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Background and objectivesTo understand the role of premature (defined as ≤ 60 years) cardiovascular disease (CVD) in brain health earlier in life, we examined the associations of premature CVD with midlife cognition and white matter health.MethodsWe studied a prospective cohort in the Coronary Artery Risk Development in Young Adults study, who were 18-30 years at baseline (1985-1986) and followed up to 30 years when 5 cognitive tests measuring different domains were administered. A subset (656 participants) had brain MRI measures of white matter hyperintensity (WMH) and white matter integrity. A premature CVD event was adjudicated based on medical records of coronary heart disease, stroke/TIA, congestive heart failure, carotid artery disease, and peripheral artery disease. We conducted linear regression to determine the associations of nonfatal premature CVD with cognitive performance (z-standardized), cognitive decline, and MRI measures.ResultsAmong 3,146 participants, the mean age (57% women and 48% Black) was 55.1 ± 3.6 years, with 5% (n = 147) having premature CVD. Adjusting for demographics, education, literacy, income, depressive symptoms, physical activity, diet, and APOE, premature CVD was associated with lower cognition in 4 of 5 domains: global cognition (-0.22, 95% CI -0.37 to -0.08), verbal memory (-0.28, 95% CI -0.44 to -0.12), processing speed (-0.46, 95% CI -0.62 to -0.31), and executive function (-0.38, 95% CI -0.55 to -0.22). Premature CVD was associated with greater WMH (total, temporal, and parietal lobes) and higher white matter mean diffusivity (total and temporal lobes) after adjustment for covariates. These associations remained significant after adjusting for cardiovascular risk factors (CVRFs) and excluding those with stroke/TIA. Premature CVD was also associated with accelerated cognitive decline over 5 years (adjusted OR 3.07, 95% CI 1.65-5.71).DiscussionPremature CVD is associated with worse midlife cognition and white matter health, which is not entirely driven by stroke/TIA and even independent of CVRFs. Preventing CVD in early adulthood may delay the onset of cognitive decline and promote brain health over the life course.

The prognostic value of traditional atherosclerotic cardiovascular disease (ASCVD) risk factors may decrease with age. We sought to determine whether the association between traditional ASCVD risk factors and incident coronary artery calcium (CAC) differs for younger versus older persons. We included 5,108 participants with baseline CAC = 0. Repeat CAC scoring occurred over 3 to 11 years of follow-up. Multivariable Cox proportional hazards regression assessed the association between traditional risk factors and incident CAC in young (32 to 45 years), middle-aged (46 to 64 years), and older adults (65 to 84 years). A total of 61% of the participants were women and 37% were Black. The proportion with incident CAC ranged from 22% among young adults, 34% for middle-aged adults, and 45% for older adults. In young adults, traditional risk factors were significantly associated with incident CAC except for diastolic blood pressure and high-density lipoprotein (HDL) cholesterol, whereas only total cholesterol/HDL cholesterol ≥3.5 (p = 0.04) was significantly associated with incident CAC in older persons. Non-HDL cholesterol (p = 0.02) was more strongly associated with incident CAC in young (hazard ratio [HR] 1.20, 95% confidence interval [CI] 1.09 to 1.31) and middle aged (HR 1.14, 95% CI 1.07 to 1.23) compared to older adults (HR 1.11, 95% CI 0.99 to 1.23). When added to demographics, traditional risk factors provided a greater C-statistic improvement for incident CAC prediction in young (0.752, +0.070, p

BackgroundDifferent 25-hydroxyvitamin D [25(OH)D] thresholds for treatment with vitamin D supplementation have been suggested and are derived almost exclusively from observational studies. Whether other characteristics, including race/ethnicity, BMI, and estimated glomerular filtration rate (eGFR), should also influence the threshold for treatment is unknown.ObjectivesThe aim was to identify clinical and biomarker characteristics that modify the response to vitamin D supplementation.MethodsA total of 666 older adults in the Multi-Ethnic Study of Atherosclerosis (MESA) were randomly assigned to 16 wk of oral vitamin D3 (2000 IU/d; n = 499) or placebo (n = 167). Primary outcomes were changes in serum parathyroid hormone (PTH) and 1,25-dihydroxyvitamin D [1,25(OH)2D] concentrations from baseline to 16 wk.ResultsAmong 666 participants randomly assigned (mean age: 72 y; 53% female; 66% racial/ethnic minority), 611 (92%) completed the study. The mean (SD) change in PTH was -3 (16) pg/mL with vitamin D3 compared with 2 (18) pg/mL with placebo (estimated mean difference: -5; 95% CI: -8, -2 pg/mL). Within the vitamin D3 group, lower baseline 25-hydroxyvitamin D [25(OH)D] was associated with a larger decline in PTH in a nonlinear fashion. With baseline 25(OH)D ≥30 ng/mL as the reference, 25(OH)D

