Multi-Ethnic Study Of Atherosclerosis Research Articles

Implications of Race Adjustment in Lung-Function Equations.

Adjustment for race is discouraged in lung-function testing, but the implications of adopting race-neutral equations have not been comprehensively quantified. We obtained longitudinal data from 369,077 participants in the National Health and Nutrition Examination Survey, U.K. Biobank, the Multi-Ethnic Study of Atherosclerosis, and the Organ Procurement and Transplantation Network. Using these data, we compared the race-based 2012 Global Lung Function Initiative (GLI-2012) equations with race-neutral equations introduced in 2022 (GLI-Global). Evaluated outcomes included national projections of clinical, occupational, and financial reclassifications; individual lung-allocation scores for transplantation priority; and concordance statistics (C statistics) for clinical prediction tasks. Among the 249 million persons in the United States between 6 and 79 years of age who are able to produce high-quality spirometric results, the use of GLI-Global equations may reclassify ventilatory impairment for 12.5 million persons, medical impairment ratings for 8.16 million, occupational eligibility for 2.28 million, grading of chronic obstructive pulmonary disease for 2.05 million, and military disability compensation for 413,000. These potential changes differed according to race; for example, classifications of nonobstructive ventilatory impairment may change dramatically, increasing 141% (95% confidence interval [CI], 113 to 169) among Black persons and decreasing 69% (95% CI, 63 to 74) among White persons. Annual disability payments may increase by more than $1 billion among Black veterans and decrease by $0.5 billion among White veterans. GLI-2012 and GLI-Global equations had similar discriminative accuracy with regard to respiratory symptoms, health care utilization, new-onset disease, death from any cause, death related to respiratory disease, and death among persons on a transplant waiting list, with differences in C statistics ranging from -0.008 to 0.011. The use of race-based and race-neutral equations generated similarly accurate predictions of respiratory outcomes but assigned different disease classifications, occupational eligibility, and disability compensation for millions of persons, with effects diverging according to race. (Funded by the National Heart Lung and Blood Institute and the National Institute of Environmental Health Sciences.).

LXR signaling pathways link cholesterol metabolism with risk for prediabetes and diabetes.

BACKGROUNDPreclinical studies suggest that cholesterol accumulation leads to insulin resistance. We previously reported that alterations in a monocyte cholesterol metabolism transcriptional network (CMTN) - suggestive of cellular cholesterol accumulation - were cross-sectionally associated with obesity and type 2 diabetes (T2D). Here, we sought to determine whether the CMTN alterations independently predict incident prediabetes/T2D risk, and correlate with cellular cholesterol accumulation.METHODSMonocyte mRNA expression of 11 CMTN genes was quantified among 934 Multi-Ethnic Study of Atherosclerosis (MESA) participants free of prediabetes/T2D; cellular cholesterol was measured in a subset of 24 monocyte samples.RESULTSDuring a median 6-year follow-up, lower expression of 3 highly correlated LXR target genes - ABCG1 and ABCA1 (cholesterol efflux) and MYLIP (cholesterol uptake suppression) - and not other CMTN genes, was significantly associated with higher risk of incident prediabetes/T2D. Lower expression of the LXR target genes correlated with higher cellular cholesterol levels (e.g., 47% of variance in cellular total cholesterol explained by ABCG1 expression). Further, adding the LXR target genes to overweight/obesity and other known predictors significantly improved prediction of incident prediabetes/T2D.CONCLUSIONThese data suggest that the aberrant LXR/ABCG1-ABCA1-MYLIP pathway (LAAMP) is a major T2D risk factor and support a potential role for aberrant LAAMP and cellular cholesterol accumulation in diabetogenesis.FUNDINGThe MESA Epigenomics and Transcriptomics Studies were funded by NIH grants 1R01HL101250, 1RF1AG054474, R01HL126477, R01DK101921, and R01HL135009. This work was supported by funding from NIDDK R01DK103531 and NHLBI R01HL119962.

The association of body mass index variability with cardiovascular disease and mortality: a mediation analysis of pooled cohorts

AimWe aimed to investigate the effect of BMI variability on CVD and mortality and to explore the mediation effects of the main cardiovascular risk factors contributing to this association.MethodParticipants aged 40-65 years were pooled from three cohort studies(ARIC [Atherosclerosis Risk in Communities], MESA [Multi-ethnic Study of Atherosclerosis], and TLGS [Tehran Lipid and Glucose Study]. We employed root mean squared error of the fractional mixed model to calculate BMI variability in the measurement period. In the event assessment period, the hazard ratios for CVD and mortality were estimated using Cox proportional hazard regression models. In the next step, the mediation and interaction effects of fasting plasma glucose, total cholesterol, and systolic blood pressure were determined.ResultsA total of 19073 participants were included in this pooled analysis. During a median of 20.7 years of follow-up, 3900 (20.44%) CVD and 6480 (33.97%) all-cause mortality events were recorded. After adjusting for potential confounders, BMI variability was linked to the 1.3 (1.2-1.4) and 1.7 (1.6-1.8) increased risk of CVD and mortality, respectively. Fasting plasma glucose mediated approximately 24% and 8% of the effect of BMI variability on CVD and mortality, respectively. However, systolic blood pressure and total cholesterol did not have mediation effects in this association.ConclusionHigh BMI variability is independently associated with the development of CVD and mortality. This association is partly mediated through fasting plasma glucose. Modern cardiometabolic therapies that lower fasting glucose may reduce the risk of future CVD and mortality in individuals with high BMI variability.

