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Coronary artery calcification (CAC), a measure of subclinical atherosclerosis, predicts future symptomatic coronary artery disease (CAD). Identifying genetic risk factors for CAC may point to new therapeutic avenues for prevention. Currently, there are only four known risk loci for CAC identified from genome-wide association studies (GWAS) in the general population. Here we conducted the largest multi-ancestry GWAS meta-analysis of CAC to date, which comprised 26,909 individuals of European ancestry and 8,867 individuals of African ancestry. We identified 11 independent risk loci, of which eight were new for CAC and five had not been reported for CAD. These new CAC loci are related to bone mineralization, phosphate catabolism and hormone metabolic pathways. Several new loci harbor candidate causal genes supported by multiple lines of functional evidence and are regulators of smooth muscle cell-mediated calcification ex vivo and in vitro. Together, these findings help refine the genetic architecture of CAC and extend our understanding of the biological and potential druggable pathways underlying CAC.

We investigated inter-arm systolic blood pressure (sIAD) difference, reproducibility, and incident cardiovascular disease (CVD). We hypothesized that higher sIAD values have low prevalence and nonpersistence over years, but that CVD risk is higher starting from the time of first high absolute sIAD. In Multi-Ethnic Study of Atherosclerosis participants (n = 6725, 53% female, 45-84 years old), Doppler systolic blood pressure (SBP) measurements were made in both arms (10-minute interval) thrice over 9.5 years. Proportional hazards for CVD (coronary heart disease, heart failure, stroke, peripheral arterial disease (PAD)) over 16.4 years were tested according to time-varying absolute inter-arm difference with covariates: (1) age, gender, race, and clinic; (2) model 1 plus height, heart rate, BP, antihypertensives, BMI, smoking status, lipids, lipid lowering medication, and diabetes. High sIAD was not persistent across exams. Maximum absolute sIAD ≥ 15 mmHg was found at least once in 815 persons. Maximum absolute sIAD had a graded relationship with incident stroke or PAD: 6.2% events; model 2 hazard ratio per 10 mmHg 1.34 (95% CI, 1.15-1.56) and this risk was approximately doubled for maximum absolute sIAD ≥ 15 mmHg vs 0-4 mmHg. Total CVD risk (18.4% events) was increased only for maximum absolute sIAD ≥25 mmHg. Associations with incident CVD did not differ for higher SBP in left vs right arm. A higher maximum absolute sIAD at any exam was associated with greater risk for stroke and PAD especially for values ≥ 15 mmHg, and ≥25 mmHg for other CVD. Measuring SBP between arms may help identify individuals at risk for CVD.

Alcohol is a widely consumed substance in the United States, however its effect on aging remains understudied. In this study of young adults, we examined whether cumulative alcohol consumption, i.e., alcohol years of beer, liquor, wine, and total alcohol, and recent binge drinking, were associated with four measures of age-related epigenetic changes via blood DNA methylation. A random subset of study participants in the Coronary Artery Risk Development in Young Adults Study underwent DNA methylation profiling using the Illumina MethylationEPIC Beadchip. Participants with alcohol consumption and methylation data at examination years 15 (n = 1,030) and 20 (n = 945) were included. Liquor and total alcohol consumption were associated with a 0.31-year (P = 0.002) and a 0.12-year (P = 0.013) greater GrimAge acceleration (GAA) per additional five alcohol years, while beer and wine consumption observed marginal (P = 0.075) and no associations (P = 0.359) with GAA, respectively. Any recent binge drinking and the number of days of binge drinking were associated with a 1.38-year (P < 0.001) and a 0.15-year (P < 0.001) higher GAA, respectively. We observed statistical interactions between cumulative beer (P < 0.001) and total alcohol (P = 0.004) consumption with chronological age, with younger participants exhibiting a higher average in GAA compared to older participants. No associations were observed with the other measures of epigenetic aging. These results suggest cumulative liquor and total alcohol consumption and recent binge drinking may alter age-related epigenetic changes as captured by GAA. With the increasing aging population and widespread consumption of alcohol, these findings may have potential implications for lifestyle modification to promote healthy aging.

Despite the prognostic value of arterial stiffness (AS) and pulsatile hemodynamics (PH) for cardiovascular morbidity and mortality, epigenetic modifications that contribute to AS/PH remain unknown. To gain a better understanding of the link between epigenetics (DNA methylation) and AS/PH, we examined the relationship of eight measures of AS/PH with CpG sites and co-methylated regions using multi-ancestry participants from Trans-Omics for Precision Medicine (TOPMed) Multi-Ethnic Study of Atherosclerosis (MESA) with sample sizes ranging from 438 to 874. Epigenome-wide association analysis identified one genome-wide significant CpG (cg20711926-CYP1B1) associated with aortic augmentation index (AIx). Follow-up analyses, including gene set enrichment analysis, expression quantitative trait methylation analysis, and functional enrichment analysis on differentially methylated positions and regions, further prioritized three CpGs and their annotated genes (cg23800023-ETS1, cg08426368-TGFB3, and cg17350632-HLA-DPB1) for AIx. Among these, ETS1 and TGFB3 have been previously prioritized as candidate genes. Furthermore, both ETS1 and HLA-DPB1 have significant tissue correlations between Whole Blood and Aorta in GTEx, which suggests ETS1 and HLA-DPB1 could be potential biomarkers in understanding pathophysiology of AS/PH. Overall, our findings support the possible role of epigenetic regulation via DNA methylation of specific genes associated with AIx as well as identifying potential targets for regulation of AS/PH.

BackgroundStudies found associations between pulmonary function (PF) and cognition, but these are limited by mostly cross-sectional design and a single measure of PF (typically forced expiratory volume in 1 second [FEV1]). Our objective was to prospectively analyze the association of repeatedly measured PF with cognition.MethodsWe studied 3 499 participants in the Coronary Artery Risk Development in Young Adults cohort with cognition measured at year 25 (Y25) and Y30, and PF (FEV1 and forced vital capacity [FVC], reflecting better PF) measured up to 6 times from Y0 to Y20. Cognition was measured via Stroop test, Rey-Auditory Verbal Learning Test [RAVLT], and digit symbol substitution test [DSST], which capture executive function, verbal learning and memory, and attention and psychomotor speed, respectively; lower Stroop, and higher RAVLT and DSST scores indicate better cognition. We modeled linear, cross-sectional associations between cognition and PF at Y30 (mean age 55), and mixed models to examine associations between cognition at Y25-Y30 and longitudinal PF (both annual rate of change, and cumulative PF from Y0 to Y20).ResultsAt Y30, FEV1 and FVC were cross-sectionally associated with all 3 measures of cognition (β = 0.08-0.12, p < .01-.02). Annual change from peak FEV1/FVC ratio was associated with Stroop and DSST (β = 18.06, 95% CI = 7.71-28.40; β = 10.30, 95% CI = 0.26-20.34, respectively), but not RAVLT. Cumulative FEV1 and FVC were associated with Stroop and DSST (β = 0.07-0.12, p < .01-.02), but only cumulative FEV1 was associated with RAVLT (β = 0.07, 95% CI = 0.00-0.14).ConclusionsWe identified prospective associations between measures of PF and cognition even at middle ages, adding evidence of a prospective association between reduced PF and cognitive decline.