BackgroundRaised low-density lipoprotein cholesterol (LDL-C) in young adulthood (aged 18-39 years) is associated with atherosclerotic cardiovascular disease (ASCVD) later in life. Most young adults with elevated LDL-C do not currently receive lipid-lowering treatment.ObjectivesThis study aimed to estimate the prevalence of elevated LDL-C in ASCVD-free U.S. young adults and the cost-effectiveness of lipid-lowering strategies for raised LDL-C in young adulthood compared with standard care.MethodsThe prevalence of raised LDL-C was examined in the U.S. National Health and Nutrition Examination Survey. The CVD Policy Model projected lifetime quality-adjusted life years (QALYs), health care costs, and incremental cost-effectiveness ratios (ICERs) for lipid-lowering strategies. Standard care was statin treatment for adults aged ≥40 years based on LDL-C, ASCVD risk, or diabetes plus young adults with LDL-C ≥190 mg/dL. Lipid lowering incremental to standard care with moderate-intensity statins or intensive lifestyle interventions was simulated starting when young adult LDL-C was either ≥160 mg/dL or ≥130 mg/dL.ResultsApproximately 27% of ASCVD-free young adults have LDL-C of ≥130 mg/dL, and 9% have LDL-C of ≥160 mg/dL. The model projected that young adult lipid lowering with statins or lifestyle interventions would prevent lifetime ASCVD events and increase QALYs compared with standard care. ICERs were US$31,000/QALY for statins in young adult men with LDL-C of ≥130 mg/dL and US$106,000/QALY for statins in young adult women with LDL-C of ≥130 mg/dL. Intensive lifestyle intervention was more costly and less effective than statin therapy.ConclusionsStatin treatment for LDL-C of ≥130 mg/dL is highly cost-effective in young adult men and intermediately cost-effective in young adult women.

The INdividual response to VITamin D (INVITe) trial was a randomized, placebo-controlled, parallel group trial of vitamin D3 supplementation (2000 IU daily) designed to determine clinical and genetic characteristics that modify the response to vitamin D supplementation. To enhance internal and external validity and reduce cost, the INVITe trial was nested within the Multi-Ethnic Study of Atherosclerosis (MESA), an ongoing prospective observational cohort study. The INVITe trial enrolled a community-based population of 666 racially and ethnically diverse participants from January 2017 to April 2019. This represents 30% of 2210 MESA participants approached for screening, and 96% of those found to be eligible. Barriers to enrollment included delayed initiation of the trial relative to scheduled MESA study visits, a lower number of available MESA participants than expected, and a high prevalence (18%) of high-dose vitamin D supplementation (>1000 IU daily, an exclusion criterion). The final study visit was attended by 611 participants (92%), and median adherence was 98%. Our experience suggests that integration of a randomized trial into an existing observational cohort study may leverage strengths of the source population and enhance enrollment, retention, and adherence, although with limited enrollment capacity. The INVITe trial will use rigorously-collected data to advance understanding of individual determinants of vitamin D response.