Normative Values of Echocardiographic Chamber Size and Function in Older Healthy Adults: The Multi-Ethnic Study of Atherosclerosis.

Echocardiographic (2-dimensional echocardiography) thresholds indicating disease or impaired functional status compared with normal physiological aging in individuals aged ≥65 years are not clearly defined. In the present study, we sought to establish standard values for 2-dimensional echocardiography parameters related to chamber size and function in older adults without cardiopulmonary or cardiometabolic conditions. In this cross-sectional study of 3032 individuals who underwent 2-dimensional echocardiography at exam 6 in the MESA (Multi-Ethnic Study of Atherosclerosis), 608 participants fulfilled our inclusion criteria of healthy aging, with normative values defined as the mean ± 1.96 standard deviation and compared across sex and race and ethnicity. Functional status measures included NT-proBNP (N-terminal pro-B-type natriuretic peptide), 6-minute walk distance, and Kansas City Cardiomyopathy Questionnaire. Prognostic performance using MESA cutoffs was compared with established guideline cutoffs using time-to-event analysis. The normative aging cohort (69.5±7.0 years, 46.2% male, 47.5% White) had lower NT-proBNP, higher 6-minute walk distance, and higher (better) Kansas City Cardiomyopathy Questionnaire summary values. Women had significantly smaller chamber sizes and better biventricular systolic function. White participants had the largest chamber dimensions, whereas Chinese participants had the smallest, even after adjustment for body size. Current guidelines identified 81.6% of healthy older adults in MESA as having cardiac abnormalities. Among a large, diverse group of healthy older adults, we found significant differences in cardiac structure and function by sex and race/ethnicity, which may signal sex-specific cardiac remodeling with advancing age. It is crucial for existing guidelines to consider the observed and clinically significant differences in cardiac structure and function associated with healthy aging. Our study highlights that existing guidelines, which grade abnormalities in echocardiographic cardiac chamber size and function based on younger individuals, may not adequately address the anticipated changes associated with normal aging.

Fatherhood and Cardiovascular Health, Disease, and Mortality: Associations From the Multi-Ethnic Study of Atherosclerosis

IntroductionEmerging literature links fatherhood to men's health, but lacks comprehensive assessment of health outcomes, especially among multi-ethnic populations. Our objective was to evaluate the associations of fatherhood (age at onset and status) with cardiovascular health (CVH) scores, incident cardiovascular disease (CVD), CVD death and all-cause mortality, examining differences by race/ethnicity. MethodsWe included men from Multi-Ethnic Study of Atherosclerosis (MESA), prospective cohort study which enrolled adults aged 45 to 84 years without known CVD at baseline. CVH was defined using the American Heart Association Life's Essential 8 (LE8) scores (0-100), excluding sleep (CVH score). ResultsIn this sample of 2,814 men, mean age at CVH assessment was 62.2 years, 82% were fathers, 24% self-identified as Black, 13% Chinese, 22% Hispanic, and 41% White. Fathers who were <20 and 20-24 years old at their oldest child's birth had worse overall CVH compared with fathers who were >35 years old (adjusted mean score 61.1 vs 64.7, p=0.01 and 61.0 vs 64.7, p<0.001 respectively). Fathers had worse overall CVH (adjusted mean score 63.2 vs 64.7, p=0.03) and more nicotine exposure (63.1 vs 66.6, p=0.04), than non-fathers. In age-adjusted models, fathers overall (hazard ratio [HR]=0.82; 95%CI, 0.69–0.98) and Black fathers (HR=0.73; 95%CI, 0.53–0.999) had a lower rate of all-cause mortality rate than non-fathers, but these associations were no longer significant in fully adjusted models. ConclusionFatherhood is a social determinant of health and understanding its influence may provide opportunities to improve men's health, particularly among men of color.

