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Objective: To investigate the association of lipoprotein-associated phospholipase A(2) (LpPLA(2)) mass and activity with incident cardiovascular disease (CVD) in a population with high prevalences of insulin resistance and diabetes, conditions for which epidemiological data remain sparse.Research Design and Methods: We conducted a nested, case-control study (n = 1,008) within a population-based cohort of American Indians. Case subjects were defined by incidence of first-ever CVD up to 10 years later. Control subjects comprised participants free of CVD events during the follow-up period who were frequency matched to case subjects by age, sex, and diabetes status. LpPLA(2) mass and activity were measured using commercially available assays.Results: LpPLA(2) mass and activity were moderately correlated with each other (r = 0.30), but only LpPLA(2) activity exhibited moderate correlations with lipid fractions. After extensive adjustment for covariates, both LpPLA(2) measures were significantly associated with incident CVD, but the relationship was inverse for LpPLA(2) mass (highest versus lowest tertile, relative risk [RR] 0.55 [95% CI 0.39-0.79]) and positive for LpPLA(2) activity (highest versus lowest tertile, 1.65 [1.12-2.42]). These associations were similar when participants with and without diabetes were examined separately.Conclusions: In this population-based cohort enriched with dysmetabolic phenotypes, LpPLA(2) mass and activity showed divergent associations with CVD. The inverse relationship for LpPLA(2) mass is contrary to observations from predominantly nondiabetic populations and will require independent replication. Whether this finding relates to redistribution of LpPLA(2) to lipoprotein classes where it is less atherogenic or reflects incomplete measurement of LpPLA(2) mass associated with altered lipoprotein composition in insulin resistance warrants further investigation. [ABSTRACT FROM AUTHOR]

Hypertensive disorders of pregnancy (HDP), including pre-existing hypertension, gestational hypertension, and preeclampsia, further complicate already high-risk pregnancies in women with diabetes mellitus (DM). Women with both pre-existing and gestational diabetes are at increased risk for HDP, leading to higher maternal and fetal morbidity. Further, particularly in diabetic women and women with a history of gestational diabetes, HDP significantly increases the risk for future cardiovascular events. For clinicians, women with hypertension and diabetes during pregnancy pose a management challenge. Specifically, preconception management should stress strict control of glycemia, blood pressure, and prevention of diabetic complications, specifically nephropathy, which specifically increases the risk for preeclampsia. During gestation, clinicians must be aware of potential maternal and fetal complications associated with various anti-hypertensive therapies, including known fetotoxicity of ACE inhibitors and ARBs when given in the 2nd or 3rd trimester, and the risks and benefits of expectant management versus delivery in cases of severe gestational hypertension or preeclampsia. Indeed, diabetic women must be followed closely prior to conception and throughout gestation to minimize the risk of HDP and its associated complications. [ABSTRACT FROM AUTHOR]

BACKGROUND: Alterations in plasma fatty acid distribution are linked to metabolic abnormalities related to type 2 diabetes and cardiovascular disease. OBJECTIVE: The aim of this study was to investigate genetic factors influencing plasma fatty acid distribution in Alaskan Eskimos from the Genetics of Coronary Artery Disease in Alaska Natives (GOCADAN) study. DESIGN: Fatty acids in plasma were measured by gas chromatography in 761 related individuals (>35 y of age). RESULTS: Quantitative genetic analyses showed that fatty acid distribution is significantly heritable (P < 0.001), with heritabilities ranging from 0.33 to 0.55. A genome-wide scan for plasma fatty acids identified a 20-cM region on chromosome 8 (p12-p21) with a quantitative trait locus for monounsaturated fatty acids (logarithm of odds score = 3.8). The same region had a quantitative trait locus for polyunsaturated fatty acids (logarithm of odds score = 2.6). We genotyped single nucleotide polymorphisms (SNPs) in candidate genes in 8p12-p21 and found a significant association between fatty acids and SNPs in apolipoprotein J (APOJ), lipoprotein lipase (LPL), macrophage scavenger receptor 1 (MSR1), and tumor necrosis factor receptor superfamily member 10b (TNFRSF10B). A Bayesian quantitative trait nucleotide analysis based on a measured genotype model showed that SNPs in LPL, TNFRSF10B, and APOJ had strong statistical evidence of a functional effect (posterior probability > or =75%) on plasma fatty acid distribution. CONCLUSIONS: The results indicate that there is strong genetic influence on plasma fatty acid distribution and that genetic variation in APOJ, LPL, and TNFRSF10B may play a role. The GOCADAN study was registered at www.clinicaltrials.gov as NCT00006192. © 2010 American Society for Nutrition [ABSTRACT FROM AUTHOR]