BackgroundIndependent associations between cardiovascular risk factor exposures during midlife and later life development of heart failure (HF) with preserved ejection fraction (HFpEF) versus reduced EF (HFrEF) have not been previously studied.MethodsWe pooled data from 4 US cohort studies (Atherosclerosis Risk in Communities, Cardiovascular Health, Health , Aging and Body Composition, and Multi-Ethnic Study of Atherosclerosis) and imputed annual risk factor trajectories for body mass index, systolic and diastolic blood pressure, low-density lipoprotein and high-density lipoprotein cholesterol, and glucose starting from age 40 years. Time-weighted average exposures to each risk factor during midlife and later life were calculated and analyzed for associations with the development of HFpEF or HFrEF.ResultsA total of 23,861 participants were included (mean age at first in-person visit, 61.8 ±1 0.2 years; 56.6% female). During a median follow-up of 12 years, there were 3666 incident HF events, of which 51% had EF measured, including 934 with HFpEF and 739 with HFrEF. A high midlife systolic blood pressure and low midlife high-density lipoprotein cholesterol were associated with HFrEF, and a high midlife body mass index, systolic blood pressure, pulse pressure, and glucose were associated with HFpEF. After adjusting for later life exposures, only midlife pulse pressure remained independently associated with HFpEF.ConclusionsMidlife exposure to cardiovascular risk factors are differentially associated with HFrEF and HFpEF later in life. Having a higher pulse pressure during midlife is associated with a greater risk for HFpEF but not HFrEF, independent of later life exposures.

BackgroundBlood pressure (BP) and cholesterol are major modifiable risk factors for cardiovascular disease (CVD), but effects of exposures during young adulthood on later life CVD risk have not been well quantified.ObjectiveThe authors sought to evaluate the independent associations between young adult exposures to risk factors and later life CVD risk, accounting for later life exposures.MethodsThe authors pooled data from 6 U.S. cohorts with observations spanning the life course from young adulthood to later life, and imputed risk factor trajectories for low-density lipoprotein (LDL) and high-density lipoprotein cholesterols, systolic and diastolic BP starting from age 18 years for every participant. Time-weighted average exposures to each risk factor during young (age 18 to 39 years) and later adulthood (age ≥40 years) were calculated and linked to subsequent risks of coronary heart disease (CHD), heart failure (HF), or stroke.ResultsA total of 36,030 participants were included. During a median follow-up of 17 years, there were 4,570 CHD, 5,119 HF, and 2,862 stroke events. When young and later adult risk factors were considered jointly in the model, young adult LDL ≥100 mg/dl (compared with

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.

Background & aimsInsulin resistance is a risk marker for non-alcoholic fatty liver disease, and a risk factor for liver disease progression. We assessed temporal trajectories of insulin resistance and β-cell response to serum glucose concentration throughout adulthood and their association with diabetes risk in non-alcoholic fatty liver disease.MethodsThree thousand and sixty participants from Coronary Artery Risk Development in Young Adults, a prospective bi-racial cohort of adults age 18-30 years at baseline (1985-1986; Y0) who completed up to 5 exams over 25 years and had fasting insulin and glucose measurement were included. At Y25 (2010-2011), non-alcoholic fatty liver disease was assessed by noncontrast computed tomography after exclusion of other liver fat causes. Latent mixture modelling identified 25-year trajectories in homeostatic model assessment insulin resistance and β-cell response homeostatic model assessment-β.ResultsThree distinct trajectories were identified, separately, for homeostatic model assessment insulin resistance (low-stable [47%]; moderate-increasing [42%]; and high-increasing [12%]) and homeostatic model assessment-β (low-decreasing [16%]; moderate-decreasing [63%]; and high-decreasing [21%]). Y25 non-alcoholic fatty liver disease prevalence was 24.5%. Among non-alcoholic fatty liver disease, high-increasing homeostatic model assessment insulin resistance (referent: low-stable) was associated with greater prevalent (OR 95% CI = 8.0, 2.0-31.9) and incident (OR = 10.5, 2.6-32.8) diabetes after multivariable adjustment including Y0 or Y25 homeostatic model assessment insulin resistance. In contrast, non-alcoholic fatty liver disease participants with low-decreasing homeostatic model assessment-β (referent: high-decreasing) had the highest odds of prevalent (OR = 14.1, 3.9-50.9) and incident (OR = 10.3, 2.7-39.3) diabetes.ConclusionTrajectories of insulin resistance and β-cell response during young and middle adulthood are robustly associated with diabetes risk in non-alcoholic fatty liver disease. Thus, how persons with non-alcoholic fatty liver disease develop resistance to insulin provides important information about risk of diabetes in midlife above and beyond degree of insulin resistance at the time of non-alcoholic fatty liver disease assessment.