Associations between Hysterectomy and Metabolic Syndrome: The Multi-Ethnic Study of Atherosclerosis

Metabolic syndrome is linked to an increased risk of incident cardiovascular disease (CVD) and all-cause mortality. Notable associations exist between hysterectomy with bilateral salpingo-oophorectomy and metabolic syndrome. However, there is emerging evidence that even with ovarian conservation, hysterectomy may be independently associated with long-term CVD risk. To examine the associations between hysterectomy with ovarian preservation and metabolic syndrome risk in a multi-ethnic cohort. We studied 3,367 female participants in the Multi-Ethnic Study of Atherosclerosis who had data on self-reported history of hysterectomy, oophorectomy, hystero-oophorectomy and metabolic syndrome at baseline (2000-2002). We used adjusted logistic regression to assess the cross-sectional associations between hysterectomy/oophorectomy subgroups and prevalent metabolic syndrome at baseline. Furthermore, we investigated 1,355 participants free of baseline metabolic syndrome and used adjusted Cox regression models to evaluate incident metabolic syndrome from exams 2 (2002-2004) to 6 (2016-2018). The mean±SD age was 59.0±9.5 years, with 42% White, 27% Black, 19% Hispanic, and 13% Chinese American participants. 29% and 22% had a history of hysterectomy and oophorectomy, respectively. Over a median follow-up period of 10.5 (3.01-17.62) years, there were 750 metabolic syndrome events. Hysterectomy [HR, 1.32 (95%CI, 1.01-1.73)] and hystero-oophorectomy [1.40 (1.13-1.74)] were both strongly associated with incident metabolic syndrome compared to having neither hysterectomy or oophorectomy. Hysterectomy, even with ovarian preservation, may be independently associated with a higher risk of metabolic syndrome. If other studies confirm these findings, screening and preventive strategies focused on females with ovary-sparing hysterectomy and the mechanisms underpinning these associations may be explored.

Relationship of Apolipoprotein C-III proteoform composition with ankle-brachial index and peripheral artery disease in the Multi-Ethnic Study of Atherosclerosis (MESA)

Background and aimsApolipoprotein C-III (apoC-III) proteoform composition show distinct relationships with plasma lipids and cardiovascular risk. The present study tested whether apoC-III proteoforms are associated with risk of peripheral artery disease (PAD). MethodsApoC-III proteoforms, i.e., native (C-III0a), and glycosylated with zero (C-III0b), one (C-III1) or two (C-III2) sialic acids, were measured by mass spectrometry immunoassay on 5,734 Multi-Ethnic Study of Atherosclerosis participants who were subsequently followed for clinical PAD over 17 years. Ankle-brachial index (ABI) was also assessed at baseline and then 3 and 10 years later in 4,830 participants. ResultsHigher baseline C-III0b/C-III1 and lower baseline C-III2/C-III1 were associated with slower decline in ABI (follow-up adjusted for baseline) over time, independently of cardiometabolic risk factors, and plasma triglycerides and HDL cholesterol levels (estimated differences per 1 SD were 0.31% for both, p <0.01). The associations between C-III2/C-III1 and changes in ABI were stronger in men (-1.21% vs. -0.27% in women), and in Black and Chinese participants (-0.83% and -0.86% vs. 0.12% in White). Higher C-III0b/C-III1 was associated with a trend for lower risk of PAD (HR=0.84 [95%CI: 0.67-1.04]) that became stronger after excluding participants on lipid-lowering medications (0.73 [95%CI: 0.57-0.94]). Neither change in ABI nor clinical PAD were related to total apoC-III levels. ConclusionsWe found associations of apoC-III proteoform composition with changes in ABI that were independent of other risk factors, including plasma lipids. Our data further support unique properties of apoC-III proteoforms in modulating vascular health that go beyond total apoC-III levels.

Association of High-Density Lipoprotein Parameters and Risk of HeartFailure: A Multicohort Analysis.

High-density lipoprotein (HDL) is commonly characterized by its cholesterol concentration (HDL-C) and inverse association with atherosclerotic cardiovascular disease. The authors sought to evaluate the association of HDL particle concentration (HDL-P), HDL particle size (HDL-size), HDL-C, and cholesterol content per particle (HDL-C/HDL-P) with risk of overall heart failure (HF) and subtypes. Participants from the Atherosclerosis Risk In Communities Study, Dallas Heart Study, Multi-Ethnic Study of Atherosclerosis, and Prevention of Renal and Vascular End-stage Disease studies without HF history were included. Associations of HDL-P, HDL-size, HDL-C, and HDL-C/HDL-P with risk of overall HF, HF with reduced and preserved ejection fraction were assessed using adjusted Cox models. Among 16,925 participants (53.5% women; 21.8% Black), there were 612 incident HF events (3.6%) (HF with reduced ejection fraction, 309 [50.5%]; HF preserved ejection fraction, 303 [49.5%]) over median follow-up of 11.4 years. In adjusted models, higher HDL-P was significantly associated with lower HF risk (HR of highest vs lowest tertile of HDL-P: 0.76 [95%CI: 0.62-0.93]). Larger HDL-size was significantly associated with higher overall HF risk (HR of largest vs smallest tertile of HDL-size: 1.27 [95%CI: 1.03-1.58]). HF risk associated with HDL-P and HDL-size was similar for HF subtypes. In adjusted analyses, there was no significant association between HDL-C and HF risk. Higher HDL-C/HDL-P was significantly associated with higher overall HF risk (HR of highest vs lowest tertile of HDL-C/HDL-P: 1.29 [95%CI: 1.04-1.60]). Higher HDL-P was associated with a lower risk of HF. In contrast, larger HDL-size was associated with higher risk of HF and there was no significant association observed between HDL-C and HF risk after accounting for cardiovascular risk factors.

