Proteomics, Human Environmental Exposure, and Cardiometabolic Risk.

BACKGROUND: The biological mechanisms linking environmental exposures with cardiovascular disease pathobiology are incompletely understood. We sought to identify circulating proteomic signatures of environmental exposures and examine their associations with cardiometabolic and respiratory disease in observational cohort studies. METHODS: We tested the relations of >6500 circulating proteins with 29 environmental exposures across the built environment, green space, air pollution, temperature, and social vulnerability indicators in ≈3000 participants of the CARDIA study (Coronary Artery Risk Development in Young Adults) across 4 centers using penalized and ordinary linear regression. In >3500 participants from FHS (Framingham Heart Study) and JHS (Jackson Heart Study), we evaluated the prospective relations of proteomic signatures of the envirome with cardiovascular disease and mortality using Cox models. RESULTS: Proteomic signatures of the envirome identified novel/established cardiovascular disease-relevant pathways including DNA damage, fibrosis, inflammation, and mitochondrial function. The proteomic signatures of the envirome were broadly related to cardiometabolic disease and respiratory phenotypes (eg, body mass index, lipids, and left ventricular mass) in CARDIA, with replication in FHS/JHS. A proteomic signature of social vulnerability was associated with a composite of cardiovascular disease/mortality (1428 events; FHS: hazard ratio, 1.16 [95% CI, 1.08-1.24]; P=1.77×10-5; JHS: hazard ratio, 1.25 [95% CI, 1.14-1.38]; P=6.38×10-6; hazard ratio expressed as per 1 SD increase in proteomic signature), robust to adjustment for known clinical risk factors. CONCLUSIONS: Environmental exposures are related to an inflammatory-metabolic proteome, which identifies individuals with cardiometabolic disease and respiratory phenotypes and outcomes. Future work examining the dynamic impact of the environment on human cardiometabolic health is warranted.

Proteomic Risk Score of Increased Respiratory Susceptibility: A Multi-Cohort Study.

RATIONALE: Accelerated decline in lung function is associated with incident COPD, hospitalizations and death. However, identifying this trajectory with longitudinal spirometry measurements is challenging in clinical practice. OBJECTIVE: To determine whether a proteomic risk score trained on accelerated decline in lung function can assess risk of future respiratory disease and mortality. METHODS: In CARDIA, a population-based cohort starting in young adulthood, longitudinal measurements of FEV1 percent predicted (up to six timepoints over 30 years) were used to identify accelerated and normal decline trajectories. Protein aptamers associated with an accelerated decline trajectory were identified with multivariable logistic regression followed by LASSO regression. The proteomic respiratory susceptibility score was derived based on these circulating proteins and applied to the UK Biobank and COPDGene studies to examine associations with future respiratory morbidity and mortality. MEASUREMENTS AND RESULTS: Higher susceptibility score was independently associated with all-cause mortality (UKBB: HR 1.56, 95%CI 1.50-1.61; COPDGene: HR 1.75, 95%CI 1.63-1.88), respiratory mortality (UKBB: HR 2.39, 95% CI 2.16-2.64; COPDGene: HR 1.83, 95%CI 1.33-2.51), incident COPD (UKBB: HR 1.84, 95%CI 1.71-1.98), incident respiratory exacerbation (COPDGene: OR 1.11, 95%CI 1.03-1.20), and incident exacerbation requiring hospitalization (COPDGene: OR 1.18, 95%CI 1.08-1.28). CONCLUSIONS: A proteomic signature of increased respiratory susceptibility identifies people at risk of respiratory death, incident COPD, and respiratory exacerbations. This susceptibility score is comprised of proteins with well-known and novel associations with lung health and holds promise for the early detection of lung disease without requiring years of spirometry measurements.

Association of 20-Year Longitudinal Depressive Symptoms With Left Ventricular Geometry Outcomes in the Coronary Artery Risk Development in Young Adults Study: A Role for Androgens?

