A Clinical Tool to Relate Youth Risk Factors to Adult Cardiovascular Events and Type 2 Diabetes: The International Childhood Cardiovascular Cohort Consortium.

OBJECTIVE: To translate data relating childhood cardiovascular (CV) risk factors and adult CV disease and type 2 diabetes mellitus (T2DM) to clinically actionable values. STUDY DESIGN: This was a prospective observational study (n = 38 589) in the International Childhood Cardiovascular Cohort Consortium. Children at age 3 through 19 years were enrolled in the 1970s and 1980s and followed for more than 30 years. Five childhood CV risk factors (smoking, body mass index [BMI], systolic blood pressure, triglycerides, and total cholesterol) were related to adult CV events. Secondary analyses in a subset included low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, glucose, and insulin level. Age- and sex-specific z scores were calculated for each risk factor, and a combined-risk z score was calculated by averaging z scores for the 5 key CV risk factors. Risk factor z scores were back-transformed to natural units for clinical interpretation, with hazard ratios for adult CV events presented in color-coded tables (green: no increased risk; orange: 1.4 to <2.0-fold increased risk; red: at least doubling of risk). Risk levels for development of adult T2DM on the basis of BMI, glucose, and insulin were similarly calculated and presented. RESULTS: Increased risk for CV events was observed at levels lower than currently defined abnormal clinical thresholds except for TC. Doubling of risk was observed at high normal levels just below the clinical cut point for abnormality. Risk for adult T2DM began at levels of BMI and glucose currently considered normal. CONCLUSIONS: On the basis of data showing significant relationships between childhood CV risk factors and adult CV events and T2DM, this study shows that risk in childhood begins below levels currently considered normal.

Associations of disordered eating and unhealthy weight control behaviors with cardiovascular health: The coronary artery risk development in young adults study.

OBJECTIVE: Few studies have investigated disordered eating and unhealthy weight control behaviors and cardiovascular health (CVH) outside of adolescence and early adulthood. We examined the cross-sectional and prospective associations of these behaviors and CVH in middle adulthood. METHOD: A total of 2,095 Coronary Artery Risk Development in Young Adults participants were assessed at Year 10 (Y10, 1995-1996) and Year 30 (Y30, 2015-2016). The Y10-administered Questionnaire on Eating and Weight Patterns-Revised was used to create the problematic relationship to eating and food (PREF) score (range 0-8). Higher scores indicated greater disordered eating and/or unhealthy weight control behaviors across eight components. PREF was modeled categorically: 0-1 (reference), 2-3, and 4-8. Diet, physical activity, smoking, blood pressure, cholesterol, glucose, and body mass index (BMI) were measured at Y10 and Y30 (diet at Y7 and Y20) and used to define CVH. CVH was modeled categorically: poor-to-intermediate (0-9) and ideal (10-14; reference). Logistic regression was used to evaluate associations between PREF and CVH categories and components. RESULTS: PREF 4-8 was associated with Y10 poor-to-intermediate CVH (OR = 2.35, 95% confidence interval (CI) [1.78, 3.10]) but not Y30 (OR = 1.34, 95% CI [0.96, 1.87]) compared to PREF 0-1. PREF 2-3 was not associated with Y10 or Y30 CVH. Individual PREF components were not uniformly associated with individual CVH components, although all PREF components were associated with Y10 poor-to-intermediate BMI. CONCLUSIONS: Disordered eating and unhealthy weight control behaviors are cross-sectionally but not prospectively associated with poorer CVH during middle age. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Choline Metabolites and 15-Year Risk of Incident Diabetes in a Prospective Cohort of Adults: Coronary Artery Risk Development in Young Adults (CARDIA) Study.