Association of Water Arsenic With Incident Diabetes in U.S. Adults: The Multi-Ethnic Study of Atherosclerosis and the Strong Heart Study.

We examined the association of arsenic in federally regulated community water systems (CWSs) and unregulated private wells with type 2 diabetes (T2D) incidence in the Strong Heart Family Study (SHFS), a prospective study of American Indian communities, and the Multi-Ethnic Study of Atherosclerosis (MESA), a prospective study of racially and ethnically diverse urban U.S. communities. We evaluated 1,791 participants from SHFS and 5,777 participants from MESA who had water arsenic estimates available and were free of T2D at baseline (2001-2003 and 2000-2002, respectively). Participants were followed for incident T2D until 2010 (SHFS cohort) or 2019 (MESA cohort). We used Cox proportional hazards mixed-effects models to account for clustering by family and residential zip code, with adjustment for sex, baseline age, BMI, smoking status, and education. T2D incidence was 24.4 cases per 1,000 person-years (mean follow-up, 5.6 years) in SHFS and 11.2 per 1,000 person-years (mean follow-up, 14.0 years) in MESA. In a meta-analysis across the SHFS and MESA cohorts, the hazard ratio (95% CI) per doubling in CWS arsenic was 1.10 (1.02, 1.18). The corresponding hazard ratio was 1.09 (0.95, 1.26) in the SHFS group and 1.10 (1.01, 1.20) in the MESA group. The corresponding hazard ratio (95% CI) for arsenic in private wells and incident T2D in SHFS was 1.05 (0.95, 1.16). We observed statistical interaction and larger magnitude hazard ratios for participants with BMI <25 kg/m2 and female participants. Low to moderate water arsenic levels (<10 µg/L) were associated with T2D incidence in the SHFS and MESA cohorts.

Sleep stage prediction using multimodal body network and circadian rhythm.

Quality sleep plays a vital role in living beings as it contributes extensively to the healing process and the removal of waste products from the body. Poor sleep may lead to depression, memory deficits, heart, and metabolic problems, etc. Sleep usually works in cycles and repeats itself by transitioning into different stages of sleep. This study is unique in that it uses wearable devices to collect multiple parameters from subjects and uses this information to predict sleep stages and sleep patterns. For the multivariate multiclass sleep stage prediction problem, we have experimented with both memoryless (ML) and memory-based models on seven database instances, that is, five from the collected dataset and two from the existing datasets. The Random Forest classifier outclassed the ML models that are LR, MLP, kNN, and SVM with accuracy (ACC) of 0.96 and Cohen Kappa 0.96, and the memory-based model long short-term memory (LSTM) performed well on all the datasets with the maximum attained accuracy of 0.88 and Kappa 0.82. The proposed methodology was also validated on a longitudinal dataset, the Multiethnic Study of Atherosclerosis (MESA), with ACC and Kappa of 0.75 and 0.64 for ML models and 0.86 and 0.78 for memory-based models, respectively, and from another benchmarked Apple Watch dataset available on Physio-Net with ACC and Kappa of 0.93 and 0.93 for ML and 0.92 and 0.87 for memory-based models, respectively. The given methodology showed better results than the original work and indicates that the memory-based method works better to capture the sleep pattern.

0002 Associations Between Sleep and Rest-Activity Rhythms with Diet Quality in the Multi-Ethnic Study of Atherosclerosis

0002 Associations Between Sleep and Rest-Activity Rhythms with Diet Quality in the Multi-Ethnic Study of Atherosclerosis

Reference Values for Indexed Echocardiographic Chamber Sizes in Older Adults: The Multi-Ethnic Study of Atherosclerosis.