OBJECTIVE: Depression is a risk factor for coronary heart disease and left ventricular hypertrophy (LVH) is a potent predictor of coronary heart disease events. Whether depression is associated with LVH has received limited investigation. This study assessed cross-sectional and 20-year longitudinal associations of depressive symptoms with LVH outcomes after accounting for important known confounders. METHODS: From 5115 participants enrolled in 1985-1986 in the Coronary Artery Risk Development in Young Adults Study, 2533 had serial measures of depressive symptoms and subsequent echocardiography to measure normal LV geometry, concentric remodeling, and LVH. The primary exposure variable was trajectories of the Center for Epidemiologic Studies Depression (CES-D) scale score from 1990-1991 to 2010-2011. Multivariable polytomous logistic regression was used to assess associations of trajectories with a composite LV geometry outcome created using echocardiogram data measured in 2010-2011 and 2015-2016. Sex-specific conflicting results led to exploratory models that examined potential importance of testosterone and sex hormone-binding globulin. RESULTS: Overall CES-D and Somatic subscale trajectories had significant associations with LVH for female participants only. Odds ratios for the subthreshold (mean CES-D ≈ 14) and stable (mean CES-D ≈ 19) groups were 1.49 (95% confidence interval = 1.05-2.13) and 1.88 (95% confidence interval = 1.16-3.04), respectively. For female participants, sex hormone-binding globulin was inversely associated with LVH, and for male participants, bioavailable testosterone was positively associated with concentric geometry. CONCLUSIONS: Findings from cross-sectional and longitudinal regression models for female participants, but not male ones, and particularly for Somatic subscale trajectories suggested a plausible link among depression, androgens, and LVH. The role of androgens to the depression-LVH relation requires additional investigation in future studies.

Missense Genetic Variation of ICAM1 and Incident Heart Failure.

BACKGROUND: Intercellular adhesion molecule-1 (ICAM-1) is a cell surface protein that participates in endothelial activation and is hypothesized to play a central role in heart failure (HF). We evaluated associations of ICAM1 missense genetic variants with circulating ICAM-1 levels and with incident HF. METHODS AND RESULTS: We identified 3 missense variants within ICAM1 (rs5491, rs5498 and rs1799969) and evaluated their associations with ICAM-1 levels in the Coronary Artery Risk Development in Young Adults Study and the Multi-Ethnic Study of Atherosclerosis (MESA). We determined the association among these 3 variants and incident HF in MESA. We separately evaluated significant associations in the Atherosclerosis Risk in Communities (ARIC) study. Of the 3 missense variants, rs5491 was common in Black participants (minor allele frequency [MAF] > 20%) and rare in other race/ethnic groups (MAF < 5%). In Black participants, the presence of rs5491 was associated with higher levels of circulating ICAM-1 at 2 timepoints separated by 8 years. Among Black participants in MESA (n = 1600), the presence of rs5491 was associated with an increased risk of incident HF with preserved ejection fraction (HFpEF; HR = 2.30; [95% CI 1.25-4.21; P = 0.007]). The other ICAM1 missense variants (rs5498 and rs1799969) were associated with ICAM-1 levels, but there were no associations with HF. In ARIC, rs5491 was significantly associated with incident HF (HR = 1.24 [95% CI 1.02 - 1.51]; P = 0.03), with a similar direction of effect for HFpEF that was not statistically significant. CONCLUSIONS: A common ICAM1 missense variant among Black individuals may be associated with increased risk of HF, which may be HFpEF-specific.

Comparing Racial Differences in Emphysema Prevalence Among Adults With Normal Spirometry: A Secondary Data Analysis of the CARDIA Lung Study.

BACKGROUND: Computed tomography (CT) imaging complements spirometry and may provide insight into racial disparities in respiratory health. OBJECTIVE: To determine the difference in emphysema prevalence between Black and White adults with different measures of normal spirometry results. DESIGN: Observational study using clinical data and spirometry from the CARDIA (Coronary Artery Risk Development in Young Adults) study obtained in 2015 to 2016 and CT scans done in 2010 to 2011. SETTING: 4 U.S. centers. PARTICIPANTS: Population-based sample of Black and White adults. MEASUREMENTS: Self-identified race and visually identified emphysema on CT in participants with different measures of "normal" spirometry results, calculated using standard race-specific and race-neutral reference equations. RESULTS: A total of 2674 participants (485 Black men, 762 Black women, 659 White men, and 768 White women) had both a CT scan and spirometry available for analysis. Among participants with a race-specific FEV1 between 80% and 99% of predicted, 6.5% had emphysema. In this group, emphysema prevalence was 3.9-fold (95% CI, 2.1- to 7.1-fold; 15.5% vs. 4.0%) higher among Black men than White men and 1.9-fold (CI, 1.0- to 3.8-fold; 6.6% vs. 3.4%) higher among Black women than White women. Among participants with a race-specific FEV1 between 100% and 120% of predicted, 4.0% had emphysema. In this category, Black men had a 6.4-fold (CI, 2.2- to 18.7-fold; 13.9% vs. 2.2%) higher prevalence of emphysema than White men, whereas Black and White women had a similar prevalence of emphysema (2.6% and 2.0%, respectively). The use of race-neutral equations to identify participants with an FEV1 percent predicted between 80% and 120% attenuated racial differences in emphysema prevalence among men and eliminated racial differences among women. LIMITATION: No CT scans were obtained during the most recent study visit (2015 to 2016) when spirometry was done. CONCLUSION: Emphysema is often present before spirometry findings become abnormal, particularly among Black men. Reliance on spirometry alone to differentiate lung health from lung disease may result in the underrecognition of impaired respiratory health and exacerbate racial disparities. PRIMARY FUNDING SOURCE: National Institutes of Health.