OBJECTIVE: The potential for choline metabolism to influence the development of diabetes has received increased attention. Previous studies on circulating choline metabolites and incident diabetes have been conducted in samples of older adults, often with a high prevalence of risk factors. RESEARCH DESIGN AND METHODS: Participants were from year 15 of follow-up (2000-2001) in the Coronary Artery Risk Development in Young Adults (CARDIA) Study (n = 3,133, aged 33-45 years) with plasma choline metabolite (choline, betaine, and trimethylamine N-oxide [TMAO]) data. We quantified associations between choline metabolites and 15-year risk of incident diabetes (n = 387) among participants free of diabetes at baseline using Cox proportional hazards regression models adjusted for sociodemographics, health behaviors, and clinical variables. RESULTS: Betaine was inversely associated with 15-year risk of incident diabetes (hazard ratio 0.76 [95% CI 0.67, 0.88] per 1-SD unit betaine), and TMAO was positively associated with 15-year risk of incident diabetes (1.11 [1.01, 1.22] per 1-SD unit). Choline was not significantly associated with 15-year risk of incident diabetes (1.05 [0.94, 1.16] per 1-SD). CONCLUSIONS: Our findings are consistent with other published literature supporting a role for choline metabolism in diabetes. Our study extends the current literature by analyzing a racially diverse population-based cohort of early middle-aged individuals in whom preventive activities may be most relevant.

The Relationship of Cardiorespiratory Fitness, Physical Activity, and Coronary Artery Calcification to Cardiovascular Disease Events in CARDIA Participants.

AIMS: Moderate-to-vigorous-intensity physical activity (MVPA), cardiorespiratory fitness (CRF), and coronary artery calcification (CAC) are associated with cardiovascular disease (CVD) risk. While a U-shaped relationship between CRF or MVPA and CAC has been reported, the presence of CAC among highly fit individuals might be benign. We examined interactive associations of CRF or MVPA and CAC with outcomes and evaluated the relationship of CRF and MVPA to CAC incidence. METHODS: CARDIA participants with CAC assessed in 2005-06 were included (n=3,141, mean age 45). MVPA was assessed by self-report and accelerometer. CRF was estimated with a maximal graded exercise test. Adjudicated CVD events and mortality data were obtained through 2019. CAC was reassessed in 2010-11. Cox models were constructed to assess hazard ratios (HRs) for CVD, coronary heart disease (CHD), and mortality in groups defined by CAC presence/absence and lower/higher CRF or MVPA levels. Logistic models were constructed to assess associations with CAC incidence. Adjustment was made for sociodemographic and CVD risk factors. RESULTS: Relative to participants with no CAC and higher CRF, the adjusted HRs for CVD were 4.68 for CAC and higher CRF, 2.22 for no CAC and lower CRF, and 3.72 for CAC and lower CRF. For CHD, the respective HRs were 9.98, 2.28, and 5.52. For mortality, the HRs were 1.15, 1.58, and 3.14, respectively. Similar findings were observed when MVPA, measured either by self-report or accelerometer, was substituted for CRF. A robust inverse association of CRF and accelerometer-derived MVPA with CAC incidence was partly accounted for by adjusting for CVD risk factors. CONCLUSIONS: In middle-aged adults, CRF and MVPA demonstrated an inverse association with CAC incidence but did not mitigate the increased cardiovascular risk associated with CAC, indicating that CAC is not benign in individuals with higher CRF or MVPA levels.

This study explored the relationship between physical fitness, physical activity, and coronary artery calcification (CAC) in predicting heart disease risk. CAC is the build-up of calcium deposits in the coronary arteries, indicating the presence of atherosclerosis. Involving approximately 3,000 adults with an average age of 45, the study measured physical activity through self-report and accelerometer, fitness via treadmill tests, and CAC at two time points, five years apart. Being fit and active was associated with a lower chance of developing new CAC. Similarly, higher fitness and physical activity levels were associated with a lower risk of experiencing heart disease events and death over 13 years of follow-up. In contrast, the presence of CAC strongly predicted elevated heart disease risk and death. Furthermore, having CAC eliminated the heart health benefits of being physically active or fit. The study concludes that while being fit and active is beneficial, CAC remains a serious risk factor for heart disease, even in individuals with higher fitness and physical activity levels. In middle-aged adults, being aerobically fit and physically active is associated with an overall benefit regarding heart disease events and mortality.Despite this, having CAC significantly increases the risk of heart disease events, even for those who are fit and active.

Association of Changes in C-Reactive Protein Level Trajectories Through Early Adulthood With Cognitive Function at Midlife: The CARDIA Study.