Background: Studies examining sleep in the hemodialysis (HD) population have largely lacked an adequate comparison group. It therefore is uncertain whether poor sleep quality in the HD population reflects age, chronic health conditions, or effects of conventional HD therapy.Study Design: Cross-sectional matched-group study.Setting& Participants: Forty-six in-center HD patients were compared with 137 community participants participating in the Sleep Heart Health Study matched for age, sex, body mass index, and race.Predictor: HD patients compared with community-dwelling non-HD participants.Outcomes& Measurements: Home unattended polysomnography was performed and scored by using similar protocols. Sleep habits and sleepiness were assessed by using the Sleep Habits Questionnaire and Epworth Sleepiness Scale.Results: Average age of study samples was 63 years, 72% were white, and average body mass index was 28 +/- 5 kg/m(2). HD patients were significantly more likely than community participants to have short sleep (odds ratio, 3.27; 95% confidence interval, 1.16 to 9.25) and decreased sleep efficiency (odds ratio, 5.5; 95% confidence interval, 1.5 to 19.6). HD patients reported more difficulty getting back to sleep (odds ratio, 2.25; 95% confidence interval, 1.11 to 4.60) and waking up too early (odds ratio, 2.39; 95% confidence interval, 1.01 to 5.66). There was no association between polysomnography sleep time and self-reported sleep time (r = 0.09; P = 0.6) or between the Epworth Sleepiness Scale and severity of sleep apnea (r = 0.10; P = 0.5) in the HD population.Limitations: The study was limited to participants older than 45 years.Conclusions: Kidney failure treated with thrice-weekly HD is significantly associated with poor subjective and objective sleep quality. [ABSTRACT FROM AUTHOR]

Context: Individuals with diabetes are at increased risk for cardiovascular disease (CVD), but more aggressive targets for risk factor control have not been tested.Objective: To compare progression of subclinical atherosclerosis in adults with type 2 diabetes treated to reach aggressive targets of low-density lipoprotein cholesterol (LDL-C) of 70 mg/dL or lower and systolic blood pressure (SBP) of 115 mm Hg or lower vs standard targets of LDL-C of 100 mg/dL or lower and SBP of 130 mm Hg or lower.Design, Setting, and Participants: A randomized, open-label, blinded-to-end point, 3-year trial from April 2003-July 2007 at 4 clinical centers in Oklahoma, Arizona, and South Dakota. Participants were 499 American Indian men and women aged 40 years or older with type 2 diabetes and no prior CVD events.Interventions: Participants were randomized to aggressive (n=252) vs standard (n=247) treatment groups with stepped treatment algorithms defined for both.Main Outcome Measures: Primary end point was progression of atherosclerosis measured by common carotid artery intimal medial thickness (IMT). Secondary end points were other carotid and cardiac ultrasonographic measures and clinical events.Results: Mean target LDL-C and SBP levels for both groups were reached and maintained. Mean (95% confidence interval) levels for LDL-C in the last 12 months were 72 (69-75) and 104 (101-106) mg/dL and SBP levels were 117 (115-118) and 129 (128-130) mm Hg in the aggressive vs standard groups, respectively. Compared with baseline, IMT regressed in the aggressive group and progressed in the standard group (-0.012 mm vs 0.038 mm; P < .001); carotid arterial cross-sectional area also regressed (-0.02 mm(2) vs 1.05 mm(2); P < .001); and there was greater decrease in left ventricular mass index (-2.4 g/m(2.7) vs -1.2 g/m(2.7); P = .03) in the aggressive group. Rates of adverse events (38.5% and 26.7%; P = .005) and serious adverse events (n = 4 vs 1; P = .18) related to blood pressure medications were higher in the aggressive group. Clinical CVD events (1.6/100 and 1.5/100 person-years; P = .87) did not differ significantly between groups.Conclusions: Reducing LDL-C and SBP to lower targets resulted in regression of carotid IMT and greater decrease in left ventricular mass in individuals with type 2 diabetes. Clinical events were lower than expected and did not differ significantly between groups. Further follow-up is needed to determine whether these improvements will result in lower long-term CVD event rates and costs and favorable risk-benefit outcomes.Trial Registration: clinicaltrials.gov Identifier: NCT00047424. [ABSTRACT FROM AUTHOR]