BackgroundMarijuana is the third most commonly used drug in the USA and efforts to legalize it for medical and recreational use are growing. Despite the increase in use, marijuana's effect on aging remains understudied and understanding the effects of marijuana on molecular aging may provide novel insights into the role of marijuana in the aging process. We therefore sought to investigate the association between cumulative and recent use of marijuana with epigenetic age acceleration (EAA) as estimated from blood DNA methylation.ResultsA random subset of participants from The Coronary Artery Risk Development in Young Adults (CARDIA) Study with available whole blood at examination years (Y) 15 and Y20 underwent epigenomic profiling. Four EAA estimates (intrinsic epigenetic age acceleration, extrinsic epigenetic age acceleration, PhenoAge acceleration, and GrimAge acceleration) were calculated from DNA methylation levels measured at Y15 and Y20. Ever use and cumulative marijuana-years were calculated from the baseline visit to Y15 and Y20, and recent marijuana use (both any and number of days of use in the last 30 days) were calculated at Y15 and Y20. Ever use of marijuana and each additional marijuana-year were associated with a 6-month (P

BackgroundHigher levels of intra-abdominal adipose tissue (IAAT) comprising visceral adipose tissue (VAT), intermuscular adipose tissue (IMAT), and liver fat are posited drivers of obesity-related chronic disease risk. Fast food is hypothesized to contribute to IAAT patterns.ObjectivesWe quantified levels of abdominal subcutaneous adipose tissue (SAT), IAAT, and odds of metabolic-associated fatty liver disease (MAFLD) in middle age according to average fast-food intake over the preceding 25 y.MethodsWe analyzed data from the Coronary Artery Risk Development in Young Adults (CARDIA) study. Participants underwent 6 clinical exams and measurements over 25 y with computed tomography-measured VAT, SAT, and IMAT (n = 3156), plus MAFLD defined by liver attenuation (≤40 Hounsfield units) and 1 metabolic abnormality at year 25 (2010, n = 3001, n cases = 302). We estimated means of VAT, SAT, IMAT, and liver attenuation at the year 25 exam according to categories of average fast-food intake over the previous 25 y adjusted for sociodemographic and lifestyle factors and logistic regression to estimate the odds ratio of MAFLD at year 25.ResultsWith higher average fast-food intake over 25 y (categorized as follows: never-1×/mo, >1×-3×/mo, 1-

The Collaborative Cohort of Cohorts for COVID-19 Research (C4R) is a national prospective study of adults comprising 14 established US prospective cohort studies. Starting as early as 1971, investigators in the C4R cohort studies have collected data on clinical and subclinical diseases and their risk factors, including behavior, cognition, biomarkers, and social determinants of health. C4R links this pre-coronavirus disease 2019 (COVID-19) phenotyping to information on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and acute and postacute COVID-related illness. C4R is largely population-based, has an age range of 18-108 years, and reflects the racial, ethnic, socioeconomic, and geographic diversity of the United States. C4R ascertains SARS-CoV-2 infection and COVID-19 illness using standardized questionnaires, ascertainment of COVID-related hospitalizations and deaths, and a SARS-CoV-2 serosurvey conducted via dried blood spots. Master protocols leverage existing robust retention rates for telephone and in-person examinations and high-quality event surveillance. Extensive prepandemic data minimize referral, survival, and recall bias. Data are harmonized with research-quality phenotyping unmatched by clinical and survey-based studies; these data will be pooled and shared widely to expedite collaboration and scientific findings. This resource will allow evaluation of risk and resilience factors for COVID-19 severity and outcomes, including postacute sequelae, and assessment of the social and behavioral impact of the pandemic on long-term health trajectories.

Background The enterosalivary nitrate-nitrite-nitric oxide (NO3-NO2-NO) pathway generates NO following oral microbiota-mediated production of salivary nitrite, potentially linking the oral microbiota to reduced cardiometabolic risk. Nitrite depletion by oral bacteria may also be important for determining the net nitrite available systemically. We examine if higher abundance of oral microbial genes favoring increased oral nitrite generation and decreased nitrite depletion is associated with a better cardiometabolic profile cross-sectionally. Methods and Results This study includes 764 adults (mean [SD] age 32 [9] years, 71% women) enrolled in ORIGINS (Oral Infections, Glucose Intolerance, and Insulin Resistance Study). Microbial DNA from subgingival dental plaques underwent 16S rRNA gene sequencing; PICRUSt2 was used to estimate functional gene profiles. To represent the different components and pathways of nitrogen metabolism in bacteria, predicted gene abundances were operationalized to create summary scores by (1) bacterial nitrogen metabolic pathway or (2) biochemical product (NO2, NO, or ammonia [NH3]) formed by the action of the bacterial reductases encoded. Finally, nitrite generation-to-depletion ratios of gene abundances were created from the above summary scores. A composite cardiometabolic Z score was created from cardiometabolic risk variables, with higher scores associated with worse cardiometabolic health. We performed multivariable linear regression analysis with cardiometabolic Z score as the outcome and the gene abundance summary scores and ratios as predictor variables, adjusting for sex, age, race, and ethnicity in the simple adjusted model. A 1 SD higher NO versus NH3 summary ratio was inversely associated with a -0.10 (false discovery rate q=0.003) lower composite cardiometabolic Z score in simple adjusted models. Higher NH3 summary score (suggestive of nitrite depletion) was associated with higher cardiometabolic risk, with a 0.06 (false discovery rate q=0.04) higher composite cardiometabolic Z score. Conclusions Increased net capacity for nitrite generation versus depletion by oral bacteria, assessed through a metagenome estimation approach, is associated with lower levels of cardiometabolic risk.

The purpose of this study was to investigate whether long-term television viewing patterns, a common sedentary behavior, in early to mid-adulthood is associated with gray matter brain volume in midlife and if this is independent of physical activity. We evaluated 599 participants (51% female, 44% black, mean age 30.3 ± 3.5 at baseline and 50.2 ± 3.5 years at follow-up and MRI) from the prospective Coronary Artery Risk Development in Young Adults (CARDIA) study. We assessed television patterns with repeated interviewer-administered questionnaire spanning 20 years. Structural MRI (3T) measures of frontal cortex, entorhinal cortex, hippocampal, and total gray matter volumes were assessed at midlife. Over the 20 years, participants reported viewing an average of 2.5 ± 1.7 h of television per day (range: 0-10 h). After multivariable adjustment, greater television viewing was negatively associated with gray matter volume in the frontal (β = - 0.77; p = 0.01) and entorhinal cortex (β = - 23.83; p = 0.05) as well as total gray matter (β = - 2.09; p = 0.003) but not hippocampus. These results remained unchanged after additional adjustment for physical activity. For each one standard deviation increase in television viewing, the difference in gray matter volume z-score was approximately 0.06 less for each of the three regions (p

BackgroundSmoking starts in early adulthood and persists throughout the life course, but the association between these trajectories and midlife cognition remains unclear.ObjectiveDetermine the association between early to midlife smoking trajectories and midlife cognition.DesignProspective cohort study.ParticipantsParticipants 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 measuresSmoking 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.ResultsFive 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.ConclusionsThe 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.