BACKGROUND AND OBJECTIVES: Late-life inflammation has been linked to dementia risk and preclinical cognitive decline, but less is known about early adult inflammation and whether this could influence cognition in midlife. We aimed to identify inflammation levels through early adulthood and determine association of these trajectories with midlife cognition. METHODS: We used data from the Coronary Artery Risk Development in Young Adults study to identify inflammation trajectories (C-reactive protein [CRP] level <10 mg/L) over 18 years through early adulthood (age range 24-58) in latent class analysis and to assess associations with cognition 5 years after the last CRP measurement (age range 47-63). Six cognitive domains were evaluated from tests of verbal memory, processing speed, executive function, verbal and category fluency, and global cognition; poor cognitive performance was defined as a decline of ≥1 SD less than the mean on each domain. The primary outcome was poor cognitive performance. Logistic regression was used to adjust for demographics, smoking, alcohol use, physical activity, and APOE 4 status. RESULTS: Among 2,364 participants, the mean (SD) age was 50.2 (3.5) years; 55% were female, and 57% were White. Three CRP trajectories emerged over 18 years: lower stable (45%), moderate/increasing (16%), and consistently higher (39%). Compared with lower stable CRP, both consistently higher (adjusted odds ratio [aOR] 1.67, 95% CI 1.23-2.26) and moderately/increasing (aOR 2.04, 95% CI 1.40-2.96) CRP had higher odds of poor processing speed; consistently higher CRP additionally had higher odds of poor executive function (aOR 1.36, 95% CI 1.00-1.88). For memory (moderately/increasing aOR 1.36, 95% CI 1.00-1.88; consistently higher aOR 1.18, 95% CI 0.90-1.54), letter fluency (moderately/increasing aOR 1.00, 95% CI 0.69-1.43; consistently higher aOR 1.05, 95% CI 0.80-1.39), category fluency (moderately/increasing aOR 1.16, 95% CI 0.82-1.63; consistently higher aOR 1.11, 95% CI 0.85-1.45), or global cognition (moderately/increasing aOR 1.16, 95% CI 0.82-1.63; consistently higher aOR 1.11, 95% CI 0.85-1.45), no association was observed. DISCUSSION: Consistently higher or moderate/increasing inflammation starting in early adulthood may lead to worse midlife executive function and processing speed. Study limitations include selection bias due to loss to follow-up and reliance on CRP as the only inflammatory marker. Inflammation is important for cognitive aging and may begin much earlier than previously known.

Non-cigarette tobacco products, aryl-hydrocarbon receptor repressor gene methylation and smoking-related health outcomes.

INTRODUCTION: Cigarette smoking leads to altered DNA methylation at the aryl-hydrocarbon receptor repressor (AHRR) gene. However, it remains unknown whether pipe or cigar smoking is associated with AHRR methylation. We evaluated associations of non-cigarette tobacco use with AHRR methylation and determined if AHRR methylation was associated with smoking-related health outcomes. METHODS: Data were pooled across four population-based cohorts that enrolled participants from 1985 to 2002. Tobacco exposures were evaluated using smoking questionnaires. AHRR cg05575921 methylation was measured in peripheral blood leucocyte DNA. Spirometry and respiratory symptoms were evaluated at the time of methylation measurements and in subsequent visits. Vital status was monitored using the National Death Index. RESULTS: Among 8252 adults (mean age 56.7±10.3 years, 58.1% women, 40.6% black), 4857 (58.9%) participants used cigarettes and 634 (7.7%) used non-cigarette tobacco products. Exclusive use of non-cigarette tobacco products was independently associated with lower AHRR methylation (-2.44 units, 95% CI -4.42 to -0.45), though to a lesser extent than exclusive use of cigarettes (-6.01 units, 95% CI -6.01 to -4.10). Among participants who exclusively used non-cigarette tobacco products, reduced AHRR methylation was associated with increased respiratory symptom burden (OR 1.60, 95% CI 1.03 to 2.68) and higher all-cause mortality (log-rank p=0.02). CONCLUSION: Pipe and cigar smoking were independently associated with lower AHRR methylation in a multiethnic cohort of US adults. Among users of non-cigarette tobacco products, lower AHRR methylation was associated with poor respiratory health outcomes and increased mortality. AHRR methylation may identify non-cigarette tobacco users with an increased risk of adverse smoking-related health outcomes.

Urine Epidermal Growth Factor and Kidney Function Decline in Middle-Aged Adults.