Background: There have been no studies that use longitudinal data with more than 2 measurements and methods of longitudinal data analysis to identify risk factors for incident albuminuria over time more effectively.Study Design: Longitudinal study.Settings& Participants: A subgroup of participants in the Strong Heart Study, a population-based sample of American Indians, in central Arizona, Oklahoma, and North and South Dakota. Participants with diabetes without albuminuria were followed up for a mean of 4 years.Predictors: Age, sex, study center, high-density lipoprotein and low-density lipoprotein cholesterol levels, triglyceride level, body mass index, systolic blood pressure, use of antihypertensive medication, smoking, hemoglobin A(1c) level, fasting glucose level, type of diabetes therapy, diabetes duration, plasma creatinine level, and urinary albumin-creatinine ratio (UACR).Outcomes& Measurements: Albuminuria was defined as UACR of 30 mg/g or greater. Urine creatinine and albumin were measured by using the picric acid method and a sensitive nephelometric technique, respectively.Results: Of 750 and 568 participants with diabetes without albuminuria and with normal plasma creatinine levels at the first and second examinations, 246 and 132 developed albuminuria by the second and third examinations, respectively. Incident albuminuria was predicted by baseline UACR, fasting glucose level, systolic blood pressure, plasma creatinine level, study center, current smoking, and use of angiotensin-converting enzyme inhibitors and antidiabetic medications. UACR of 10 to 30 mg/g increased the odds of developing albuminuria 2.7-fold compared with UACR less than 5 mg/g.Limitations: Single random morning urine specimen.Conclusions: Many risk factors identified for incident albuminuria can be modified. Control of blood pressure and glucose level, smoking cessation, and use of angiotensin-converting enzyme inhibitors may reduce the incidence of albuminuria. [ABSTRACT FROM AUTHOR]

BACKGROUND: 'Normal' albuminuria has been defined as urinary albumin-creatinine ratio (UACR) less than 30 mg/g (3.4 mg/mmol). Whether higher UACR within this range independently predicts cardiovascular disease (CVD) and CVD death is uncertain. METHODS: A total of 3,000 participants aged 45 to 74 years with a UACR less than 30 mg/g and free of CVD at the baseline examination of the Strong Heart Study (SHS) were evaluated. Survival time was calculated from the baseline examination to the first nonfatal CVD, fatal CVD, or December 31, 2002. RESULTS: During follow-up (average, 10.4 years), 383 incident nonfatal CVD and 145 fatal CVD cases were ascertained. After adjustment for conventional CVD risk factors, participants with a UACR in the third (UACR >or= 5.4 to <10.2 mg/g [>or=0.6 to <1.1 mg/mmol] in men, >or=7.6 to <12.9 mg/g [>or=0.9 to <1.4 mg/mmol] in women) and the fourth (UACR >or=10.2 to <30 mg/g in men, >or=12.9 to <30 mg/g in women) quartiles had 41% and 72% greater risks of all CVD events and 118% and 199% greater risks of CVD mortality than those in the lowest quartile (UACR < 2.7 mg/g [<0.3 mg/mmol] in men, <4.3 mg/g [<0.5 mg/mmol] in women), respectively. In subgroup analysis, these associations were more pronounced in persons with diabetes. CONCLUSION: In the SHS cohort of middle-aged to elderly American Indians, albuminuria levels less than the traditional cutoff value predict CVD. Our findings agree with a growing number of studies questioning the concept that UACR less than 30 mg/g is normal. Copyright © 2007 by the National Kidney Foundation, Inc. [ABSTRACT FROM AUTHOR]