Periodontitis affects up to 50% of individuals worldwide, and 8.5% are diagnosed with diabetes. The high-comorbidity rate of these diseases may suggest, at least in part, a shared etiology and pathophysiology. Changes in oral microbial communities have been documented in the context of severe periodontitis and diabetes, both independently and together. However, much less is known about the early oral microbial markers of these diseases. We used a subset of the ORIGINS project dataset, which collected detailed periodontal and cardiometabolic information from 787 healthy individuals, to identify early microbial markers of periodontitis and its association with markers of cardiometabolic health. Using state-of-the-art compositional data analysis tools, we identified the log-ratio of Treponema to Corynebacterium bacteria to be a novel Microbial Indicator of Periodontitis (MIP), and found that this MIP correlates with poor periodontal health and cardiometabolic markers early in disease pathogenesis in both subgingival plaque and saliva.

ObjectivesThe radial artery pulse waveform is a continuous measure of pressure throughout the cardiac cycle, and thus can provide more information than just systolic and diastolic blood pressures. New indices based on a Windkessel model of the waveform, PTC1 and PTC2, are related to arterial compliance and add information for prediction of incident cardiovascular disease (coronary heart disease, stroke, myocardial infarction) but their association with heart failure is unknown.MethodsAmong 6229 adults (mean age 62 years) from four race/ethnic groups who were initially free of clinical cardiovascular disease and heart failure in 2000-2002, we evaluated the associations of baseline PTC1 and PTC2 with incident heart failure.ResultsMean ± standard deviation PTC1 and PTC2 were 394 ± 334 and 94 ± 46 ms, respectively. During a median of 15.7 years follow-up, there were 357 heart failure events (148 with reduced, 150 with preserved, and 59 with unknown ejection fraction). After adjustment for traditional risk factors, the hazard ratio for heart failure per 1 standard deviation higher PTC2 was 0.73 (95% confidence interval: 0.63--0.85). Higher PTC2 was also significantly associated with lower risk of heart failure with reduced ejection fraction (hazard ratio = 0.67; 95% confidence interval: 0.56--0.80). There was no evidence of a significant association between PTC2 and heart failure with preserved ejection fraction or between PTC1 and heart failure.ConclusionThe PTC2 measure of the radial artery pulse waveform may represent a novel phenotype related to heart failure, especially heart failure with reduced ejection fraction.

Background To determine if accelerometer measured sedentary behavior (SED), light-intensity physical activity (LPA), and moderate-to-vigorous-intensity physical activity (MVPA) in midlife is prospectively associated with cognitive function. Methods and Results Participants were 1970 adults enrolled in the CARDIA (Coronary Artery Risk Development in Young Adults) study who wore an accelerometer in 2005 to 2006 (ages 38-50 years) and had cognitive function assessments completed 5 and/or 10 years later. SED, LPA, and MVPA were measured by an ActiGraph 7164 accelerometer. Cognitive function tests included the Digit Symbol Substitution Test, Rey Auditory Verbal Learning Test, and Stroop Test. Compositional isotemporal substitution analysis examined associations of SED, LPA, and MVPA with repeated measures of the cognitive function standardized scores. In men, statistical reallocation of 30 minutes of LPA with 30 minutes of MVPA resulted in an estimated difference of SD 0.07 (95% CI, 0.01-0.14), SD 0.09 (95% CI, 0.02-0.17), and SD -0.11 (95% CI, -0.19 to -0.04) in the Digit Symbol Substitution Test, Rey Auditory Verbal Learning Test, and Stroop scores, respectively, indicating better performance. Associations were similar when reallocating time in SED with MVPA, but results were less robust. Reallocation of time in SED with LPA resulted in an estimated difference of SD -0.05 (95% CI, -0.06 to -0.03), SD -0.03 (95% CI, -0.05 to -0.01), and SD 0.05 (95% CI, 0.03- 0.07) in the Digit Symbol Substitution Test, Rey Auditory Verbal Learning Test, and Stroop scores, respectively, indicating worse performance. Associations were largely nonsignificant among women. Conclusions Our findings support the idea that for men, higher-intensity activities (MVPA) may be necessary in midlife to observe beneficial associations with cognition.

BackgroundAirflow obstruction is associated with cognitive dysfunction but studies have not assessed how emphysema, a structural phenotype of lung disease, might be associated with cognitive function independent from pulmonary function measured by spirometry. We aimed to determine the relationship between the presence of visually detectable emphysema on chest computed tomography (CT) imaging and cognitive function.MethodsWe examined 2491 participants, mean age of 50 years, from the Coronary Artery Risk Development in Young Adults study who were assessed for the presence of emphysema on chest CT imaging and had cognitive function measured 5 years later with a battery of six cognitive tests.ResultsOf those assessed, 172 (7%) had emphysema. After adjusting for age, sex, height, study centre, race, body mass index, education and smoking, visual emphysema was significantly associated with worse performance on most cognitive tests. Compared to those without emphysema, participants with emphysema performed worse on cognitive testing: 0.39 sd units lower (95% CI -0.53- -0.25) on the Montreal Cognitive Assessment, 0.27 sd units lower (95% CI -0.42- -0.12) on the Rey Auditory Verbal Learning Test, 0.29 sd units lower (95% CI -0.43- -0.14) on the Digit Symbol Substitution Test and 0.25 sd units lower (95% CI -0.42- -0.09) on letter fluency. Further adjustment for forced expiratory volume in 1 s (FEV1), peak FEV1 and annualised FEV1 decline did not attenuate these associations.ConclusionsThe presence of emphysema on chest CT is associated with worse cognitive function, independent of airflow obstruction. These data suggest that emphysema may be a novel risk factor for cognitive impairment.

ObjectiveTo examine the associations between change in plant-centered diet quality and type 2 diabetes risk and change in body size.Research design and methodsA prospective study conducted in the U.S. enrolled adults ages 18-30 years in 1985-1986 (examination year [Y0]) and followed them through 2015-2016. We analyzed the associations between change in plant-centered diet quality over 20 years (Y0-Y20) and diabetes (Y20-30; n = 2,534) and change (Y0-Y20 and Y20-30) in BMI, waist circumference (WC), and weight (n > 2,434). Plant-centered diet quality was measured using the A Priori Diet Quality Score (APDQS); a higher score favors nutritionally rich plant foods. Cox regression models were used to assess diabetes risk, and linear regression models were used to examine change in body size.ResultsDuring a mean follow-up of 9.3 (± 1.7) years, 206 case subjects with incident diabetes were observed. In multivariable analysis, participants with the largest increase in APDQS over 20 years had a 48% (95% CI 0.31-0.85; P trend < 0.001) lower risk of diabetes over the subsequent 10 years compared with participants whose score remained stable. Each 1-SD increment in APDQS over 20 years was associated with lower gains in BMI (-0.39 kg/m2; SE 0.14; P = 0.004), WC (-0.90 cm; SE 0.27; P < 0.001) and weight (-1.14 kg; SE 0.33; P < 0.001) during the same period, but not with subsequent changes.ConclusionsYoung adults who increased plant-centered diet quality had a lower diabetes risk and gained less weight by middle adulthood.