PDAY risk score predicts cardiovascular events in young adults: the CARDIA study.

AIMS: Atherosclerotic cardiovascular disease (ASCVD) risk prediction equations apply to older adults. For this study, the Pathobiologic Determinants of Atherosclerosis in Youth (PDAY) risk score, based on post-mortem measurements of atherosclerosis in 15-34-year olds dying accidentally, was used to predict ASCVD events, specifically myocardial infarction and revascularization, in middle age, from risk measured at ≤40 years of age. METHODS AND RESULTS: The Coronary Artery Risk Development in Young Adults Study (CARDIA) collected longitudinal cardiovascular risk data, coronary artery calcium (CAC) scores, and ASCVD data beginning at age 18 and 30 years with 30-year follow-up. Predictive accuracy for ASCVD of the PDAY risk score, calculated at baseline (mean age 24) and at all six CARDIA examinations up until year 15, was examined. We also examined whether the presence of CAC improved model discrimination. The cohort for this study comprised 5004 Black and White men and women, at baseline and 3558 with data at year 15. Each standard deviation increase in PDAY score, at each examination, was significantly associated with future ASCVD. Hazard ratios (per standard deviation) increased from 1.74 to 2.04 from year 0 to year 15. C-statistics ranged from 0.771 to 0.794. Coronary artery calcium measurement at age 33-45 years improved risk prediction only if the score was 0. Cumulative risk exposure over the first 15 years of the CARDIA study also had high-predictive value (c-statistic 0.798, 95% confidence interval 0.762-0.835). CONCLUSION: The PDAY risk score may be used in young adults, prior to age 40 years to predict ASCVD events.

Associations of Chronic Burden, Sleep Characteristics, and Metabolic Syndrome in the Coronary Artery Risk Development in Young Adults Study.

OBJECTIVE: Chronic exposure to stress is associated with metabolic syndrome (MetS), but the mechanism is unclear. We investigated the associations between chronic burden, sleep, and MetS in the Coronary Artery Risk Development in Young Adults Study. METHODS: Chronic burden was self-reported (2000-2001) according to experiences with stressors for longer than 6 months. Wrist actigraphy-measured sleep duration and sleep efficiency were collected for 6 days; sleep duration, sleep quality, and daytime sleepiness were self-reported (2003-2004). MetS was measured during the clinic visit, from 2005 to 2006. Multivariable logistic and Cox proportional hazard models were fit to determine the associations of interest. Mediation by sleep was assessed using the product of coefficients approach. RESULTS: Among participants ( n = 606), the average (standard deviation) age was 40 (3.6) years, 58% were female, and 43% were Black. The prevalences of chronic burden, short sleep (≤6 hours), and MetS were 35%, 43% and 20.5%, respectively. High versus low chronic burden was associated with shorter self-reported sleep duration and higher daytime sleepiness. Chronic burden was associated with 1.85 higher odds (95% confidence interval = 1.11-3.09) of MetS. Sleep characteristics were not associated with MetS. There was no evidence that sleep mediated the chronic burden-MetS relation. CONCLUSION: Burden of chronic stress may be an emerging novel risk factor for both poor sleep and MetS.

Association between Cardiorespiratory Fitness and Bronchiectasis at CT: A Long-term Population-based Study of Healthy Young Adults Aged 18-30 Years in the CARDIA Study.