Rationale & Objective: The diagnosis and prognostication of chronic kidney disease (CKD) largely rely on glomerular measures that may not reflect tubular damage. We investigated the associations of urine kidney tubule biomarkers with estimated glomerular filtration rate (eGFR) change among middle-aged adults, when chronic diseases typically emerge. Study Design: An observational cohort study. Setting & Participants: A total of 1,145 participants of the Coronary Artery Risk Development in Young Adults (CARDIA) study without CKD, hypertension, or cardiovascular disease at the year 20 visit. Exposures: Seven different biomarkers of tubular health: urine epidermal growth factor (EGF), alpha-1-microglobulin (α1m), interleukin-18, kidney injury molecule-1, monocyte chemoattractant protein-1, uromodulin, and chitinase-3-like protein 1. Outcomes: Ten-year eGFR change and incident reduced eGFR (new onset of eGFR < 60 mL/min/1.73 m2). Analytical Approach: We examined associations of tubular health biomarkers with 10-year eGFR change and incident reduced eGFR with linear mixed models and interval-censored proportional hazards regression models, respectively. Both minimally and fully adjusted models were controlled for urine creatinine levels. Results: The mean age of participants was 44.8 ± 3.7 years, with 39% African American and 56% female. The average 10-year change in eGFR was -18.6 mL/min/1.73 m2 (95% CI, -19.4 to -17.8). In contrast to the other tubular biomarkers, which showed conflicting results, EGF demonstrated strong, consistent associations with both kidney outcomes. Each 1-standard deviation (SD) higher EGF was associated with a 2.37 mL/min/1.73 m2 (95% CI, 0.64-4.10) smaller 10-year decrease in eGFR and a 42% (95% CI, 4%-64%) lower risk of incident reduced eGFR in the fully adjusted model. Limitations: Observational design, measurements of eGFR were done only at 5-year intervals during follow-up. Conclusions: In middle-aged, community-dwelling adults without hypertension, cardiovascular disease or CKD, higher urine EGF concentrations are associated with slower eGFR decline, whereas other kidney tubule biomarkers lacked a consistent association with kidney function decline.

Current measures of chronic kidney disease (CKD) rely on markers of glomerular health and function. This approach inadequately captures the role of kidney tubule health, a known histopathological predictor of CKD development. We investigated associations of 7 biomarkers of kidney tubule health with 10-year estimated glomerular filtration rate (eGFR) change and incident reduced eGFR. Among 7 biomarkers, only epidermal growth factor showed persistent and inverse associations with both 10-year eGFR change and incident reduced eGFR. These findings suggest that epidermal growth factor has an association with kidney function changes and might play a protective role in kidney disease development.

Cardiovascular Risk Factors in Childhood and Adulthood and Cardiovascular Disease in Middle Age.

Importance: Recent evidence suggests that childhood levels of serum lipids, blood pressure, body mass index (BMI), and smoking contribute to adult risk of cardiovascular disease (CVD). Evidence is lacking on whether this is independent of adult risk levels. Objective: To quantify direct and indirect effects of childhood risk factors on adult CVD via adulthood risk factors using mediation analysis, and to quantify their relative importance during different life-course stages using a life-course approach. Design, Setting, and Participants: This prospective cohort study followed participants from the US, Finland, and Australia from childhood (1970s-1990s) until 2019, with data on CVD risk factors in childhood and adulthood. Longitudinal childhood and adulthood risk factors were summarized to describe BMI, lipids, and blood pressure cumulatively. Childhood and adulthood smoking were assessed with questionnaires. Data analysis was performed May 2022 to August 2023. Main Outcomes and Measures: The primary outcomes were fatal and nonfatal cardiovascular events in adulthood. Mediation analysis was used to estimate the direct and indirect effects of the childhood risk factors with CVD events, reported as incidence rate ratios (RRs) and 95% CIs. Results: A total of 10 634 participants (4506 male participants [42.4%]; mean [SD] age at childhood visit, 13.3 [3.0] years; mean [SD] age at adulthood visit, 32.3 [6.0] years) were included in the cohort. The mean (SD) age at CVD event or censoring was 49.2 (7.0) years. The median (IQR) follow-up time was 23.6 (18.7-30.2) years. Childhood risk factors, (low-density lipoprotein cholesterol [LDL-C], total cholesterol [TC], triglycerides, systolic blood pressure [SBP], smoking, BMI, and a combined score of these) were associated with CVD. BMI (direct effect for incidence RR per 1 SD unit, 1.18; 95% CI, 1.05-1.34) and LDL-C (direct effect incidence RR, 1.16; 95% CI, 1.01-1.34) in particular were found to play an important role via direct pathways, whereas the indirect effects were larger for TC, triglycerides, SBP, and the combined score. Childhood smoking only affected CVD via adulthood smoking. Life-course models confirmed that for the risk of CVD, childhood BMI plays nearly as important role as adulthood BMI, whereas for the other risk factors and the combined score, adulthood was the more important period. Conclusions and Relevance: In this cohort study of 10 634 participants, childhood risk factors were found to be associated both directly and indirectly to adult CVD, with the largest direct effect seen for BMI and LDL-C. These findings suggest that intervention for childhood risk factors, in particular BMI, is warranted to reduce incidence of adult CVD as it cannot be fully mitigated by risk factor management in adulthood.