ObjectiveTo test the hypothesis that end-stage renal disease (ESRD) risk exposure during young adulthood is related to worse cognitive performance in midlife.MethodsWe included 2,604 participants from the population-based Coronary Artery Risk Development in Young Adults (CARDIA) Study (mean age 35 years, 54% women, 45% Black). Estimated glomerular filtration rate and albumin-to-creatinine ratio were measured every 5 years at year (Y) 10 through Y30. At each visit, moderate/high risk of ESRD according to the Kidney Disease: Improving Global Outcomes guidelines (estimated glomerular filtration rate 30 mg/g) was defined, totaled over examinations, and categorized into 0 episodes, 1 episode, and >1 episodes of ESRD risk. At Y30, participants underwent global and multidomain cognitive assessment. We used analysis of covariance to assess the association of ESRD risk categories with cognitive function, controlling for cardiovascular risk factors.ResultsOver the course of 20 years, 427 participants (16% of the study population) had ≥1 episodes of ESRD risk exposure. Individuals with more risk episodes had lower composite cognitive function (p < 0.001), psychomotor speed (p < 0.001), and executive function (p = 0.007). All these associations were independent of sociodemographic status and cardiovascular risk factors.ConclusionsIn this population-based longitudinal study, we show that episodes of decline in kidney function over the young-adulthood course are associated with worse cognitive performance at midlife. Preserving kidney function in young age needs to be investigated as a potential strategy to preserve cognitive function in midlife.

ObjectiveIncreasing evidence supports an association between midlife cardiovascular risk factors (CVRFs) and risk of dementia, but less is known about whether CVRFs influence cognition in midlife. We examined the relationship between CVRFs and midlife cognitive decline.MethodsIn 2,675 black and white middle-aged adults (mean age 50.2 ± 3.6 years, 57% female, 45% black), we measured CVRFs at baseline: hypertension (31%), diabetes mellitus (11%), obesity (43%), high cholesterol (9%), and current cigarette smoking (15%). We administered cognitive tests of memory, executive function, and processing speed at baseline and 5 years later. Using logistic regression, we estimated the association of CVRFs with accelerated cognitive decline (race-specific decline ≥1.5 SD from the mean change) on a composite cognitive score.ResultsFive percent (n = 143) of participants had accelerated cognitive decline over 5 years. Smoking, hypertension, and diabetes mellitus were associated with an increased likelihood of accelerated decline after multivariable adjustment (adjusted odds ratio [AOR] 1.65, 95% confidence interval [CI] 1.00-2.71; AOR 1.87, 95% CI 1.26-2.75; AOR 2.45, 95% CI 1.54-3.88, respectively), while obesity and high cholesterol were not associated with risk of decline. These results were similar when stratified by race. The likelihood of accelerated decline also increased with greater number of CVRFs (1-2 CVRFs: AOR 1.77, 95% CI 1.02-3.05; ≥3 CVRFs: AOR 2.94, 95% CI 1.64-5.28) and with Framingham Coronary Heart Disease Risk Score ≥10 (AOR 2.29, 95% CI 1.21-4.34).ConclusionsMidlife CVRFs, especially hypertension, diabetes mellitus, and smoking, are common and associated with accelerated cognitive decline at midlife. These results identify potential modifiable targets to prevent midlife cognitive decline and highlight the need for a life course approach to cognitive function and aging.

BackgroundAlthough microvascular dysfunction is known to result from diabetes, it might also lead to diabetes. Lower values of C2, a derivative of the radial artery pressure waveform, indicate microvascular dysfunction and predict hypertension and cardiovascular disease (CVD). We studied the association of C2 with incident diabetes in subjects free of overt CVD.MethodsAmong multi-ethnic participants (n = 5214), aged 45-84 years with no diabetes, C2 was derived from the radial artery pressure waveform. Incident diabetes (N = 651) was diagnosed as new fasting glucose ≥ 126 mg/dL or antidiabetic medicine over ~ 10 years. The relative incidence density (RID) for incident diabetes per standard deviation (SD) of C2 was studied during ~ 10 years follow-up using four levels of adjustment.ResultsMean C2 at baseline was 4.58 ± 2.85 mL/mmHg × 100. The RID for incident diabetes per SD of C2 was 0.90 (95% CI 0.82-0.99, P = 0.03). After adjustment for demographics plus body size, the corresponding RID was 0.81 (95% CI 0.73-0.89, P

Aims/hypothesisThe evidence for the role of contemporary dietary patterns, trends and predominant aspects of energy intake in a typical American diet and in type 2 diabetes risk is limited. Therefore, we examined the association between dietary pattern scores created to reflect the 2015 Dietary Guidelines for Americans (DGA) Scientific Report, a Palaeolithic (Palaeo) diet, a diet high in 'empty calories', and the A Priori Diet Quality Score (APDQS) (cohort reference) and type 2 diabetes risk over time.MethodsWe carried out a prospective analysis of 4719 young adult black and white men and women from the Coronary Artery Risk Development in Young Adults (CARDIA) study with repeated dietary histories collected at study years 0, 7 and 20. Using multivariable Cox proportional hazards regression models, we examined the association between time-dependent cumulative average dietary pattern scores and incident type 2 diabetes.ResultsDuring the 30 year follow-up period, 680 (14.4%) incident cases of type 2 diabetes occurred. There was no association between the 2015 DGA, Palaeo or empty calorie scores and type 2 diabetes risk in the overall population. Participants in the fourth quartile of the APDQS, reflecting a more healthful dietary pattern, had a 45% lower risk of type 2 diabetes compared with those in the lowest quartile (HR 0.55 [95% CI 0.41, 0.74]). In stratified analyses there was an inverse association for the 2015 DGA in non-smokers per SD (HR 0.86 [95% CI 0.74, 0.99]) and an inverse association for the empty calorie score in white women (HR 0.76 [95% CI 0.60, 0.96]) as well as in a subgroup analysis of the Palaeo index of participants who maintained a high score over 20 years (per SD, HR 0.59 [95% CI 0.39, 0.88]).Conclusions/interpretationHigher levels of the APDQS, which largely aligns with the 2015 DGA, were strongly inversely associated with 30 year type 2 diabetes risk in the CARDIA cohort; the results from the other patterns were nuanced and need to be considered in the context of the study and potential biases.