Objectives: This study was designed to facilitate clinical use of central pulse pressure (PP). We sought to determine a value that might predict adverse outcome and thereby provide a target for assessment of intervention strategies.Background: We previously documented that central PP more strongly relates to carotid hypertrophy and extent of atherosclerosis and, more importantly, better predicts incident cardiovascular disease (CVD) than brachial PP.Methods: Radial applanation tonometry was performed in the third Strong Heart Study examination to determine central blood pressure. Cox regression analyses were performed using pre-specified covariates and quartiles of central and brachial PP.Results: Among 2,405 participants without prevalent CVD, 344 suffered CVD events during 5.6 +/- 1.7 years. Quartiles of central PP (p < 0.001) predicted outcome more strongly than quartiles of brachial PP (p = 0.052). With adjustment for covariates, only the event rate in the fourth quartile of central PP (> or =50 mm Hg) was significantly higher than that in the first quartile (hazard ratio [HR]: 1.69, 95% confidence interval [CI]: 1.20 to 2.39, p = 0.003). Central PP > or =50 mm Hg was related to outcome in both men (HR: 2.06, 95% CI: 1.39 to 3.04, p < 0.001) and women (HR: 2.03, 95% CI: 1.55 to 2.65, p < 0.001); in participants with (HR: 1.84, 95% CI: 1.41 to 2.39, p < 0.001) and without diabetes (HR: 1.91, 95% CI: 1.29 to 2.83, p = 0.001); and in individuals younger (HR: 2.51, 95% CI: 1.59 to 3.95, p < 0.001) and older (HR: 1.53, 95% CI: 1.19 to 1.97, p = 0.001) than the age of 60 years.Conclusions: Central PP > or =50 mm Hg predicts adverse CVD outcome and may serve as a target in intervention strategies if confirmed in other populations and in prospective studies. [ABSTRACT FROM AUTHOR]

Rationale: Chronic lung diseases are associated with increased risk of mortality due to coronary heart disease (CHD). Nonetheless, the population attributable fraction (PAF) of lung function impairment relative to other established cardiovascular risk factors is unclear., Objective: To evaluate the PAF of low lung function for CHD mortality Methods: We harmonized and pooled lung function and clinical data across 8 US general population cohorts. Impaired lung function was defined as FEV 1 and/or FVC ≤95% predicted on baseline spirometry. The association between CHD mortality and risk factors was assessed using cause-specific proportional hazards and Fine-Gray proportional subdistribution hazards models, treating non-CHD mortality as a competing risk. Models were adjusted for lung function as well as age, sex, race/ethnicity, educational attainment, body mass index, smoking status, pack-years of smoking, diabetes mellitus, HDL, and high LDL (≥130 mg/dl). PAF was calculated as the relative change in the average absolute risk of ten-year CHD mortality by elimination of lung function lower than 95% predicted., Measurements and Main Results: Among 35143 participants, 1844 of 13174 (14.0%) deaths were due to CHD. Compared to FEV 1 pp >95%, the sub-distribution adjusted hazards ratio (95%CI) for low FEV 1pp was 1.30 (1.18-1.44). The PAF for FEV 1 pp≤95% was 12%, ranking low FEV 1 third in the list of PAF for CHD mortality, after hypertension and diabetes. Low FEV 1 pp ranked second in the subgroup of active smokers (PAF 14%), after hypertension., Conclusions: Low lung function, even in the range considered clinically normal, ranks high in the list of attributable risk factors for CHD mortality and should be considered in cardiovascular risk stratification.