Dysanapsis Genetic Risk Predicts Lung Function Across the Lifespan.

Rationale Dysanapsis refers to a mismatch between airway tree caliber and lung size arising early in life. Dysanapsis assessed by computed tomography (CT) is evident by early adulthood and associated with chronic obstructive pulmonary disease (COPD) risk later in life. Objective By examining the genetic factors associated with CT-assessed dysanapsis, we aimed to elucidate its molecular underpinnings and physiological significance across the lifespan. Methods We performed a genome-wide association study (GWAS) of CT-assessed dysanapsis in 11,951 adults, including individuals from two population-based and two COPD-enriched studies. We applied colocalization analysis to integrate GWAS and gene expression data from whole blood and lung. Genetic variants associated with dysanapsis were combined into a genetic risk score that was applied to examine association with lung function in children from a population-based birth cohort (n=1,278) and adults from the UK Biobank (n=369,157). Measurements and Main Results CT-assessed dysanapsis was associated with genetic variants from 21 independent signals in 19 gene regions, implicating HHIP, DSP, and NPNT as potential molecular targets based on colocalization of their expression. Higher dysanapsis genetic risk score was associated with obstructive spirometry among 5 year old children and among adults in the 5th, 6th and 7th decades of life. Conclusions CT-assessed dysanapsis is associated with variation in genes previously implicated in lung development and dysanapsis genetic risk is associated with obstructive lung function from early life through older adulthood. Dysanapsis may represent an endo-phenotype link between the genetic variations associated with lung function and COPD.

Sex and adrenal hormones in association with insecticide biomarkers among adolescents living in ecuadorian agricultural communities.

BACKGROUND: Organophosphate, pyrethroid, and neonicotinoid insecticides have resulted in adrenal and gonadal hormone disruption in animal and in vitro studies; limited epidemiologic evidence exists in humans. We assessed relationships of urinary insecticide metabolite concentrations with adrenal and gonadal hormones in adolescents living in Ecuadorean agricultural communities. METHODS: In 2016, we examined 522 Ecuadorian adolescents (11-17y, 50.7% female, 22% Indigenous; ESPINA study). We measured urinary insecticide metabolites, blood acetylcholinesterase activity (AChE), and salivary testosterone, dehydroepiandrosterone (DHEA), 17ß-estradiol, and cortisol. We used general linear models to assess linear (ß = % hormone difference per 50% increase of metabolite concentration) and curvilinear relationships (ß2 = hormone difference per unit increase in squared ln-metabolite) between ln-metabolite or AChE and ln-hormone concentrations, stratified by sex, adjusting for anthropometric, demographic, and awakening response variables. Bayesian Kernel Machine Regression was used to assess non-linear associations and interactions. RESULTS: The organophosphate metabolite malathion dicarboxylic acid (MDA) had positive associations with testosterone (ßboys = 5.88% [1.21%, 10.78%], ßgirls = 4.10% [-0.02%, 8.39%]), and cortisol (ßboys = 6.06 [-0.23%, 12.75%]. Para-nitrophenol (organophosphate) had negatively-trending curvilinear associations, with testosterone (ß2boys = -0.17 (-0.33, -0.003), p = 0.04) and DHEA (ß2boys = -0.49 (-0.80, -0.19), p = 0.001) in boys. The neonicotinoid summary score (ßboys = 5.60% [0.14%, 11.36%]) and the neonicotinoid acetamiprid-N-desmethyl (ßboys = 3.90% [1.28%, 6.58%]) were positively associated with 17ß-estradiol, measured in boys only. No associations between the pyrethroid 3-phenoxybenzoic acid and hormones were observed. In girls, bivariate response associations identified interactions of MDA, Para-nitrophenol, and 3,5,6-trichloro-2-pyridinol (organophosphates) with testosterone and DHEA concentrations. In boys, we observed an interaction of MDA and Para-nitrophenol with DHEA. No associations were identified for AChE. CONCLUSIONS: We observed evidence of endocrine disruption for specific organophosphate and neonicotinoid metabolite exposures in adolescents. Urinary organophosphate metabolites were associated with testosterone and DHEA concentrations, with stronger associations in boys than girls. Urinary neonicotinoids were positively associated with 17ß-estradiol. Longitudinal repeat-measures analyses would be beneficial for causal inference.