Normalization of echocardiographic chamber measurements for body surface area may result in misclassification of individuals with obesity or sarcopenia. Normalization for alternative measures of body size may be preferable, but there remains a dearth of information on their normative values and association with cardiovascular function metrics. A total of 3032 individuals underwent comprehensive 2-dimensional echocardiography at Exam 6 in MESA (Multi-Ethnic Study of Atherosclerosis). In the subgroup of 608 individuals free of cardiopulmonary disease (69.5±7.0 years, 46% male, 48% White, 17% Chinese, 15% Black, 21% Hispanic), normative values were derived for left and right cardiac chamber measurements across a variety of ratiometric (body surface area, body mass index, height) and allometric (height1.6, height2.7) scaling parameters. Normative upper and lower reference values were provided for each scaling parameter stratified across age groups, sex, and race or ethnicity. Among scaling parameters, body surface area and height were associated with the least variability across race and ethnicity categories and height2.7 was associated with the least variability across sex categories. In this diverse cohort of community-dwelling older adults, we provide normative values for common echocardiographic parameters across a variety of indexation methods.

AI-enabled cardiac chambers volumetry in coronary artery calcium scans (AI-CACTM) predicts heart failure and outperforms NT-proBNP: The multi-ethnic study of Atherosclerosis

IntroductionCoronary artery calcium (CAC) scans contain useful information beyond the Agatston CAC score that is not currently reported. We recently reported that artificial intelligence (AI)-enabled cardiac chambers volumetry in CAC scans (AI-CAC™) predicted incident atrial fibrillation in the Multi-Ethnic Study of Atherosclerosis (MESA). In this study, we investigated the performance of AI-CAC cardiac chambers for prediction of incident heart failure (HF). MethodsWe applied AI-CAC to 5750 CAC scans of asymptomatic individuals (52% female, White 40%, Black 26%, Hispanic 22% Chinese 12%) free of known cardiovascular disease at the MESA baseline examination (2000–2002). We used the 15-year outcomes data and compared the time-dependent area under the curve (AUC) of AI-CAC volumetry versus NT-proBNP, Agatston score, and 9 known clinical risk factors (age, gender, diabetes, current smoking, hypertension medication, systolic and diastolic blood pressure, LDL, HDL for predicting incident HF over 15 years. ResultsOver 15 years of follow-up, 256 HF events accrued. The time-dependent AUC [95% CI] at 15 years for predicting HF with AI-CAC all chambers volumetry (0.86 [0.82,0.91]) was significantly higher than NT-proBNP (0.74 [0.69, 0.77]) and Agatston score (0.71 [0.68, 0.78]) (p ​< ​0.0001), and comparable to clinical risk factors (0.85, p ​= ​0.4141). Category-free Net Reclassification Index (NRI) [95% CI] adding AI-CAC LV significantly improved on clinical risk factors (0.32 [0.16,0.41]), NT-proBNP (0.46 [0.33,0.58]), and Agatston score (0.71 [0.57,0.81]) for HF prediction at 15 years (p ​< ​0.0001). ConclusionAI-CAC volumetry significantly outperformed NT-proBNP and the Agatston CAC score, and significantly improved the AUC and category-free NRI of clinical risk factors for incident HF prediction.

AI-enabled left atrial volumetry in coronary artery calcium scans (AI-CACTM) predicts atrial fibrillation as early as one year, improves CHARGE-AF, and outperforms NT-proBNP: The multi-ethnic study of atherosclerosis

BackgroundCoronary artery calcium (CAC) scans contain actionable information beyond CAC scores that is not currently reported. MethodsWe have applied artificial intelligence-enabled automated cardiac chambers volumetry to CAC scans (AI-CACTM) to 5535 asymptomatic individuals (52.2% women, ages 45–84) that were previously obtained for CAC scoring in the baseline examination (2000–2002) of the Multi-Ethnic Study of Atherosclerosis (MESA). AI-CAC took on average 21 ​s per CAC scan. We used the 5-year outcomes data for incident atrial fibrillation (AF) and assessed discrimination using the time-dependent area under the curve (AUC) of AI-CAC LA volume with known predictors of AF, the CHARGE-AF Risk Score and NT-proBNP. The mean follow-up time to an AF event was 2.9 ​± ​1.4 years. ResultsAt 1,2,3,4, and 5 years follow-up 36, 77, 123, 182, and 236 cases of AF were identified, respectively. The AUC for AI-CAC LA volume was significantly higher than CHARGE-AF for Years 1, 2, and 3 (0.83 vs. 0.74, 0.84 vs. 0.80, and 0.81 vs. 0.78, respectively, all p ​< ​0.05), but similar for Years 4 and 5, and significantly higher than NT-proBNP at Years 1–5 (all p ​< ​0.01), but not for combined CHARGE-AF and NT-proBNP at any year. AI-CAC LA significantly improved the continuous Net Reclassification Index for prediction of AF over years 1–5 when added to CHARGE-AF Risk Score (0.60, 0.28, 0.32, 0.19, 0.24), and NT-proBNP (0.68, 0.44, 0.42, 0.30, 0.37) (all p ​< ​0.01). ConclusionAI-CAC LA volume enabled prediction of AF as early as one year and significantly improved on risk classification of CHARGE-AF Risk Score and NT-proBNP.