BACKGROUNDLeft ventricular hypertrophy (LVH) and dyslipidemia are strong, independent predictors for cardiovascular disease, but their relationship is less well studied. A longitudinal lipidomic profiling of left ventricular mass (LVM) and LVH is still lacking.METHODSUsing liquid chromatography-mass spectrometry (LC-MS), we repeatedly measured 1,542 lipids from 1,755 unique American Indians attending 2 exams (mean, 5 years apart). Cross-sectional associations of individual lipid species with LVM index (LVMI) were examined by generalized estimating equation (GEE), followed by replication in an independent biracial cohort (65% White, 35% Black). Baseline plasma lipids associated with LVH risk beyond traditional risk factors were identified by logistic GEE model in American Indians. Longitudinal associations between changes in lipids and changes in LVMI were examined by GEE, adjusting for baseline lipids, baseline LVMI, and covariates.RESULTSMultiple lipid species were significantly associated with LVMI or the risk of LVH in American Indians. Some lipids were confirmed in Black and White individuals. Moreover, some LVH-related lipids were inversely associated with risk of coronary heart disease (CHD). Longitudinal changes in several lipid species were significantly associated with changes in LVMI.CONCLUSIONAltered fasting plasma lipidome and its longitudinal change over time were significantly associated with LVMI and risk for LVH in American Indians. Our results offer insight into the role of individual lipid species in LV remodeling and risk of LVH, independent of known risk factors.FUNDINGThis study was supported by the NIH grant (R01DK107532). The Strong Heart Study has been funded in whole or in part with federal funds from the National Heart, Lung, and Blood Institute, NIH, Department of Health and Human Services, under contract nos. 75N92019D00027, 75N92019D00028, 75N92019D00029, and 75N92019D00030.

Background: The burden of kidney disease is exceedingly high among American Indians (AIs). We sought to examine the relationship of diet quality, a modifiable risk factor, and kidney outcomes in AI adolescents and adults, hypothesizing that healthier diets are associated with lower odds of incident albuminuria and eGFR decline., Methods: This is an analysis from the Strong Heart Family Study, a longitudinal study of cardiovascular disease and its risk factors among AIs from Arizona, North and South Dakota, and Oklahoma (n = 1720, mean age 39 + / - 16 years, 16% adolescents at baseline). Participants completed two exams (baseline: 2001-2003; follow-up: 2007-2009). The primary exposure was diet quality, expressed as the Alternative Healthy Eating Index 2010 (AHEI), on a 110-point scale (assessed using a 119-item Block food frequency questionnaire). The primary outcomes were as follows: 1) incident albuminuria (albumin to creatinine ratio 30 mg/g or greater); and 2) eGFR decline of 30% or greater. Generalized estimating equations were used to examine the association of AHEI (in quartiles) with outcomes., Results: Ten percent of participants (6% of adolescents) had incident albuminuria and 2% of participants (2% of adolescents) had eGFR decline. For those with normal fasting glucose levels, the odds ratio (OR) for incident albuminuria comparing extreme quartiles of diet quality (least healthy [reference] versus healthiest quartiles) was 0.48 (95% CI 0.28, 0.81) after adjustment for demographics and comorbidities., Conclusions: For American Indians with normal fasting glucose, higher diet quality decreases the odds of developing albuminuria. These findings inform future efforts to prevent CKD in American Indian adolescents and young adults., (© 2023. W. Montague Cobb-NMA Health Institute.)