Metabolic liability for weight gain in early adulthood.

While weight gain is associated with a host of chronic illnesses, efforts in obesity have relied on single "snapshots" of body mass index (BMI) to guide genetic and molecular discovery. Here, we study >2,000 young adults with metabolomics and proteomics to identify a metabolic liability to weight gain in early adulthood. Using longitudinal regression and penalized regression, we identify a metabolic signature for weight liability, associated with a 2.6% (2.0%-3.2%, p = 7.5 × 10-19) gain in BMI over ≈20 years per SD higher score, after comprehensive adjustment. Identified molecules specified mechanisms of weight gain, including hunger and appetite regulation, energy expenditure, gut microbial metabolism, and host interaction with external exposure. Integration of longitudinal and concurrent measures in regression with Mendelian randomization highlights the complexity of metabolic regulation of weight gain, suggesting caution in interpretation of epidemiologic or genetic effect estimates traditionally used in metabolic research.

Dietary nitrate intake and net nitrite-generating capacity of the oral microbiome interact to enhance cardiometabolic health: Results from the Oral Infections Glucose Intolerance and Insulin Resistance Study (ORIGINS).

Background: We investigated the association between dietary nitrate intake and early clinical cardiometabolic risk biomarkers, and explored whether the oral microbiome modifies the association between dietary nitrate intake and cardiometabolic biomarkers. Methods: Cross-sectional data from 668 (mean [SD] age 31 [9] years, 73% women) participants was analyzed. Dietary nitrate intakes and alternative healthy eating index (AHEI) scores were calculated from food frequency questionnaire responses and a validated US food database. Subgingival 16S rRNA microbial genes (Illumina, MiSeq) were sequenced, and PICRUSt2 estimated metagenomic content. The Microbiome Induced Nitric oxide Enrichment Score (MINES) was calculated as a microbial gene abundance ratio representing enhanced net capacity for NO generation. Cardiometabolic risk biomarkers included systolic and diastolic blood pressure, HbA1c, glucose, insulin, and insulin resistance (HOMA-IR), and were regressed on nitrate intake tertiles in adjusted multivariable linear models. Results: Mean nitrate intake was 190[171] mg/day. Higher nitrate intake was associated with lower insulin, and HOMA-IR but particularly among participants with low abundance of oral nitrite enriching bacteria. For example, among participants with a low MINES, mean insulin[95%CI] levels in high vs. low dietary nitrate consumers were 5.8[5.3,6.5] vs. 6.8[6.2,7.5] (p=0.004) while respective insulin levels were 6.0[5.4,6.6] vs. 5.9[5.3,6.5] (p=0.76) among partcipants with high MINES (interaction p=0.02). Conclusion: Higher dietary nitrate intake was only associated with lower insulin and insulin resistance among individuals with reduced capacity for oral microbe-induced nitrite enrichment. These findings have implications for future precision medicine-oriented approaches that might consider assessing the oral microbiome prior to enrollment into dietary interventions or making dietary recommendations.

Non-High-Density Lipoprotein Cholesterol Levels From Childhood to Adulthood and Cardiovascular Disease Events.