BackgroundObese adults who are free from metabolic risk factors may develop risk factors over time. Our objective was to characterize development of obesity and duration of metabolically healthy obese (MHO) over 30 years.MethodsParticipants in CARDIA who developed obesity (BMI ≥ 30 kg/m2) at follow-up exams during years 7, 10, 15, 20, 25, and 30 were analyzed. MHO was defined as obese and having 0 or 1 risk factor: ≥SBP/DBP 130/85 mmHg; fasting glucose ≥100 mg/dL/5.55 mmol/L; fasting triglycerides (≥150 mg/dL/1.69 mmol/L); and HDL-C (men

BackgroundEpidemiological evidence has demonstrated a positive association between artificially sweetened beverage (ASB) and sugar-sweetened beverage (SSB) consumption and type 2 diabetes (T2D) risk. However, research informing this topic in young adults is limited.ObjectiveThis study examined the association between ASB, SSB, and total sweetened beverage (TSB; combined ASB and SSB) consumption and T2D risk in young adults.MethodsA prospective analysis of 4719 Black and White men and women aged 18-30 y at baseline was conducted from the Coronary Artery Risk Development in Young Adults (CARDIA) study. Each participant's beverage intake was assessed using the CARDIA Diet History at baseline and at study Years 7 and 20. Multivariable Cox proportional hazards regression models were used to examine cumulative average ASB, SSB, and TSB intakes and risk of T2D.ResultsDuring the 30-y follow-up period, 680 participants developed T2D. ASB consumption was associated with a 12% greater risk of T2D per serving/day (HR 1.12, 95% CI 1.04-1.20) in a model adjusted for lifestyle factors, diet quality, and dieting behavior. Further adjustments for baseline BMI (HR 1.07, 95% CI 0.99-1.14) and weight change during follow-up (HR 1.04, 95% CI 0.97-1.12) attenuated the association. SSB and TSB consumption as continuous variables per 1 serving/day of intake were associated with 6% and 5% increased risks of T2D, respectively (HRSSB 1.06, 95% CI 1.01-1.10; HRTSB 1.05, 95% CI 1.01-1.09), in the model accounting for lifestyle factors, dieting behavior, baseline BMI, and weight change. Results were consistent when the exposures were modeled in categories of consumption and quintiles.ConclusionsIn young adults, long-term ASB, SSB, and TSB consumption were associated with increased risks of T2D. However, the estimates for ASB were attenuated when accounting for weight changes.

ObjectiveTo investigate whether dietary patterns (Mediterranean diet [MedDiet], Dietary Approaches to Stop Hypertension [DASH], and A Priori Diet Quality Score [APDQS]) during adulthood are associated with midlife cognitive performance.MethodsWe studied 2,621 Coronary Artery Risk Development in Young Adults (CARDIA) participants; 45% were black, 57% were female, and mean age was 25 ± 3.5 years at baseline (year 0). Mean diet scores were calculated from diet history at baseline, year 7, and year 20 (mean age 25, 32, and 45 years, respectively). Cognitive function was assessed at years 25 and 30 (mean age 50 and 55 years, respectively). Linear models were used to examine association between tertiles of diet score and change in composite cognitive function and cognitive z scores (verbal memory [Rey Auditory Verbal Learning Test], processing speed [Digit Symbol Substitution Test], and executive function [Stroop Interference test]) and the Montreal Cognitive Assessment (MoCA) at year 30.ResultsDASH was not associated with change in cognitive performance. Higher MedDiet and APDQS scores were associated with less decline in cognitive function (MedDiet: low -0.04, middle 0.03, high 0.03, p = 0.03; APDQS: low -0.04, middle -0.00, high 0.06, p < 0.01) and Stroop Interference (MedDiet: low 0.09, middle -0.06, high -0.03; APDQS: low 0.10, middle 0.01, high -0.09, both p < 0.01). Odds ratios (95% confidence interval) for poor global cognitive function (≥1 SD below mean MoCA score) comparing extreme tertiles of diet scores were 0.54 (0.39-0.74) for MedDiet, 0.48 (0.33-0.69) for APDQS, and 0.89 (0.68-1.17) for DASH.ConclusionGreater adherence to MedDiet and APDQS dietary patterns during adulthood was associated with better midlife cognitive performance. Additional studies are needed to define the combination of foods and nutrients for optimal brain health across the life course.

RationaleChronic lower respiratory diseases (CLRDs), including chronic obstructive pulmonary disease (COPD) and asthma, are the fourth leading cause of death. Prior studies suggest that albuminuria, a biomarker of endothelial injury, is increased in patients with COPD.ObjectivesTo test whether albuminuria was associated with lung function decline and incident CLRDs.MethodsSix U.S. population-based cohorts were harmonized and pooled. Participants with prevalent clinical lung disease were excluded. Albuminuria (urine albumin-to-creatinine ratio) was measured in spot samples. Lung function was assessed by spirometry. Incident CLRD-related hospitalizations and deaths were classified via adjudication and/or administrative criteria. Mixed and proportional hazards models were used to test individual-level associations adjusted for age, height, weight, sex, race/ethnicity, education, birth year, cohort, smoking status, pack-years of smoking, renal function, hypertension, diabetes, and medications.Measurements and main resultsAmong 10,961 participants with preserved lung function, mean age at albuminuria measurement was 60 years, 51% were never-smokers, median albuminuria was 5.6 mg/g, and mean FEV1 decline was 31.5 ml/yr. For each SD increase in log-transformed albuminuria, there was 2.81% greater FEV1 decline (95% confidence interval [CI], 0.86-4.76%; P = 0.0047), 11.02% greater FEV1/FVC decline (95% CI, 4.43-17.62%; P = 0.0011), and 15% increased hazard of incident spirometry-defined moderate-to-severe COPD (95% CI, 2-31%, P = 0.0021). Each SD log-transformed albuminuria increased hazards of incident COPD-related hospitalization/mortality by 26% (95% CI, 18-34%, P

ObjectiveTo determine whether intraindividual variability in fasting glucose (FG) below the threshold of diabetes is associated with cognitive function in middle adulthood beyond increasing FG.Research design and methodsWe studied 3,307 CARDIA (Coronary Artery Risk Development in Young Adults) Study participants (age range 18-30 years and enrolled in 1985-1986) at baseline and calculated two measures of long-term glucose variability: the coefficient of variation about the mean FG (CV-FG) and the absolute difference between successive FG measurements (average real variability [ARV-FG]) before the onset of diabetes over 25 and 30 years of follow-up. Cognitive function was assessed at years 25 (2010-2011) and 30 (2015-2016) with the Digit Symbol Substitution Test (DSST), Rey-Auditory Verbal Learning Test (RAVLT), Stroop Test, Montreal Cognitive Assessment, and category and letter fluency tests. We estimated the association between glucose variability and cognitive function test score with adjustment for clinical and behavioral risk factors, mean FG level, change in FG level, and diabetes development, medication use, and duration.ResultsAfter multivariable adjustment, 1-SD increment of CV-FG was associated with worse cognitive scores at year 25: DSST, standardized regression coefficient -0.95 (95% CI -1.54, -0.36); RAVLT, -0.14 (95% CI -0.27, -0.02); and Stroop Test, 0.49 (95% CI 0.04, 0.94). Findings were similar between CV-FG with each cognitive test score at year 30 and when we used an alternative measure of variability (ARV-FG) that captures variability in successive FG values.ConclusionsHigher intraindividual FG variability during young adulthood below the threshold of diabetes was associated with worse processing speed, memory, and language fluency in midlife independent of FG levels.