Investigating peripheral blood monocyte and T-cell subsets as non-invasive biomarkers for asymptomatic hepatic steatosis: results from the Multi-Ethnic Study of Atherosclerosis.

Circulating immune cells have gained interest as biomarkers of hepatic steatosis. Data on the relationships between immune cell subsets and early-stage steatosis in population-based cohorts are limited. This study included 1,944 asymptomatic participants of the Multi-Ethnic Study of Atherosclerosis (MESA) with immune cell phenotyping and computed tomography measures of liver fat. Participants with heavy alcohol use were excluded. A liver-to-spleen ratio Hounsfield units (HU) <1.0 and liver attenuation <40 HU were used to diagnose liver fat presence and >30% liver fat content, respectively. Logistic regression estimated cross-sectional associations of immune cell subsets with liver fat parameters adjusted for risk factors. We hypothesized that higher proportions of non-classical monocytes, Th1, Th17, and memory CD4+ T cells, and lower proportions of classical monocytes and naive CD4+ T cells, were associated with liver fat. Exploratory analyses evaluated additional immune cell phenotypes (n = 19). None of the hypothesized cells were associated with presence of liver fat. Higher memory CD4+ T cells were associated with >30% liver fat content, but this was not significant after correction for multiple hypothesis testing (odds ratio (OR): 1.31, 95% confidence interval (CI): 1.03, 1.66). In exploratory analyses unadjusted for multiple testing, higher proportions of CD8+CD57+ T cells were associated with liver fat presence (OR: 1.21, 95% CI: 1.02, 1.44) and >30% liver fat content (OR: 1.34, 95% CI: 1.07, 1.69). Higher circulating memory CD4+ T cells may reflect liver fat severity. CD8+CD57+ cells were associated with liver fat presence and severity, but replication of findings is required.

Trabecular bone mineral density as measured by thoracic vertebrae predicts incident hip and vertebral fractures: the multi-ethnic study of atherosclerosis.

Osteoporosis affects an enormous number of patients, of all races and both sexes, and its prevalence increases as the population ages. Few studies have evaluated the association between the vertebral trabecular bone mineral density(vBMD) and osteoporosis-related hip fracture in a multiethnic population, and no studies have demonstrated the predictive value of vBMD for fractures. We sought to determine the predictive value of QCT-based trabecular vBMD of thoracic vertebrae derived from coronary artery calcium scan for hip fractures in the Multi-Ethnic Study of Atherosclerosis(MESA), a nationwide multicenter cohort included 6814 people from six medical centers across the USA and assess if low bone density by QCT can predict future fractures. Measures were done using trabecular bone measures, adjusted for individual patients, from three consecutive thoracic vertebrae (BDI Inc, Manhattan Beach CA, USA) from non-contrast cardiac CT scans. Six thousand eight hundred fourteen MESA baseline participants were included with a mean age of 62.2 ± 10.2years, and 52.8% were women. The mean thoracic BMD is 162.6 ± 46.8mg/cm3 (95% CI 161.5, 163.7), and 27.6% of participants (n = 1883) had osteoporosis (T-score 2.5 or lower). Over a median follow-up of 17.4years, Caucasians have a higher rate of vertebral fractures (6.9%), followed by Blacks (4.4%), Hispanics (3.7%), and Chinese (3.0%). Hip fracture patients had a lower baseline vBMD as measured by QCT than the non-hip fracture group by 13.6mg/cm3 [P < 0.001]. The same pattern was seen in the vertebral fracture population, where the mean BMD was substantially lower 18.3mg/cm3 [P < 0.001] than in the non-vertebral fracture population. Notably, the above substantial relationship was unaffected by age, gender, race, BMI, hypertension, current smoking, medication use, or activity. Patients with low trabecular BMD of thoracic vertebrae showed a 1.57-fold greater risk of first hip fracture (HR 1.57, 95% CI 1.38-1.95) and a nearly threefold increased risk of first vertebral fracture (HR 2.93, 95% CI 1.87-4.59) compared to normal BMD patients. There is significant correlation between thoracic trabecular BMD and the incidence of future hip and vertebral fracture. This study demonstrates that thoracic vertebrae BMD, as measured on cardiac CT (QCT), can predict both hip and vertebral fractures without additional radiation, scanning, or patient burden. Osteopenia and osteoporosis are markedly underdiagnosed. Finding occult disease affords the opportunity to treat the millions of people undergoing CT scans every year for other indications.

