabetes risk factors. These signatures replicate across the life course.

Moderate-to-vigorous intensity physical activity from young adulthood to middle age and metabolic disease: a 30-year population-based cohort study.

OBJECTIVES: To determine the association between moderate-to-vigorous intensity physical activity (MVPA) trajectories (course over age and time) through the adult life course and onset of metabolic disease (diabetes and dyslipidaemia). METHODS: We analysed prospective community-based cohort data of 5115 participants in the Coronary Artery Risk Development in Young Adults study, who were black and white men and women aged 18-30 years at baseline (1985-1986) at four urban sites, collected through 30 years of follow-up. Individualised MVPA trajectories were developed for each participant using linear mixed models. RESULTS: Lower estimated MVPA score at age 18 was associated with a 12% (95% CI 6% to 18%) higher odds of incident diabetes, a 4% (95% CI 1% to 7%) higher odds of incident low high-density lipoprotein (HDL) and a 6% (95% CI 2% to 11%) higher odds of incident high triglycerides. Each additional annual 1-unit reduction in the MVPA score was associated with a 6% (95% CI 4% to 9%) higher annual odds of diabetes incidence and a 4% (95% CI 2% to 6%) higher annual odds of high triglyceride incidence. Analysing various MVPA trajectory groups, participants who were in the most active group at age 18 (over 300 min/week), but with sharp declines in midlife, had higher odds of high low-density lipoprotein and low HDL incidence, compared with those in the most active group at age 18 with subsequent gains. CONCLUSION: Given recent trends in declining MVPA across the life course and associated metabolic disease risk, young adulthood is an important time period for interventions to increase and begin the maintenance of MVPA.

Early to Midlife Smoking Trajectories and Cognitive Function in Middle-Aged US Adults: the CARDIA Study.

BACKGROUND: Smoking starts in early adulthood and persists throughout the life course, but the association between these trajectories and midlife cognition remains unclear. OBJECTIVE: Determine the association between early to midlife smoking trajectories and midlife cognition. DESIGN: Prospective cohort study. PARTICIPANTS: Participants were 3364 adults (mean age = 50.1 ± 3.6, 56% female, 46% Black) from the Coronary Artery Risk Development in Young Adults (CARDIA) study: 1638 ever smokers and 1726 never smokers. MAIN MEASURES: Smoking trajectories were identified in latent class analysis among 1638 ever smokers using smoking measures every 2-5 years from baseline (age 18-30 in 1985-1986) through year 25 (2010-2011). Poor cognition was based on cognitive domain scores ≥ 1 SD below the mean on tests of processing speed (Digit Symbol Substitution Test), executive function (Stroop), and memory (Rey Auditory Verbal Learning Test) at year 25. RESULTS: Five smoking trajectories emerged over 25 years: quitters (19%), and minimal stable (40%), moderate stable (20%), heavy stable (15%), and heavy declining smokers (5%). Heavy stable smokers showed poor cognition on all 3 domains compared to never smoking (processing speed AOR = 2.22 95% CI 1.53-3.22; executive function AOR = 1.58 95% CI 1.05-2.36; memory AOR = 1.48 95% CI 1.05-2.10). Compared to never smoking, both heavy declining (AOR = 1.95 95% CI 1.06-3.68) and moderate stable smokers (AOR = 1.56 95% CI 1.11-2.19) exhibited slower processing speed, and heavy declining smokers additionally had poor executive function. For minimal stable smokers (processing speed AOR = 1.12 95% CI 0.85-1.51; executive function AOR = 0.97 95% CI 0.71-1.31; memory AOR = 1.21 95% CI 0.94-1.55) and quitters (processing speed AOR = 0.96 95% CI 0.63-1.48; executive function AOR = 0.98 95% CI 0.63-1.52; memory AOR = 0.97 95% CI 0.67-1.39), no association was observed. CONCLUSIONS: The association between early to midlife smoking trajectories and midlife cognition was dose-dependent. Results underscore the cognitive health risk of moderate and heavy smoking and the potential benefits of quitting on cognition, even in midlife.

Characteristics associated with early- vs. later-onset adult diabetes: The CARDIA study.

AIMS: Differences in risk profiles for individuals with early- (<40 years old) vs. later-onset (≥40 years old) diabetes were examined. METHODS: A nested case-comparison study design using 30-year longitudinal data from the Coronary Artery Risk Development in Young Adults (CARDIA) study was used. Survey data (socio-demographics, family history, medical records, and lifestyle behaviors), obesity-related measures (body mass index, weight), blood pressure, and laboratory data (insulin, fasting glucose, 2-h glucose, and lipids) were used to examine progression patterns of diabetes development in those with early-onset vs. later-onset diabetes. RESULTS: Of 605 participants, 120 were in early-onset group while 485 were in later-onset group. Early-onset group had a lower A Priori Diet Quality Score, but not statistically significant at baseline; however, the between-group difference became significant at the time that diabetes was first detected (p = 0.026). The physical activity intensity score consistently decreased from baseline to the development of diabetes in both the early- and later-onset groups. Early-onset group showed more dyslipidemia at baseline and at the time that diabetes was first detected, and rapid weight gain from baseline to the development of diabetes. CONCLUSIONS: Emphases on lifestyle modification and risk-based diabetes screening in asymptomatic young adults are necessary for early detection and prevention.

Long-term cumulative blood pressure in young adults and incident heart failure, coronary heart disease, stroke, and cardiovascular disease: The CARDIA study.

AIMS: Cumulative blood pressure (BP) is a measure that incorporates the severity and duration of BP exposure. The prognostic significance of cumulative BP in young adults for cardiovascular diseases (CVDs) in comparison to BP severity alone is, however, unclear. METHODS AND RESULTS: We investigated 3667 Coronary Artery Risk Development in Young Adults participants who attended six visits over 15 years (year-0 (1985-1986), year-2, year-5, year-7, year-l0, and year-15 exams). Cumulative BP was calculated as the area under the curve (mmHg × years) from year 0 through year 15. Cox models assessed the association between cumulative BP (year 0 through year 15), current BP (year 15), and BP change (year 0 and year 15) and CVD outcomes. Mean (standard deviation) age at year 15 was 40.2 (3.6) years, 44.1% were men, and 44.1% were African-American. Over a median follow-up of 16 years, there were 47 heart failure (HF), 103 coronary heart disease (CHD), 71 stroke, and 191 CVD events. Cumulative systolic BP (SBP) was associated with HF (hazard ratio (HR) = 2.14 (1.58-2.90)), CHD (HR = 1.49 (1.19-1.87)), stroke (HR = 1.81 (1.38-2.37)), and CVD (HR = 1.73 (1.47-2.05)). For CVD, the C-statistic for SBP (year 15) was 0.69 (0.65-0.73) and change in C-statistic with the inclusion of SBP change and cumulative SBP was 0.60 (0.56-0.65) and 0.72 (0.69-0.76), respectively. For CVD, using year-15 SBP as a reference, the net reclassification index (NRI) for cumulative SBP was 0.40 (p < 0.0001) and the NRI for SBP change was 0.22 (p = 0.001). CONCLUSIONS: Cumulative BP in young adults was associated with the subsequent risk of HF, CHD, stroke, and CVD. Cumulative BP provided incremental prognostic value and improved risk reclassification for CVD, when compared to single BP assessments or changes in BP.