Background Protective factors against the risk of bronchiectasis are unknown. A high level of cardiorespiratory fitness is associated with a lower risk of chronic obstructive pulmonary disease. But whether fitness relates to bronchiectasis remains, to the knowledge of the authors, unknown. Purpose To examine the association between cardiorespiratory fitness and bronchiectasis. Materials and Methods This was a secondary analysis of a prospective observational study: the Coronary Artery Risk Development in Young Adults cohort (from 1985-1986 [year 0] to 2015-2016 [year 30]). During a 30-year period, healthy participants (age at enrollment 18-30 years) underwent treadmill exercise testing at year 0 and year 20 visits. Cardiorespiratory fitness was determined according to the treadmill exercise duration. The 20-year difference in cardiorespiratory fitness was used as the fitness measurement. At year 25, chest CT was performed to assess bronchiectasis and was used as the primary outcome. Multivariable logistic models were performed to determine the association between cardiorespiratory fitness changes and bronchiectasis. Results Of 2177 selected participants (at year 0: mean age, 25 years ± 4 [standard deviation]; 1224 women), 209 (9.6%) had bronchiectasis at year 25. After adjusting for age, race-sex group, study site, body mass index, pack-years smoked, history of tuberculosis, pneumonia, asthma and myocardial infarction, peak lung function, and cardiorespiratory fitness at baseline, preservation of cardiorespiratory fitness was associated with lower odds of bronchiectasis at CT at year 25 (per 1-minute-longer treadmill duration from year 0 to year 20: odds ratio [OR], 0.88; 95% CI: 0.80, 0.98; P = .02). A consistent strong association was found when cough and phlegm were included in bronchiectasis (OR, 0.72; 95% CI: 0.59, 0.87; P < .001). Conclusion In a long-term follow-up, the preservation of cardiorespiratory fitness was associated with lower odds of bronchiectasis at CT. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Stojanovska in this issue.

Association between plasminogen activator inhibitor-1 in young adulthood and nonalcoholic fatty liver disease in midlife: CARDIA.

BACKGROUND: Prior studies have demonstrated a cross-sectional association between elevated plasminogen activator inhibitor-1 (PAI-1) levels and nonalcoholic fatty liver disease (NAFLD). However, there are no prospective longitudinal assessments of the association between PAI-1 and NAFLD. We aimed to describe the association between PAI-1 levels in early adulthood with NAFLD in midlife. METHODS: Among the 5115 participants in the coronary artery risk development in young adults (CARDIA) study, participants were randomly selected from a subset that was free of obesity, diabetes and hypertension at the 1992-1993 exam and attended the 2005-2006 exam (n = 996). A subset of participants (n = 896) also had CT liver fat measured (2010-2011). Participants with secondary causes of steatosis were excluded (n = 87). NAFLD was defined as liver attenuation ≤51 Hounsfield units. Logistic regression models assessed the association between PAI-1 and NAFLD. RESULTS: Of 809 participants, 53% were female, 37% black with a mean age of 32 years. Median PAI-1 level at 1st assessment (1992-1993) was 23.4 ng/mL among participants with NAFLD vs 11.9 ng/mL among those without NAFLD (P < .0001). Median PAI-1 level at 2nd assessment (2005-2006) was 55.6 ng/mL among participants with NAFLD vs 19.5 ng/mL among those without NAFLD (P < .0001). Higher PAI-1 levels were independently associated with NAFLD (1st assessment adjusted OR [AOR] 2.16 per 1 standard deviation higher log(PAI-1) level (95% confidence interval [CI] 1.63-2.85); 2nd assessment AOR 2.71 (95% CI 2.03-3.61)). CONCLUSIONS: Plasma PAI-1 levels in young adulthood were independently associated with NAFLD in midlife. Further studies may indicate whether PAI-1 plays a role in NAFLD pathophysiology.

The Association of Optimism with Sleep Duration and Quality: Findings from the Coronary Artery Risk and Development in Young Adults (CARDIA) Study.

Optimism is associated with better health outcomes with hypothesized effects due in part to optimism's association with restorative health processes. Limited work has examined whether optimism is associated with better quality sleep, a major restorative process. We test the hypothesis that greater optimism is associated with more favorable sleep quality and duration. Main analyses included adults aged 32-51 who participated in the Coronary Artery Risk Development in Young Adults (CARDIA) study (n = 3,548) during the fifth (Year 15: 2000-2001) and sixth (Year 20: 2005-2006) follow-up visits. Optimism was assessed using the revised Life-Orientation Test. Self-report measures of sleep quality and duration were obtained twice 5 years apart. A subset of CARDIA participants (2003-2005) additionally provided actigraphic data and completed the Pittsburgh Sleep Quality Index (PSQI) and Epworth Sleepiness Scale (ESS). Multivariate regression analyses were used to examine associations of optimism and sleep indicators. In cross-sectional analyses of 3548 participants, each standard deviation (SD) higher optimism score resulted in 78% higher odds of self-reporting very good sleep quality. Prospectively, a 1-SD higher optimism score was related to higher odds of reporting persistently good sleep quality across 5-years relative to those with persistently poor sleep [OR = 1.31; 95%CI:1.10,1.56]. In participant with supplementary data, each SD higher optimism score was marginally associated with 22% greater odds of favorable sleep quality [OR = 1.22; 95%CI:1.00,1.49] as measured by the PSQI, with possible mediation by depressive symptoms. Optimism was unrelated to objective actigraphic sleep data. Findings support a positive cross-sectional and prospective association between optimism and self-reported sleep behavior.