The role that vitamin D plays in pulmonary function remains uncertain. Epidemiological studies reported mixed findings for serum 25-hydroxyvitamin D (25(OH)D)-pulmonary function association. We conducted the largest cross-sectional meta-analysis of the 25(OH)D-pulmonary function association to date, based on nine European ancestry (EA) cohorts (n 22 838) and five African ancestry (AA) cohorts (n 4290) in the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium. Data were analysed using linear models by cohort and ancestry. Effect modification by smoking status (current/former/never) was tested. Results were combined using fixed-effects meta-analysis. Mean serum 25(OH)D was 68 (sd 29) nmol/l for EA and 49 (sd 21) nmol/l for AA. For each 1 nmol/l higher 25(OH)D, forced expiratory volume in the 1st second (FEV1) was higher by 1·1 ml in EA (95 % CI 0·9, 1·3; P

BackgroundMany studies have focused on the association between a single blood pressure (BP) measurement and risk for adverse outcomes. However, the association of BP trajectories during young adulthood with subsequent decline in kidney function has not been well defined.Study designObservational cohort study.Setting & participants3,429 participants in the Coronary Artery Risk Development in Young Adulthood (CARDIA) Study enrolled between the ages of 18 and 30 years.PredictorsBP slope during the first 10 years of participation in CARDIA, derived from linear mixed models incorporating all repeated BP measures.OutcomeDecline in estimated glomerular filtration rate (eGFR) during the interval between years 10 and 20 of CARDIA participation using cystatin C measured at years 10, 15, and 20.ResultsMean age of CARDIA participants at year 0 was 25.1 years, 56% were women, and 53% were white. Every 10-mmHg higher level of systolic (SBP) and diastolic BP (DBP) in year 10 was associated with change in eGFR of -0.09 (95% CI, -0.13 to -0.06) and -0.07 (95% CI, -0.12 to -0.03) mL/min/1.73m2 per year, respectively. Every 10-mmHg increase in SBP slope between years 0 and 10 was associated with a subsequent -0.52 (95% CI, -1.02 to -0.03) mL/min/1.73m2 per year change in kidney function after adjustment for comorbid conditions and SBP at year 10. Similarly, every 10-mmHg increase in DBP slope between years 0 and 10 was associated with a subsequent change in kidney function of -0.65 (95% CI, -1.23 to -0.07) mL/min/1.73m2 per year, after adjustment for comorbid conditions and DBP in year 10.LimitationsObservational design.ConclusionsDuring young adulthood, increasing SBP and DBP are associated with a higher rate of subsequent kidney function decline, independent of BP measured at the beginning of eGFR assessment.

BackgroundPlatelet activation reduces pulmonary microvascular blood flow and contributes to inflammation; these factors have been implicated in the pathogenesis of COPD and emphysema. We hypothesized that regular use of aspirin, a platelet inhibitor, would be associated with a slower progression of emphysema-like lung characteristics on CT imaging and a slower decline in lung function.MethodsThe Multi-Ethnic Study of Atherosclerosis (MESA) enrolled participants 45 to 84 years of age without clinical cardiovascular disease from 2000 to 2002. The MESA Lung Study assessed the percentage of emphysema-like lung below -950 Hounsfield units ("percent emphysema") on cardiac (2000-2007) and full-lung CT scans (2010-2012). Regular aspirin use was defined as 3 or more days per week. Mixed-effect models adjusted for demographics, anthropometric features, smoking, hypertension, angiotensin-converting enzyme inhibitor or angiotensin II-receptor blocker use, C-reactive protein levels, sphingomyelin levels, and scanner factors.ResultsAt baseline, the 4,257 participants' mean (± SD) age was 61 ± 10 years, 54% were ever smokers, and 22% used aspirin regularly. On average, percent emphysema increased 0.60 percentage points over 10 years (95% CI, 0.35-0.94). Progression of percent emphysema was slower among regular aspirin users compared with patients who did not use aspirin (fully adjusted model: -0.34% /10 years, 95% CI, -0.60 to -0.08; P = .01). Results were similar in ever smokers and with doses of 81 and 300 to 325 mg and were of greater magnitude among those with airflow limitation. No association was found between aspirin use and change in lung function.ConclusionsRegular aspirin use was associated with a more than 50% reduction in the rate of emphysema progression over 10 years. Further study of aspirin and platelets in emphysema may be warranted.

BackgroundWhile changes in blood pressure (BP) are independently associated with cardiovascular events, less is known about the association between changes in BP and subsequent changes in renal function in adults with an estimated glomerular filtration rate (eGFR) of >60 ml/min/1.73 m2.MethodsThe present study included 3,920 participants in the Multi-Ethnic Study of Atherosclerosis (MESA) study who had ≥2 BP measurements during the first 5 years of MESA and had eGFR measurements at both year 5 and 10. Change in BP was estimated as the annualized slope of BP between year 0 and 5 based on linear mixed models (mean number of measurements = 4.0). Participants were then grouped into 1 of 3 categories based on the distribution of systolic BP (SBP), diastolic BP (DBP), and pulse pressure (PP) change (top 20%, middle 21-79%, bottom 20%). We calculated eGFR from cystatin C (ml/min/1.73 m2), estimated annual change in eGFR (ml/min/1.73 m2/year), and defined rapid kidney function decline as a >30% decrease in eGFR from year 5 to 10. We used multivariable logistic regression adjusting for year 0 demographic and clinical characteristics, including eGFR and BP, to determine associations of BP change with rapid kidney function decline.ResultsMedian age was 59 [interquartile range (IQR): 52, 67] and median eGFR at year 0 was 95.5 (IQR: 81.7, 105.9) ml/min/1.73 m2. Median SBP at year 0 was 111, 121, and 147 mm Hg for increasing, stable, and decreasing SBP change, respectively. Increasing SBP and widening PP change were each associated with higher odds of rapid kidney function decline compared with stable SBP and PP groups, respectively [odds ratio, OR 1.7 (95% confidence interval, CI 1.3, 2.4) for SBP; OR 1.4 (95% CI 1.1, 1.9) for PP]. Decreasing SBP was associated with rapid kidney function decline after adjusting for all covariates except for year 0 BP [OR 1.4 (95% CI 1.0, 1.8)], but this association was no longer statistically significant after adjustment for year 0 BP. There were no significant associations between DBP change and rapid decline in the fully adjusted models. Similar findings were seen with annual change in eGFR.ConclusionsIncreasing SBP and widening PP over time were associated with greater risk for accelerated kidney function decline even at BP levels below established hypertension thresholds.

Evidence suggests that time spent engaging in sedentary behaviors is associated with a greater risk of adverse cardiometabolic outcomes. We investigated the cross-sectional associations of 6 unique sedentary tasks (watching television, using the computer, completing paperwork, reading, talking on the telephone, and sitting in a car) with cardiometabolic risk factors, and also examined the effect of replacing one type of sedentary behavior with another on the level of cardiometabolic risk. Participants consisted of 3,211 individuals from the Coronary Artery Risk Development in Young Adults Study who visited the clinic between 2010 and 2011. Linear regression models examined the independent and joint associations of sedentary tasks with a composite cardiometabolic risk score, as well as with individual cardiometabolic risk factors (waist circumference, blood pressure, fasting glucose, insulin, triglycerides, and high density lipoprotein cholesterol) after adjusting for physical activity and other covariates. Replacing 2 hours of television viewing with 2 hours spent performing any other sedentary activity was associated with a lower cardiometabolic risk score of 0.06-0.09 standard deviations (all 95% confidence intervals: -0.13, -0.02). No other replacements of one type of sedentary task for another were significant. Study findings indicate that television viewing has a more adverse association with cardiometabolic risk factors than other sedentary behaviors.