BACKGROUND Cardiovascular health (CVH) in young adulthood (YA) has been associated with cardiovascular outcomes in older age. However, little is known about the relationship between YA CVH and mid-life blood pressure (BP) trajectories. METHODS Baseline CVH (defined by 7 of the American Heart Association's [AHA] Life's Essential 8 [LE8] metrics, excluding BP) was measured in YA with individual metrics scored and averaged as a composite LE8 score. Categorical CVH status was defined as high, moderate, and low. Latent class analysis was used to identify trajectories of mid-BP (mean of systolic blood pressure [SBP] and diastolic blood pressure [DBP]) from average ages 35 to 55 years. Multinomial logistic regression was used to estimate the association of YA CVH status (continuously and categorically) with mid-life BP trajectory group membership. RESULTS There were 3,688 participants from the Coronary Artery Risk Development in Young Adults (CARDIA) study in YA with follow-up data for mid-life BP trajectories. We observed 3 BP trajectory groups, labeled as Persistently-Low, Middle, and High-Increasing. On average, each 10-points higher baseline LE8 score (mean [SD] of 73.5 [13.1]) in YA was associated with adjusted odds ratios of 0.78 (95% CI, 0.72–0.84) for membership in the Middle and 0.65 (0.57–0.73) for membership in the High-Increasing trajectory groups. Compared with categorical low CVH status at baseline, those with high CVH were significantly less likely to be in the Middle and High-Increasing BP trajectory groups. CONCLUSIONS Moderate or low CVH status in YA is associated with elevated mid-life BP trajectory. These data suggest that young adult CVH promotion may be important for the primordial prevention of hypertension. [ABSTRACT FROM AUTHOR]

The article presents a study which hypothesized that lower childhood socioeconomic status (SES), assessed by lower parental educational attainment, would be associated with smaller adult airway tree caliber relative to lung volume. Topics discussed include characteristics of multi-ethnic study of atherosclerosis lung study participants stratified by highest educational degree obtained by both parents, ways lower childhood SES are assessed, and findings of the study.

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.

BackgroundLifetime risk of heart failure has been estimated to range from 20% to 46% in diverse sex and race groups. However, lifetime risk estimates for the 2 HF phenotypes, HF with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF), are not known.MethodsParticipant-level data from 2 large prospective cohort studies, the CHS (Cardiovascular Health Study) and MESA (Multiethnic Study of Atherosclerosis), were pooled, excluding individuals with prevalent HF at baseline. Remaining lifetime risk estimates for HFpEF (EF ≥45%) and HFrEF (EF 45 years of age (22.2% blacks, 44.8% men) who were followed up for median duration of 11.6 years with 2178 overall incident HF events with 561 HFrEF events and 726 HFpEF events. At the index age of 45 years, the lifetime risk for any HF through 90 years of age was higher in men than women (27.4% versus 23.8%). Among HF subtypes, the lifetime risk for HFrEF was higher in men than women (10.6% versus 5.8%). In contrast, the lifetime risk for HFpEF was similar in men and women. In race-stratified analyses, lifetime risk for overall HF was higher in nonblacks than blacks (25.9% versus 22.4%). Among HF subtypes, the lifetime risk for HFpEF was higher in nonblacks than blacks (11.2% versus 7.7%), whereas that for HFrEF was similar across the 2 groups. Among participants with antecedent myocardial infarction before HF diagnosis, the remaining lifetime risks for HFpEF and HFrEF were up to 2.5-fold and 4-fold higher, respectively, compared with those without antecedent myocardial infarction.ConclusionsLifetime risks for HFpEF and HFrEF vary by sex, race, and history of antecedent myocardial infarction. These insights into the distribution of HF risk and its subtypes could inform the development of targeted strategies to improve population-level HF prevention and control.

Background & aimsNon-alcoholic fatty liver disease is an epidemic. Identifying modifiable risk factors for non-alcoholic fatty liver disease development is essential to design effective prevention programmes. We tested whether 25-year patterns of body mass index change are associated with midlife non-alcoholic fatty liver disease.MethodsIn all, 4423 participants from Coronary Artery Risk Development in Young Adults, a prospective population-based biracial cohort (age 18-30), underwent body mass index measurement at baseline (1985-1986) and 3 or more times over 25 years. At Year 25, 3115 had liver fat assessed by non-contrast computed tomography. Non-alcoholic fatty liver disease was defined as liver attenuation ≤40 Hounsfield Units after exclusions. Latent mixture modelling identified 25-year trajectories in body mass index per cent change (%Δ) from baseline.ResultsWe identified four distinct trajectories of BMI%Δ: stable (26.2% of cohort, 25-year BMI %Δ = 3.1%), moderate increase (46.0%, BMI%Δ = 21.7%), high increase (20.9%, BMI%Δ = 41.9%) and extreme increase (6.9%, BMI%Δ = 65.9%). Y25 non-alcoholic fatty liver disease prevalence was higher in groups with greater BMI %Δ: 4.1%, 9.3%, 13.0%, and 17.6%, respectively (P-trend