Importance: Elevated non-high-density lipoprotein cholesterol (non-HDL-C; a recommended measure of lipid-related cardiovascular risk) is common in children and increases risk of adult cardiovascular disease (CVD). Whether resolution of elevated childhood non-HDL-C levels by adulthood is associated with reduced risk of clinical CVD events is unknown. Objective: To examine the associations of non-HDL-C status between childhood and adulthood with incident CVD events. Design, Setting, and Participants: Individual participant data from 6 prospective cohorts of children (mean age at baseline, 10.7 years) in the US and Finland. Recruitment took place between 1970 and 1996, with a final follow-up in 2019. Exposures: Child (age 3-19 years) and adult (age 20-40 years) non-HDL-C age- and sex-specific z scores and categories according to clinical guideline-recommended cutoffs for dyslipidemia. Main Outcomes and Measures: Incident fatal and nonfatal CVD events adjudicated by medical records. Results: Over a mean length of follow-up of 8.9 years after age 40 years, 147 CVD events occurred among 5121 participants (60% women; 15% Black). Both childhood and adult non-HDL-C levels were associated with increased risk of CVD events (hazard ratio [HR], 1.42 [95% CI, 1.18-1.70] and HR, 1.50 [95% CI, 1.26-1.78] for a 1-unit increase in z score, respectively), but the association for childhood non-HDL-C was reduced when adjusted for adult levels (HR, 1.12 [95% CI, 0.89-1.41]). A complementary analysis showed that both childhood non-HDL-C levels and the change between childhood and adulthood were independently associated with the outcome, suggesting that from a preventive perspective, both childhood non-HDL-C levels and the change into adulthood are informative. Compared with those whose non-HDL-C levels remained within the guideline-recommended range in childhood and adulthood, participants who had incident non-HDL-C dyslipidemia from childhood to adulthood and those with persistent dyslipidemia had increased risks of CVD events (HR, 2.17 [95% CI, 1.00-4.69] and HR, 5.17 [95% CI, 2.80-9.56], respectively). Individuals who had dyslipidemic non-HDL-C in childhood but whose non-HDL-C levels were within the guideline-recommended range in adulthood did not have a significantly increased risk (HR, 1.13 [95% CI, 0.50-2.56]). Conclusions and Relevance: Individuals with persistent non-HDL-C dyslipidemia from childhood to adulthood had an increased risk of CVD events, but those in whom dyslipidemic non-HDL-C levels resolve by adulthood have similar risk to individuals who were never dyslipidemic. These findings suggest that interventions to prevent and reduce elevated childhood non-HDL-C levels may help prevent premature CVD.

Non-alcoholic fatty liver modifies associations of body mass index and waist circumference with cardiometabolic risk: The CARDIA study.

Background: Non-alcoholic fatty liver disease (NAFLD) is recognized as a prevalent determinant of cardiometabolic diseases. The association between NAFLD and obesity warrants further research on how NAFLD modifies associations between body mass index (BMI) and Waist circumference (WC) with cardiometabolic risk (CMR). Objective: This study assessed whether NAFLD modifies associations between BMI and WC with 5-year changes in CMR in 2366 CARDIA study participants. Methods: Non-contrast CT was used to quantify liver attenuation, with ≤51 Hounsfield Units (HU) used to define NAFLD in the absence of secondary causes of excess liver fat. The dependent variable was the average Z score of fasting glucose, insulin, triglycerides [log], (-) high-density lipoprotein cholesterol (HDL-C), and systolic blood pressure(SBP). Multivariable linear regression was used to estimate the associations between BMI and WC with CMR. Effect modification by NAFLD was assessed by an interaction term between NAFLD and BMI or WC. Results: The final sample had 539 (23%) NAFLD cases. NAFLD modified the association of BMI and WC with CMR (interaction p < 0.0001 for both). BMI and WC were associated with CMR in participants without NAFLD (p < 0.001), but not among those with NAFLD. Participants with NAFLD and normal BMI and WC had CMR estimates that were higher than those without NAFLD in the obese categories. Among those without NAFLD the 5 years CMR change estimate was 0.09 (95% CI: 0.062, 0.125) for BMI ≥30 kg/m2 compared to -0.06 (-0.092, -0.018) for BMI < 25 kg/m2, and among those with NAFLD, these estimates were 0.15 (0.108, 0.193) and 0.16 (-0.035, 0.363). Conclusions: NAFLD modifies associations of BMI and WC with CMR. Compared with BMI and WC, NAFLD was more strongly associated with CMR. In the presence of NAFLD, BMI and WC were not associated with CMR. These findings have implications for clinical screening guidelines.

Associations of a plant-centered diet and lung function across early to mid-adulthood: The CARDIA Lung Study.