Respiratory Symptoms in Young Adults and Future Lung Disease. The CARDIA Lung Study.

RATIONALE: There are limited data on factors in young adulthood that predict future lung disease. OBJECTIVES: To determine the relationship between respiratory symptoms, loss of lung health, and incident respiratory disease in a population-based study of young adults. METHODS: We examined prospective data from 2,749 participants in the CARDIA (Coronary Artery Risk Development in Young Adults) study who completed respiratory symptom questionnaires at baseline and 2 years later and repeated spirometry measurements over 30 years. MEASUREMENTS AND MAIN RESULTS: Cough or phlegm, episodes of bronchitis, wheeze, shortness of breath, and chest illnesses at both baseline and Year 2 were the main predictor variables in models assessing decline in FEV1 and FVC from Year 5 to Year 30, incident obstructive and restrictive lung physiology, and visual emphysema on thoracic computed tomography scan. After adjustment for covariates, including body mass index, asthma, and smoking, report of any symptom was associated with -2.71 ml/yr excess decline in FEV1 (P < 0.001) and -2.18 in FVC (P < 0.001) as well as greater odds of incident (prebronchodilator) obstructive (odds ratio [OR], 1.63; 95% confidence interval [CI], 1.24-2.14) and restrictive (OR, 1.40; 95% CI, 1.09-1.80) physiology. Cough-related symptoms (OR, 1.56; 95% CI, 1.13-2.16) were associated with greater odds of future emphysema. CONCLUSIONS: Persistent respiratory symptoms in young adults are associated with accelerated decline in lung function, incident obstructive and restrictive physiology, and greater odds of future radiographic emphysema.

Association between Cardiorespiratory Fitness and Lung Health from Young Adulthood to Middle Age.

RATIONALE: Beyond the risks of smoking, there are limited data on factors associated with change in lung function over time. OBJECTIVES: To determine whether cardiorespiratory fitness was longitudinally associated with preservation of lung health. METHODS: Prospective data were collected from 3,332 participants in the Coronary Artery Risk Development in Young Adults study aged 18-30 in 1985 who underwent treadmill exercise testing at baseline visit, and 2,735 participants with a second treadmill test 20 years later. The association between cardiorespiratory fitness and covariate adjusted decline in lung function was evaluated. MEASUREMENTS AND MAIN RESULTS: Higher baseline fitness was associated with less decline in lung function. When adjusted for age, height, race-sex group, peak lung function, and years from peak lung function, each additional minute of treadmill duration was associated with 1.00 ml/yr less decline in FEV1 (P < 0.001) and 1.55 ml/yr less decline in FVC (P < 0.001). Greater decline in fitness was associated with greater annual decline in lung function. Each 1-minute decline in treadmill duration between baseline and Year 20 was associated with 2.54 ml/yr greater decline in FEV1 (P < 0.001) and 3.27 ml/yr greater decline in FVC (P < 0.001). Both sustaining higher and achieving relatively increased levels of fitness over 20 years were associated with preservation of lung health. CONCLUSIONS: Greater cardiopulmonary fitness in young adulthood, less decline in fitness from young adulthood to middle age, and achieving increased fitness from young adulthood to middle age are associated with less decline in lung health over time. Clinical trial registered with www.clinicaltrials.gov (NCT 00005130).

Association of Blood Pressure Classification in Young Adults Using the 2017 American College of Cardiology/American Heart Association Blood Pressure Guideline With Cardiovascular Events Later in Life.