Abstract P113: Associations of Immune Cell Subsets With Coronary Artery Calcium Incidence and Progression in the Multi-Ethnic Study of Atherosclerosis

Introduction: Coronary artery calcium (CAC) and its progression strongly associates with incident cardiovascular disease (CVD). Although immune dysregulation and related inflammation are important causes of coronary artery disease, few data exist on associations between specific immune cell subsets and CAC presence and progression. Hypothesis: We hypothesized innate &amp; adaptive immune cell subsets are associated with longitudinal CAC changes Methods: In the Multi-Ethnic Study of Atherosclerosis (MESA), we examined associations of immune cell subsets (measured at baseline in peripheral blood by flow cytometry) with incident CAC and CAC progression. Of 975 participants sampled who had CAC and immune cell subsets measured at baseline (2000-02), 378 had CAC 0 at baseline and were used to examine incident CAC from MESA exam 2 (2002-04) through 5 (2010-12); the remaining 597 participants were included to analyze CAC progression from exam 1-5. Incident CAC analyses (N=378) used Weighted Cox regressions to determine hazard ratios of incident CAC, adjusted for age, gender, race, MESA site, education, smoking status, blood pressure, body-mass index, diabetes status, cholesterol, HDL cholesterol, statin use, and antihypertensive medication. CAC progression analyses among individuals with nonzero CAC at baseline (N=597) used weighted multivariable-adjusted linear mixed models to investigate associations of baseline immune cell subsets with CAC progression, with Benjamini-Hochberg correction for multiple comparisons. Results: Among 378 participants with CAC 0 and immune cell subsets measured at baseline, 149 had incident CAC between MESA examination 2-5. Of 19 subsets measured, natural killer (NK) cells (CD3-CD16+CD56+) were associated with an elevated risk of incident CAC (hazard ratio (HR) 1.26 per standard deviation (SD) higher NK cells; 95% confidence interval (CI) 1.03-1.56, p=0.03). Two CD4+ T cell subsets, Th1 (HR 0.81, 95% CI 0.66-0.99, p=0.04) and Th2 (HR 0.80, 95% CI 0.64-0.99, p=0.04) were associated with a borderline lower risk for incident CAC. In analyses of CAC progression for participants with nonzero CAC at baseline (N=597), CD19+ B-cells were associated with CAC progression (beta-coefficient=53.1 Agatston units per SD higher B-cells proportion, 95% CI 2.0-104.2, p=0.04), while intermediate monocytes (CD14+CD16+) (beta = -71.6 Agatston units per SD higher, 95% CI -134.9 - -8.3, p=0.03) and higher T-regulatory cells (CD4+CD25+CD127-) (beta = -71.6 Agatston units per SD higher, 95% CI -119.1 - -4.8, p=0.03) were negatively associated with CAC progression. Conclusions: Among individuals with CAC 0 at baseline, NK cells were associated with incident CAC. In individuals with nonzero CAC at baseline, T-regulatory cells and intermediate monocytes were negatively associated with CAC progression, whereas B-cells were positively associated with CAC progression.

Abstract P525: Polygenic Risk Scores for Morning Chronotype and Longer Sleep Duration Are Associated With Weight and Glycemic Outcomes in the Multi-Ethnic Study of Atherosclerosis (MESA)

Introduction: Circadian rhythms regulate key physiological processes, including sleep-wake. Alterations in the circadian rhythm have been associated with greater risk of metabolic diseases. Genome-wide association studies (GWAS) have revealed genes variants associated with sleep phenotypes. Hypothesis: Polygenic risk scores (PRS) for significant SNPs reported in GWAS of chronotype (C), sleep duration (SD), and short sleep (SS, &lt;7/h) are associated with metabolic parameters. Methods: We carried out a longitudinal analysis in 6,814 adults (aged 45-84 y at baseline) from the Multi-Ethnic Study of Atherosclerosis (MESA). Glucose, insulin, insulin resistance (HOMA-IR), body mass index (BMI) and waist circumference (WC) were assessed at baseline (2000-2002) and 16-18 y follow-up (Exam 6, N=3,303). DNA was extracted from whole blood, and genotyping data were obtained by the Affymetrix 6.0 SNP array. PRS for the following phenotypes were constructed as weight sum of genoma-wide significant alleles: 1) chronotype [PRS-C]; 2) continuous SD [PRS-SD]; and 3) SS duration [PRS-SS]. Multivariable linear regression models adjusted by sociodemographic, obesity, smoking, Mediterranean diet, physical activity and antidiabetic drugs were performed to assess associations between PRS and study outcomes (fasting glucose and insulin, HOMA-IR, hemoglobin A1c, BMI, and WC) cross-sectionally and longitudinally. Results: At baseline, none of the PRS were associated with glucose, insulin or HOMA-IR (p&gt;0.05). A significant positive association was detected for PRS-C with BMI and WC: greater genetically determined morningness was associated with lower BMI (β=-20.0±3.0; p&lt;0.001) and smaller WC (β=-44.1±8.0; p&lt;0.001). Similar results were observed with PRS-SD (BMI: β=-0.1±0.0; p=0.005; WC: β=-0.3±0.1; p=0.008) and PRS-SS (BMI: β=9.3±2.8; p&lt;0.001; WC: β=19.8±7.4; p=0.007). In longitudinal analyses, we observed prospective associations between PRS-C with BMI (β=-43.5±12.2; p&lt;0.001), WC (β=-116.0.1±29.1; p&lt;0.001), and glucose (β=-204.7±90.0; p=0.024). PRS-SS was longitudinally associated with HOMA-IR (β=214.1±88.0; p=0.017) and a trend was observed for hemoglobin A1c (β=-6.6±3.4; p=0.053), but not with anthropometrics parameters. No associations were noted for PRS-SD with obesity and glycemic outcomes in longitudinal analyses. Conclusion: In the MESA population, PRS for chronotype, sleep duration, and short sleep are associated with anthropometric but not with glycemic measures in cross-sectional analyses. However, PRS for chronotype and short sleep was associated with anthropometric and glycemic parameters in longitudinal analyses, suggesting the importance of genetic predisposition for morningness and adequate sleep duration for metabolic health.