BACKGROUND: Lung function throughout adulthood predicts morbidity and mortality even among adults without chronic respiratory disease. Diet quality may represent a modifiable risk factor for lung function impairment later in life. We investigated associations between nutritionally-rich plant-centered diet and lung function across early and middle adulthood from the Coronary Artery Risk Development in Young Adults (CARDIA) Study. METHODS: Diet was assessed at baseline and years 7 and 20 of follow-up using the validated CARDIA diet history questionnaire. Plant-centered diet quality was scored using the validated A Priori Diet Quality Score (APDQS), which weights food groups to measure adherence to a nutritionally-rich plant-centered diet for 20 beneficially rated foods and 13 adversely rated foods. Scores were cumulatively averaged over follow-up and categorized into quintiles. The primary outcome was lung function decline, including forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC), measured at years 0, 2, 5, 10, 20, and 30. We estimated the association of APDQS with annual pulmonary function changes and cross-sectional differences in a repeated measures regression model, adjusting for clinically relevant covariates. RESULTS: The study included 3,787 Black and White men and women aged 18-30 in 1985-86 and followed for 30 years. In multivariable repeated measures regression models, individuals in the lowest APDQS quintile (poorest diet) had declines in FEV1 that were 1.6 ml/year greater than individuals in the highest quintile (35.0 vs. 33.4 ml/year, ß ± SE per 1 SD change APDQS 0.94 ± 0.36, p = 0.009). Additionally, declines in FVC were 2.4 ml/year greater in the lowest APDQS quintile than those in the highest quintile (37.0 vs 34.6 ml/year, ß ± SE per 1 SD change APDQS 1.71 ± 0.46, p < 0.001). The association was not different between never and ever smokers (pint = 0.07 for FVC and 0.32 for FEV1). In sensitivity analyses where current asthma diagnosis and cardiorespiratory fitness were further adjusted, results remained similar. Cross-sectional analysis at each exam year also showed significant differences in lung function according to diet after covariate adjustment. CONCLUSIONS: In this 30-year longitudinal cohort study, long-term adherence to a nutritionally-rich plant-centered diet was associated with cross-sectional differences in lung function as well as slower decline in lung function, highlighting diet quality as a potential treatable trait supporting long-term lung health.

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

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

Mortality After Major Cardiovascular Events in Survivors of Childhood Cancer.

BACKGROUND: Adult survivors of childhood cancer are at risk for cardiovascular events. OBJECTIVES: In this study, we sought to determine the risk for mortality after a major cardiovascular event among childhood cancer survivors compared with noncancer populations. METHODS: All-cause and cardiovascular cause-specific mortality risks after heart failure (HF), coronary artery disease (CAD), or stroke were compared among survivors and siblings in the Childhood Cancer Survivor Study (CCSS) and participants in the Coronary Artery Risk Development in Young Adults (CARDIA) study. Cox proportional hazard regression models were used to estimate HRs and 95% CIs between groups, adjusted for demographic and clinical factors. RESULTS: Among 25,658 childhood cancer survivors (median age at diagnosis 7 years, median age at follow-up or death 38 years) and 5,051 siblings, 1,780 survivors and 91 siblings had a cardiovascular event. After HF, CAD, and stroke, 10-year all-cause mortalities were 30% (95% CI: 26%-33%), 36% (95% CI: 31%-40%), and 29% (95% CI: 24%-33%), respectively, among survivors vs 14% (95% CI: 0%-25%), 14% (95% CI: 2%-25%), and 4% (95% CI: 0%-11%) among siblings. All-cause mortality risks among childhood cancer survivors were increased after HF (HR: 7.32; 95% CI: 2.56-20.89), CAD (HR: 5.54; 95% CI: 2.37-12.93), and stroke (HR: 3.57; 95% CI: 1.12-11.37). CAD-specific mortality risk was increased (HR: 3.70; 95% CI: 1.05-13.02). Among 5,114 CARDIA participants, 345 had a major event. Although CARDIA participants were on average decades older at events (median age 57 years vs 31 years), mortality risks were similar, except that all-cause mortality after CAD was significantly increased among childhood cancer survivors (HR: 1.85; 95% CI: 1.16-2.95). CONCLUSIONS: Survivors of childhood cancer represent a population at high risk for mortality after major cardiovascular events.