Coronary heart disease (CHD) is one of the leading causes of mortality and morbidity in the United States. Accurate time-to-event CHD prediction models with high-dimensional DNA methylation and clinical features may assist with early prediction and intervention strategies. We developed a state-of-the-art deep learning autoencoder survival analysis model (AESurv) to effectively analyze high-dimensional blood DNA methylation features and traditional clinical risk factors by learning low-dimensional representation of participants for time-to-event CHD prediction. We demonstrated the utility of our model in two cohort studies: the Strong Heart Study cohort (SHS), a prospective cohort studying cardiovascular disease and its risk factors among American Indians adults; the Women's Health Initiative (WHI), a prospective cohort study including randomized clinical trials and observational study to improve postmenopausal women's health with one of the main focuses on cardiovascular disease. Our AESurv model effectively learned participant representations in low-dimensional latent space and achieved better model performance (concordance index-C index of 0.864 ± 0.009 and time-to-event mean area under the receiver operating characteristic curve-AUROC of 0.905 ± 0.009) than other survival analysis models (Cox proportional hazard, Cox proportional hazard deep neural network survival analysis, random survival forest, and gradient boosting survival analysis models) in the SHS. We further validated the AESurv model in WHI and also achieved the best model performance. The AESurv model can be used for accurate CHD prediction and assist health care professionals and patients to perform early intervention strategies. We suggest using AESurv model for future time-to-event CHD prediction based on DNA methylation features., (© The Author(s) 2024. Published by Oxford University Press.)

We sought to evaluate the acceptability and feasibility of a culturally tailored food box intervention for improving blood pressure (BP), food security and Body Mass Index (BMI) among Chickasaw Nation adults with uncontrolled hypertension. As part of the Chickasaw Healthy Eating Environments Research Study (CHEERS), we administered a group randomized pilot study in four tribal communities (two intervention, two control). Participants in the intervention communities received six heart-healthy food boxes, culturally tailored to traditional Chickasaw diet and current food context. Outcomes were measured over 6 months. We enrolled 262 participants, and 204 with complete data on key variables were included in the analysis. The food boxes were very popular, and we achieved high retention for follow-up data collection. Intervention community participants had 2.6 mmHg lower mean systolic BP and improved diet quality and BMI compared with control participants, although, as expected for a pilot study, the differences were not statistically significant. The culturally tailored diet intervention and randomized trial study design were acceptable and feasible for Chickasaw Nation adults with uncontrolled hypertension. Our findings support the value of tribal-food bank partnerships as a potential approach for reducing food insecurity and hypertension-related disparities in Native American communities., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site–for further information please contact journals.permissions@oup.com.)

Background: Despite the high burden of diabetes and cardiovascular risk factors in American Indian communities in the United States, prospective studies of heart failure (HF) in this population group are scarce, and the generalizability of previous HF risk scales may be limited. We developed a parsimonious HF risk prediction equation that accounts for relevant risk factors affecting American Indian communities, focusing on diabetes and kidney damage., Methods and Results: A total of 3059 participants from the SHS (Strong Heart Study) (56±8 years of age, 58% women) were included. Five hundred seven developed HF. Progressively adjusted Cox proportional hazards models were used to identify risk factors for HF and HF subtypes. Predictors of risk at 5 and 10 years included older age (hazard ratio [HR], 1.79 [95% CI, 1.43-2.25]; HR, 1.68 [95% CI, 1.44-1.95]), smoking (HR, 2.26 [95% CI, 1.23-4.13]; HR, 2.08 [95% CI, 1.41-3.06]), macroalbuminuria (HR, 8.38 [95% CI, 4.44-15.83]; HR, 5.20 [95% CI, 3.42-7.9]), microalbuminuria (HR, 2.72 [95% CI, 1.51-4.90]; HR, 1.92 [95% CI, 1.33, 2.78]), and previous myocardial infarction (HR, 6.58 [95% CI, 2.54-17.03]; HR, 3.87 [95% CI, 2.29-6.54]), respectively. These predictors, together with diabetes diagnosis and glycated hemoglobin were significant at 10 and 28 years. High discrimination performance was achieved (C index, 0.81 [95% CI, 0.76-0.84]; C index, 0.78 [95% CI, 0.75-0.81]; and C index, 0.77 [95% CI, 0.74-0.78] at 5, 10, and up to 28 years of follow up, respectively). Some associations varied across HF subtypes, although diabetes, albuminuria, and previous myocardial infarction were associated with all subtypes., Conclusions: This prospective study of HF risk factors in American Indian communities identifies that smoking, body mass index, and indicators of diabetes control and kidney damage (glycated hemoglobin and albuminuria) are major determinants of HF. Our findings can improve HF risk assessment in populations with a high burden of diabetes.