Importance: Little is known regarding the association between level of blood pressure (BP) in young adulthood and cardiovascular disease (CVD) events by middle age. Objective: To assess whether young adults who developed hypertension, defined by the 2017 American College of Cardiology (ACC)/American Heart Association (AHA) BP guideline, before age 40 years have higher risk for CVD events compared with those who maintained normal BP. Design, Setting, and Participants: Analyses were conducted in the prospective cohort Coronary Artery Risk Development in Young Adults (CARDIA) study, started in March 1985. CARDIA enrolled 5115 African American and white participants aged 18 to 30 years from 4 US field centers (Birmingham, Alabama; Chicago, Illinois; Minneapolis, Minnesota; and Oakland, California). Outcomes were available through August 2015. Exposures: Using the highest BP measured from the first examination to the examination closest to, but not after, age 40 years, each participant was categorized as having normal BP (untreated systolic BP [SBP] <120 mm Hg and diastolic BP [DBP] <80 mm Hg; n = 2574); elevated BP (untreated SBP 120-129 mm Hg and DBP <80 mm Hg; n = 445); stage 1 hypertension (untreated SBP 130-139 mm Hg or DBP 80-89 mm Hg; n = 1194); or stage 2 hypertension (SBP ≥140 mm Hg, DBP ≥90 mm Hg, or taking antihypertensive medication; n = 638). Main Outcomes and Measures: CVD events: fatal and nonfatal coronary heart disease (CHD), heart failure, stroke, transient ischemic attack, or intervention for peripheral artery disease (PAD). Results: The final cohort included 4851 adults (mean age when follow-up for outcomes began, 35.7 years [SD, 3.6]; 2657 women [55%]; 2441 African American [50%]; 206 taking antihypertensive medication [4%]). Over a median follow-up of 18.8 years, 228 incident CVD events occurred (CHD, 109; stroke, 63; heart failure, 48; PAD, 8). CVD incidence rates for normal BP, elevated BP, stage 1 hypertension, and stage 2 hypertension were 1.37 (95% CI, 1.07-1.75), 2.74 (95% CI, 1.78-4.20), 3.15 (95% CI, 2.47-4.02), and 8.04 (95% CI, 6.45-10.03) per 1000 person-years, respectively. After multivariable adjustment, hazard ratios for CVD events for elevated BP, stage 1 hypertension, and stage 2 hypertension vs normal BP were 1.67 (95% CI, 1.01-2.77), 1.75 (95% CI, 1.22-2.53), and 3.49 (95% CI, 2.42-5.05), respectively. Conclusions and Relevance: Among young adults, those with elevated blood pressure, stage 1 hypertension, and stage 2 hypertension before age 40 years, as defined by the blood pressure classification in the 2017 American College of Cardiology/American Heart Association (ACC/AHA) guidelines, had significantly higher risk for subsequent cardiovascular disease events compared with those with normal blood pressure before age 40 years. The ACC/AHA blood pressure classification system may help identify young adults at higher risk for cardiovascular disease events.

Pathobiological Determinants of Atherosclerosis in Youth (PDAY) Risk Score in Young Adults Predicts Coronary Artery and Abdominal Aorta Calcium in Middle Age: The CARDIA Study.

BACKGROUND: We explored whether, the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) coronary and abdominal risk scores measured at 18 to 30 years of age and changes in these scores would more strongly predict coronary artery calcium (CAC) and abdominal aortic calcium (AAC) assessed 25 years later, than scores measured 25 years later. METHODS AND RESULTS: In the Coronary Artery Risk Development in Young Adults (CARDIA) study, 3008 participants had measurements of risk score components at 5-year intervals beginning at 18 to 30 years of age. CAC and AAC were assessed at 43 to 55 years of age. Odds ratios (ORs) for the presence and extent of CAC/AAC per/point higher score and c-statistics for predicting CAC/AAC were calculated. The prevalence of CAC was 28% and AAC was 53%. For each 1 point higher PDAY score, the odds of CAC were higher using baseline scores than year 25 scores (OR, 1.29; 95% confidence interval [CI], 1.25-1.33 versus OR, 1.12; 95% CI, 1.11-1.14). For AAC, ORs at years 0 and 25 were similar (OR, 1.29; 95% CI, 1.24-1.34 versus OR, 1.22; 95% CI, 1.19-1.26). C-statistic for CAC prediction was higher at year 0 than year 25 (0.731 versus 0.705) but similar at years 0 and 25 for AAC (0.665 versus 0.670). ORs for CAC were highest at baseline, and, for AAC, ORs were highest at year 10. Including change in PDAY scores with baseline scores improved prediction. CONCLUSIONS: Atherosclerosis risk and change in risk assessed in young adulthood years before subclinical atherosclerosis imaging provide strong prediction of future subclinical atherosclerosis. CAC and AAC reflect chronic risk exposure in addition to risk measured at the time of study.

Prevalence and Predictors of Diastolic Dysfunction According to Different Classification Criteria: The Coronary Artery Risk Development in Young in Adults Study.