Abstract P131: Individualized Risk Prediction for Type 2 Diabetes: A Secondary Analysis of the Diabetes Prevention Program

Introduction: Type 2 diabetes (T2D) risk prediction models that predict risk with individualized preventive intervention effects can help targeted prevention. Hypothesis: An individualized T2D risk prediction model developed in the Diabetes Prevention Program (DPP) randomized trial that incorporates differential treatment effects based on an individual’s fasting glucose (FG) level and body mass index (BMI) will provide more accurate predictions than a model without individualized treatment effects. Methods: We included 2640 DPP participants randomized to the placebo, metformin, or lifestyle arms. Using 50% of the DPP sample, we developed a non-individualized Cox model predicting T2D risk over 3 years with adjustment for sex, hemoglobin A1c, triglycerides, FG, BMI, and treatment, and an individualized model with adjustment for these variables plus interactions between treatment and age, FG, and BMI. In the remaining 50%, we evaluated the prediction accuracy of both models using the concordance (C)-statistic. We repeated this process 100 times with different random splits. We externally validated models among Multi-Ethnic Study of Atherosclerosis (MESA) adults with prediabetes (n=1067) where model predictions were computed for each intervention scenario and averaged for all participants. Results: Mean (standard deviation) age of participants was 51 (11) years in the DPP and 64 (10) in MESA, with 67% and 54% women, respectively. Mean C-statistics for our individualized and non-individualized prediction models (100 splits) in DPP were 0.71 and 0.70, respectively (table). The individualized model predicted higher benefit of lifestyle intervention at lower BMI levels and higher benefit of both metformin and lifestyle at higher FG. The C-statistic of the individualized model was 0.78 in the MESA validation. Conclusion: Creating individualized estimates of intervention effects can improve accuracy of T2D risk prediction models, allowing patients to make more informed decisions about prevention strategies.

Abstract P127: Health Literacy and COVID-19 Infection and Vaccination: The C4R-MESA Study

Rationale: Health literacy (HL) is associated with health prevention behaviors and may influence COVID-19 outcomes. Objective: To test associations of HL, risk of COVID-19 infection, and receipt of COVID-19 vaccines in a multi-ethnic US community-based sample. Methods: The Multi-Ethnic Study of Atherosclerosis (MESA) assessed participant levels of HL via follow-up phone calls in year 18 (2016-18), as well as the impact of the COVID-19 pandemic via questionnaires designed by the Collaborative Cohort of Cohorts for COVID-19 Research (C4R) Study (2020-23). The 4 HL items asked about difficulty in the ability to read, comprehend, and complete medical materials and understand medical statistics (scales 1-5, low to high difficulty); scores were summed and dichotomized into adequate (≤10) or low (&gt;10) HL. COVID-19 data included infection and vaccination status and time (days) until infection and vaccination (March 2020-February 2023). Unadjusted comparisons of COVID-19 data and HL were assessed by Chi-square and T-tests. Cox proportional hazards models were adjusted for age, sex, race/ethnicity, and then additionally for income and education. Results: Of 3412 participants (mean age 77 years; 54% female; 41% White, 13% Chinese, 26% Black 20% Hispanic), 409 (12%) had low HL and 360 (11%) had incident COVID-19 infections. In the subset with vaccination data (N=1781), 94% were vaccinated. While HL was not significantly associated with incident COVID-19 infection, low (vs adequate) HL was significantly associated with longer time-to-vaccination and lower adjusted hazards of vaccination ( Table ). Conclusions: Our findings suggest that low levels of HL are associated with delayed COVID-19 vaccination, even after accounting for demographic and socioeconomic indicators. Improving health literacy in the population may empower and encourage individuals to engage in disease prevention behaviors, including vaccination. Table: Associations of Health Literacy (HL) with COVID-19 Infection and Vaccination