BackgroundClinical and epidemiological studies of older persons have implicated clusterin in Alzheimer's disease (AD) pathogenesis. In the context of identifying early biomarkers of risk, we examined associations of plasma clusterin and characteristics of AD in middle-aged individuals from the community.Materials and methodsSubjects were 639 cognitively normal individuals (mean age 50 ± 3.5) from the Coronary Artery Risk Development in Young Adults (CARDIA) Brain MRI sub-study. Clusterin was quantified using ELISA (mean 255± 31 ng/ml). Associations were assessed between clusterin and volumes of brain regions known to atrophy in early AD, including entorhinal cortex (ECV), hippocampus (HV), and medial temporal lobe (MTLV) volumes (cm3). Total brain volume (TBV) and volumes of structures affected in later AD were examined for comparison.ResultsIn multivariable models, higher clusterin had a negative non-linear association with ECV (combined left and right hemispheres), and this association was influenced by the highest clusterin levels. Compared to mean clusterin, 1 and 2 standard deviation (SD) level increases in clusterin were associated with -2.1% (95% CI: -3.3,-0.9) and -7.3% (95% CI: -11.3,-3.3) lower ECV, respectively. Similar relationships were observed between clusterin and HV, although the relationship was stronger for left-side HV than the right-side. However, the association was not significant after adjusting for covariates. Negative non-linear associations between clusterin and MTLV were strongest for the left side: compared to mean clusterin, 1 and 2 SD level increases in clusterin were associated with -0.9% (95% CI: -1.9, 0.1) and -3.7% (95% CI: -7.1, -0.3) lower MTLV. There were no significant associations between clusterin and brain structures affected in later AD.ConclusionsIn middle-aged adults unselected for AD, plasma clusterin was associated with lower volume of the entorhinal cortex, an area that atrophies early in AD. Clusterin could be informative as part of a multi-component preclinical marker for AD.

ObjectiveWe examined imaging surrogates of white matter microstructural abnormalities which may precede white matter lesions (WML) and represent a relevant marker of cerebrovascular injury in adults in midlife.MethodsIn 698 community-dwelling adults (mean age 50 years ±3.5 SD) from the Coronary Artery Risk Development in Young Adults (CARDIA) Brain MRI sub-study, WML were identified on structural MR and fractional anisotropy (FA), representing WM microstructural integrity, was derived using Diffusion Tensor Imaging. FA and WML maps were overlaid on a parcellated T1-template, based on an expert-delineated brain atlas, which included 42 WM tract ROIs. Analyses occurred in stages: 1) WML were quantified for the different tracts (i.e., frequency, volume, volume relative to tract size); 2) the interdependence of FA in normal appearing WM (NAWM) and WML was examined across tracts; 3) associations of NAWM FA and hypertension status were assessed controlling for WML volume. In the latter analysis, both overall hypertension (i.e. hypertension vs. normotension and prehypertension vs. normotension) and hypertension categorized by antihypertensive treatment status (yes/no) and blood pressure control (e.g., diastolic

BackgroundHigher blood pressure during young adulthood may increase cardiovascular and kidney disease risk later in life. This study examined the association of cumulative systolic blood pressure (SBP) exposure during young adulthood through midlife with urine albumin-to-creatinine ratios (ACR) measured during midlife.MethodsWe used data from the Coronary Artery Risk Development in Young Adults (CARDIA) study, a biracial cohort recruited in 4 urban areas during years 1985-1986. Cumulative SBP was calculated as the average SBP between 2 exams multiplied by years between exams over 20 year years. ACR was measured 20 years after baseline when participants were age 43-50 years (midlife). A generalized additive model was used to examine the association of log ACR as a function of cumulative SBP with adjustment for covariates including SBP measured concurrently with ACR.ResultsCumulative SBP ranged from a low of 1,671 to a high of 3,260 mm Hg. Participants in the highest cumulative SBP quartile were more likely to be male (61.4% vs. 20.7%; P < 0.001), Black (61.5% vs. 25.6%; P < 0.001) and have elevated ACR (18.7% vs. 4.8%; P < 0.001) vs. lowest quartile. Spline regression curves of ACR vs. cumulative SBP demonstrated an inflection point in ACR with cumulative SBP levels >2,350 mm Hg with linear increases in ACR above this threshold. Adjusted geometric mean ACR values were significantly higher with cumulative SBP ≥2,500 vs.

BackgroundExposures to cholinesterase inhibitor pesticides (e.g. organophosphates) have been associated with children's neurobehavioral alterations, including attention deficit and impulsivity. Animal studies have observed transient alterations in neurobehavioral performance in relation to cholinesterase inhibitor pesticide exposures; however, limited evidence exists regarding transient effects in humans.MethodsWe estimated the associations between neurobehavioral performance and time after Mother's Day flower harvest (the end of a heightened pesticide usage period) among 308 4-to 9-year-old children living in floricultural communities in Ecuador in 2008 who participated in the ESPINA study. Children's neurobehavior was examined once (NEPSY-II: 11 subtests covering 5 domains), between 63 and 100days (SD: 10.8days) after Mother's Day harvest (blood acetylcholinesterase activity levels can take 82days to normalize after irreversible inhibition with organophosphates).ResultsThe mean (SD) neurobehavioral scaled scores across domains ranged from 6.6 (2.4) to 9.9 (3.3); higher values reflect greater performance. Children examined sooner after Mother's Day had lower neurobehavioral scores than children examined later, in the domains of (score difference per 10.8days, 95%CI): Attention/Inhibitory Control (0.38, 0.10-0.65), Visuospatial Processing (0.60, 0.25-0.95) and Sensorimotor (0.43, 0.10-0.77). Scores were higher with longer time post-harvest among girls (vs. boys) in Attention/Inhibitory Control.ConclusionsOur findings, although cross-sectional, are among the first in non-worker children to suggest that a peak pesticide use period may transiently affect neurobehavioral performance, as children examined sooner after the flower harvest had lower neurobehavioral performance than children examined later. Studies assessing pre- and post-exposure measures are needed.

Treatments for mucopolysaccharidoses (MPSs) have increased longevity, but cardiovascular disease causes mortality in a significant percentage of survivors. Markers must be developed to predict MPS cardiac risk and monitor efficacy of investigational therapies.MPS patients underwent carotid artery ultrasonography from which carotid intima-media thickness (cIMT) and three measures of arterial stiffness were calculated: carotid artery distensibility (cCSD), compliance (cCSC), and incremental elastic modulus (cIEM). MPS carotid measurements were compared to corresponding data from pediatric and adult healthy cohorts. 33 MPS patients (17 MPS I, 9 MPS II, 4 MPS IIIA, and 3 MPS VI; mean age 12.5 ± 4.7 years), 560 pediatric controls (age 13.1 ± 4.0 years), and 554 adult controls (age 39.2 ± 2.2 years) were studied. Age and sex-adjusted aggregate MPS cIMT (0.56 ± 0.05 mm) was significantly greater than both pediatric (+0.12 mm; 95% CI +0.10 to +0.14 mm) and adult (+0.10 mm; 95% CI +0.06 to +0.14 mm) control cohorts; similar findings were observed for all MPS subtypes. Mean MPS cIMT approximated the 80th percentile of the adult cohort cIMT. MPS patients also demonstrated significantly increased adjusted arterial stiffness measurements, evidenced by reduced cCSD, cCSC, and increased cIEM, compared to pediatric and adult control cohorts. Regardless of treatment, MPS patients demonstrate increased cIMT and arterial stiffness compared to healthy pediatric and adult controls. These data suggest that relatively young MPS patients demonstrate a "structural vascular age" of at least 40 years old.