Heart failure with preserved ejection fraction is often preceded by diastolic dysfunction (DD). Of several published DD criteria, it is unclear which, if any, are applicable to data obtained in epidemiologic cohorts. We evaluated the prevalence of DD using previously published definitions in a population-based study, the Coronary Artery Risk Development in Young Adults (CARDIA) Study, using data gathered in 2010-2011. Echocardiography was performed on 3,474 individuals (mean age = 50.2 years) at the CARDIA year 25 examination. Four published definitions of DD were studied. We calculated DD prevalence for each definition and determined the overlap between definitions. We used logistic regression to assess the strength of associations between demographic and clinical factors and the definitions of DD. Prevalence of DD ranged from 2% to 32% across the 4 definitions, with a minority of cases identified by more than 1 definition. Two definitions classified 38%-39% of the study sample as indeterminate for DD. Associations of risk factors with DD varied considerably, with male sex being associated positively with DD for one definition (odds ratio = 1.4, 95% confidence interval: 1.2, 1.6) and inversely for another (odds ratio = 0.7, 95% confidence interval: 0.6, 0.8). Prevalence of DD varies markedly in CARDIA by the definition applied. A uniform, reliable, and accurate definition of DD for epidemiologic studies is needed.

Association of the Interaction Between Smoking and Depressive Symptom Clusters With Coronary Artery Calcification: The CARDIA Study.

OBJECTIVE: Depressive symptom clusters are differentially associated with prognosis among patients with cardiovascular disease (CVD). Few studies have prospectively evaluated the association between depressive symptom clusters and risk of CVD. Previously, we observed that smoking and global depressive symptoms were synergistically associated with coronary artery calcification (CAC). The purpose of this study was to determine whether the smoking by depressive symptoms interaction, measured cumulatively over 25 years, differed by depressive symptom cluster (negative affect, anhedonia, and somatic symptoms) in association with CAC. METHODS: Participants (N = 3,189: 54.5% female; 51.5% Black; average age = 50.1 years) were followed from 1985-1986 through 2010-2011 in the Coronary Artery Risk Development in Young Adults (CARDIA) study. Smoking exposure was measured by cumulative cigarette pack-years (cigarette packs smoked per day × number of years smoking; year 0 through year 25). Depressive symptoms were measured using a 14-item, 3-factor (negative affect, anhedonia, somatic symptoms) model of the Center for Epidemiologic Studies Depression (CES-D) Scale (years 5, 10, 15, 20, and 25). CAC was assessed at year 25. Logistic regression models were used to evaluate the association between the smoking by depressive symptom clusters interactions with CAC ( = 0 vs. > 0), adjusted for CVD-related sociodemographic, behavioral, and clinical covariates. RESULTS: 907 participants (28% of the sample) had CAC > 0 at year 25. The depressive symptom clusters did not differ significantly between the two groups. Only the cumulative somatic symptom cluster by cumulative smoking exposure interaction was significantly associated with CAC > 0 at year 25 (p = .028). Specifically, adults with elevated somatic symptoms (score 9 out of 18) who had 10, 20, or 30 pack-years of smoking exposure had respective odds ratios (95% confidence intervals) of 2.06 [1.08, 3.93], 3.71 [1.81, 7.57], and 6.68 [2.87, 15.53], ps < .05. Negative affect and anhedonia did not significantly interact with smoking exposure associated with CAC >0, ps > .05. CONCLUSIONS: Somatic symptoms appear to be a particularly relevant cluster of depressive symptomatology in the relationship between smoking and CVD risk.

Low-Density Lipoprotein Cholesterol Concentrations and Association of High-Sensitivity C-Reactive Protein Concentrations With Incident Coronary Heart Disease in the Multi-Ethnic Study of Atherosclerosis.

High-sensitivity C-reactive protein (hs-CRP) has been associated with coronary heart disease (CHD) in numerous but not all observational studies, and whether low levels of low-density lipoprotein cholesterol (LDL-C) alter this association is unknown. In the Multi-Ethnic Study of Atherosclerosis (2000-2012), we prospectively assessed the association of hs-CRP concentrations with incident CHD in participants who did not receive lipid-lowering therapy, as well as in those with LDL-C concentrations less than 130 mg/dL (n = 3,106) and those with LDL-C concentrations of 130 mg/dL or greater (n = 1,716) at baseline (2000-2002). Cox proportional hazard analyses were used to assess the associations after adjustment for socioeconomic status, traditional risk factors, body mass index, diabetes, aspirin use, kidney function, and coronary artery calcium score. Loge hs-CRP was associated with incident CHD in participants with LDL-C concentrations of 130 mg/dL or higher (hazard ratio (HR) = 1.29, 95% confidence interval (CI): 1.05, 1.60) but not in those with LDL-C concentrations less than 130 mg/dL (HR = 0.88, 95% CI: 0.74, 1.05; P for interaction = 0.003). As a whole, loge hs-CRP was not associated with incident CHD in participants who had not received lipid-lowering therapy at baseline (HR = 1.05, 95% CI: 0.92, 1.20) and who had mean LDL-C concentrations less than 130 mg/dL. These findings suggest that LDL-C concentrations might be a moderator of the contribution of hs-CRP to CHD.