The aims of this study are to assess the relationships of visit-to-visit blood pressure (BP) variability in young adulthood to hippocampal volume and integrity at middle age. We used data over 8 examinations spanning 25 years collected in the CARDIA study (Coronary Artery Risk Development in Young Adults) of black and white adults (age, 18-30 years) started in 1985 to 1986. Visit-to-visit BP variability was defined as by SDBP and average real variability (ARVBP, defined as the absolute differences of BP between successive BP measurements). Hippocampal tissue volume standardized by intracranial volume (%) and integrity assessed by fractional anisotropy were measured by 3-Tesla magnetic resonance imaging at the year-25 examination (n=545; mean age, 51 years; 54% women and 34% African Americans). Mean systolic BP (SBP)/diastolic BP levels were 110/69 mm Hg at year 0 (baseline), 117/73 mm Hg at year 25, and ARVSBP and SDSBP were 7.7 and 7.9 mm Hg, respectively. In multivariable-adjusted linear models, higher ARVSBP was associated with lower hippocampal volume (unstandardized regression coefficient [standard error] with 1-SD higher ARVSBP: -0.006 [0.003]), and higher SDSBP with lower hippocampal fractional anisotropy (-0.02 [0.01]; all P

ObjectiveTo evaluate 25-year physical activity (PA) trajectories from young to middle age and assess associations with the prevalence of coronary artery calcification (CAC).Patients and methodsThis study includes 3175 participants in the Coronary Artery Risk Development in Young Adults (CARDIA) study who self-reported PA by questionnaire at 8 follow-up examinations over 25 years (from March 1985-June 1986 through June 2010-May 2011). The presence of CAC (CAC>0) at year 25 was measured using computed tomography. Group-based trajectory modeling was used to identify PA trajectories with increasing age.ResultsWe identified 3 distinct PA trajectories: trajectory 1, below PA guidelines (n=1813; 57.1%); trajectory 2, meeting PA guidelines (n=1094; 34.5%); and trajectory 3, 3 times PA guidelines (n=268; 8.4%). Trajectory 3 participants had higher adjusted odds of CAC>0 (adjusted odds ratio [OR], 1.27; 95% CI, 0.95-1.70) vs those in trajectory 1. Stratification by race showed that white participants who engaged in PA 3 times the guidelines had higher odds of developing CAC>0 (OR, 1.80; 95% CI, 1.21-2.67). Further stratification by sex showed higher odds for white males (OR, 1.86; 95% CI, 1.16-2.98), and similar but nonsignificant trends were noted for white females (OR, 1.71; 95% CI, 0.79-3.71). However, no such higher odds of CAC>0 for trajectory 3 were observed for black participants.ConclusionWhite individuals who participated in 3 times the recommended PA guidelines over 25 years had higher odds of developing coronary subclinical atherosclerosis by middle age. These findings warrant further exploration, especially by race, into possible biological mechanisms for CAC risk at very high levels of PA.

Background & aimsCardiovascular disease (CVD) is the leading cause of death among patients with nonalcoholic fatty liver disease (NAFLD). Moderate drinking (vs abstinence) is associated with lower risk of CVD in the general population. We assessed whether alcohol use is associated with CVD risk in patients with NAFLD.MethodsWe analyzed data from participants in the Coronary Artery Risk Development in Young Adults longitudinal cohort study of 5115 black and white young adults, 18-30 years old, recruited from 4 cities in the United States from 1985 through 1986. Participants self-reported alcohol use at study entry and then again after 15, 20, and 25 years. At year 25 (2010-2011), participants underwent computed tomography examination of the thorax and abdomen and tissue Doppler echocardiography with myocardial strain measured by speckle tracking. Coronary artery calcification was defined as an Agatston score above 0. NAFLD was defined as liver attenuation