PurposeWe examined whether sedentary lifestyle habits and physical activity level are associated with abdominal visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), intermuscular adipose tissue (IMAT), and liver attenuation, independently of one another and potential confounders.MethodsThis study analyzed 3010 African American and Caucasian men and women, 42-59 yr old, from the Coronary Artery Risk Development in Young Adults (CARDIA) study, who completed multiple-slice abdominal computed tomography in 2010-2011. Participants reported average hours per day sitting (television, computing, paperwork, music, telephone, and car). Physical activity was assessed with the CARDIA physical activity history. VAT, SAT, IMAT, and liver attenuation were estimated from computed tomography. Multivariable general linear regression models regressed means of fat depots on total sedentary time, task-specific sedentary time, and total physical activity.ResultsTelevision viewing was positively, and physical activity inversely, associated with fat depots. For each 1 SD increment in television viewing (1.5 h·d), VAT, SAT, and IMAT were greater by 3.5, 3.4, and 3.9 cm, respectively (P < 0.03 for all). For each 1 SD increment in physical activity (275 exercise units), VAT, SAT, and IMAT were lower by 7.6, 6.7, and 8.1 cm, respectively, and liver attenuation was greater (indicating more liver fat) by 0.5 Hounsfield units (P < 0.01 for all). Total sedentary time was associated with VAT, IMAT, and liver attenuation in White men only after controlling for physical activity, SAT, and other potential confounders (P ≤ 0.01 for all). No other task-specific sedentary behaviors were associated with fat depots.ConclusionsSedentary behaviors, particularly television viewing, and physical activity levels have distinct, independent associations with fat deposition.

Little is known regarding the epigenetic basis of atherosclerosis. Here we present the CD14+ blood monocyte transcriptome and epigenome signatures associated with human atherosclerosis. The transcriptome signature includes transcription coactivator, ARID5B, which is known to form a chromatin derepressor complex with a histone H3K9Me2-specific demethylase and promote adipogenesis and smooth muscle development. ARID5B CpG (cg25953130) methylation is inversely associated with both ARID5B expression and atherosclerosis, consistent with this CpG residing in an ARID5B enhancer region, based on chromatin capture and histone marks data. Mediation analysis supports assumptions that ARID5B expression mediates effects of cg25953130 methylation and several cardiovascular disease risk factors on atherosclerotic burden. In lipopolysaccharide-stimulated human THP1 monocytes, ARID5B knockdown reduced expression of genes involved in atherosclerosis-related inflammatory and lipid metabolism pathways, and inhibited cell migration and phagocytosis. These data suggest that ARID5B expression, possibly regulated by an epigenetically controlled enhancer, promotes atherosclerosis by dysregulating immunometabolism towards a chronic inflammatory phenotype.The molecular mechanisms mediating the impact of environmental factors in atherosclerosis are unclear. Here, the authors examine CD14+ blood monocyte's transcriptome and epigenome signatures to find differential methylation and expression of ARID5B to be associated with human atherosclerosis.

ObjectiveHigher circulating concentrations of cellular adhesion molecules (CAMs) can be used as markers of endothelial dysfunction. Given that the brain is highly vascularized, we assessed whether endothelial function is associated with cognitive performance.MethodWithin the Coronary Artery Risk Development in Young Adults (CARDIA) Study, excluding N = 54 with stroke before year 25, we studied CAMs among N = 2,690 black and white men and women in CARDIA year 7 (1992-1993, ages 25-37) and N = 2,848 in CARDIA year 15 (2000-2001, ages 33-45). We included subjects with levels of circulating soluble CAMs measured in year 7 or 15 and cognitive function testing in year 25 (2010-2011, ages 43-55). Using multiple regression analysis, we evaluated the association between CAMs and year 25 cognitive test scores: Rey Auditory Verbal Learning Test (RAVLT, memory), Digit Symbol Substitution Test (DSST, speed of processing), and the Stroop Test (executive function).ResultAll CAM concentrations were greater in year 15 vs. year 7. Adjusting for age, race, sex, education, smoking, alcohol, diet, physical activity, participants in the fourth vs. the first quartile of CARDIA year 7 of circulating intercellular adhesion molecule-1 (ICAM-1) scored worse on RAVLT, DSST, and Stroop Test (p ≤ 0.05) in CARDIA year 25. Other CAMs showed little association with cognitive test scores. Findings were similar for ICAM-1 assessed at year 15. Adjustment for possibly mediating physical factors attenuated the findings.ConclusionHigher circulating ICAM-1 at average ages 32 and 40 was associated with lower cognitive skills at average age 50. The study is consistent with the hypothesis that endothelial dysfunction is associated with worse short-term memory, speed of processing, and executive function.

BackgroundEvaluation of impaired left ventricular (LV) filling has focused on intrinsic causes of LV dysfunction; however, pulmonary vascular changes may contribute to reduced LV filling and dyspnea. We hypothesized that lower total pulmonary vascular volume (TPVV) on computed tomography (CT) would be associated with dyspnea and decrements in LV end-diastolic volume, particularly among ever-smokers.MethodsThe Multi-Ethnic Study of Atherosclerosis recruited adults without clinical cardiovascular disease in 2000-02. In 2010-12, TPVV was ascertained as the volume of arteries and veins in the lungs detectable on non-contrast chest CT (vessels ≥1 mm diameter). Cardiac measures were assessed by magnetic resonance imaging (MRI). Dyspnea was self-reported.ResultsOf 2303 participants, 53% had ever smoked cigarettes. Among ever-smokers, a lower TPVV was associated with a lower LV end-diastolic volume (6.9 mL per SD TPVV), stroke volume, and cardiac output and with dyspnea (all P-values

Conflicting results have been reported concerning a relationship between smoking and serum PTH. Our study objective was to examine whether smoking was associated with serum PTH independent of correlates of PTH among young adults, and explore potential mechanisms. This was a cross-sectional study of healthy individuals, 24-36 years old, examined during 1992 through 1993 in California, USA (a subset of Coronary Artery Risk Development in Young Adults study). Linear regression was used to obtain adjusted means of PTH according to smoking habit (current, former, never). Biomarkers for calcium metabolism and bone turnover (including serum concentrations of osteocalcin, bone-specific alkaline phosphatase, and 24-hour urinary excretion of calcium) and bone mineral density were similarly compared by smoking. 376 participants were analyzed (171 women, 181 black). Over half reported never smoking. We observed lower PTH in current smokers compared to non-smokers and found no evidence of an interaction by race and sex. PTH was lowest in current smokers, intermediate in former smokers, and highest in never smokers (geometric mean PTH: 23.6, 26.7, 27.4 pg/mL, respectively: P for trend, 0.006) after adjusting for potential confounders including calcium intake. Among the biomarkers, serum osteocalcin concentration and 24-hour urinary excretion of calcium were lowest in current smokers. We observed no smoking-related difference in bone mineral density. In this community-based sample of young adult men and women, smoking was associated with significantly lower PTH concentration. The mechanism and clinical implication of the finding, however, remains uncertain.