Association of nonalcoholic fatty liver disease with subclinical myocardial remodeling and dysfunction: A population-based study.

UNLABELLED: Nonalcoholic fatty liver disease (NAFLD) and heart failure (HF) are obesity-related conditions with high cardiovascular mortality. Whether NAFLD is independently associated with subclinical myocardial remodeling or dysfunction among the general population is unknown. We performed a cross-sectional analysis of 2,713 participants from the multicenter, community-based Coronary Artery Risk Development in Young Adults (CARDIA) study who underwent concurrent computed tomography (CT) quantification of liver fat and comprehensive echocardiography with myocardial strain measured by speckle tracking during the Year-25 examination (age, 43-55 years; 58.8% female and 48.0% black). NAFLD was defined as liver attenuation ≤40 Hounsfield units after excluding other causes of liver fat. Subclinical left ventricular (LV) systolic dysfunction was defined using values of absolute peak global longitudinal strain (GLS). Diastolic dysfunction was defined using Doppler and tissue Doppler imaging markers. Prevalence of NAFLD was 10.0%. Participants with NAFLD had lower early diastolic relaxation (e') velocity (10.8 ± 2.6 vs. 11.9 ± 2.8 cm/s), higher LV filling pressure (E/e' ratio: 7.7 ± 2.6 vs. 7.0 ± 2.3), and worse absolute GLS (14.2 ± 2.4% vs. 15.2 ± 2.4%) than non-NAFLD (P < 0.0001 for all). When adjusted for HF risk factors or body mass index, NAFLD remained associated with subclinical myocardial remodeling and dysfunction (P < 0.01). The association of NAFLD with e' velocity (ß = -0.36 [standard error = 0.15] cm/s; P = 0.02), E/e' ratio (ß = 0.35 [0.16]; P = 0.03), and GLS (ß = -0.42 [0.18]%; P = 0.02) was attenuated after controlling for visceral adipose tissue. Effect modification by race and sex was not observed. CONCLUSIONS: NAFLD is independently associated with subclinical myocardial remodeling and dysfunction and provides further insight into a possible link between NAFLD and HF.

Association of endogenous testosterone with subclinical atherosclerosis in men: the multi-ethnic study of atherosclerosis.

OBJECTIVES: Whether endogenous sex hormones play a role in cardiovascular disease (CVD) risk in men is unclear. Few studies have examined associations of sex hormones with atherosclerosis measured by coronary artery calcium score (CACS) and carotid intima-media thickness (cIMT). We evaluated the association of testosterone (T) and other sex hormones with CACS and cIMT. METHODS: Using the large multi-ethnic cohort of 3164 men without known CVD in the Multi-Ethnic Study of Atherosclerosis (MESA), cross-sectional associations of tertiles of endogenous sex hormones with CACS and cIMT were analysed. RESULTS: In regard to CAC, there was a significant negative trend (P-trend = 0·02) for CACS>0 over tertiles of free T (FT) with RRs (95% CI) for the lowest to highest tertiles. There was also a marginally significant positive trend (P-trend = 0·06) for CACS>0 over tertiles of sex hormone-binding globulin (SHBG) with RRs for the lowest to highest tertiles. There were no significant associations with CACS >0 for tertiles of TT (Total T), bioavailable T (BT), oestradiol (E2) and dehydroepiandrosterone (DHEA). There was significantly higher log CACS after adjustment for CVD risk factors for lower TT levels, compared to higher levels, using 9·54 and 10·4 nmol/l as cut-off points. In regard to cIMT, there was a significant positive trend (P = 0·003) in mean cIMT over the tertiles of BT, but not for TT, FT, E2, DHEA and SHBG. There was significantly lower cIMT after adjustment for CVD risk factors for lower TT levels compared to higher levels. CONCLUSION: In a population of male subjects with no known CVD, lower FT is associated with higher RR of CACS>0 and lower TT is associated with higher log CACS. Lower BT and TT are associated with lower cIMT. While these findings support the positive correlation between low T and coronary atherosclerosis, the opposite findings on cIMT warrant further evaluation.