Conflicting clinical trial results on omega-3 highly unsaturated fatty acids (n-3 HUFA) have prompted uncertainty about their cardioprotective effects. While the VITAL trial found no overall cardiovascular benefit from n-3 HUFA supplementation, its substantial African American (AfAm) enrollment provided a unique opportunity to explore racial differences in response to n-3 HUFA supplementation. The current observational study aimed to simulate randomized clinical trial (RCT) conditions by matching 3766 AfAm and 15,553 non-Hispanic White (NHW) individuals from the VITAL trial utilizing propensity score matching to address the limitations related to differences in confounding variables between the two groups. Within matched groups (3766 AfAm and 3766 NHW), n-3 HUFA supplementation's impact on myocardial infarction (MI), stroke, and cardiovascular disease (CVD) mortality was assessed. A weighted decision tree analysis revealed belonging to the n-3 supplementation group as the most significant predictor of MI among AfAm but not NHW. Further logistic regression using the LASSO method and bootstrap estimation of standard errors indicated n-3 supplementation significantly lowered MI risk in AfAm (OR 0.17, 95% CI [0.048, 0.60]), with no such effect in NHW. This study underscores the critical need for future RCT to explore racial disparities in MI risk associated with n-3 HUFA supplementation and highlights potential causal differences between supplementation health outcomes in AfAm versus NHW populations.

Background: Selenium (Se) is an essential nutrient linked to adverse health endpoints at low and high levels. The mechanisms behind these relationships remain unclear and there is a need to further understand the epigenetic impacts of Se and their relationship to disease. We investigated the association between urinary Se levels and DNA methylation (DNAm) in the Strong Heart Study (SHS), a prospective study of cardiovascular disease (CVD) among American Indians adults., Methods: Selenium concentrations were measured in urine (collected in 1989-1991) using inductively coupled plasma mass spectrometry among 1,357 participants free of CVD and diabetes. DNAm in whole blood was measured cross-sectionally using the Illumina MethylationEPIC BeadChip (850 K) Array. We used epigenome-wide robust linear regressions and elastic net to identify differentially methylated cytosine-guanine dinucleotide (CpG) sites associated with urinary Se levels., Results: The mean (standard deviation) urinary Se concentration was 51.8 (25.1) μg/g creatinine. Across 788,368 CpG sites, five differentially methylated positions (DMP) (hypermethylated: cg00163554, cg18212762, cg11270656, and hypomethylated: cg25194720, cg00886293) were significantly associated with Se in linear regressions after accounting for multiple comparisons (false discovery rate p-value: 0.10). The top hypermethylated DMP (cg00163554) was annotated to the Disco Interacting Protein 2 Homolog C (DIP2C) gene, which relates to transcription factor binding. Elastic net models selected 425 hypo- and hyper-methylated DMPs associated with urinary Se, including three sites (cg00163554 [DIP2C], cg18212762 [MAP4K2], cg11270656 [GPIHBP1]) identified in linear regressions., Conclusions: Urinary Se was associated with minimal changes in DNAm in adults from American Indian communities across the Southwest and the Great Plains in the United States, suggesting that other mechanisms may be driving health impacts. Future analyses should explore other mechanistic biomarkers in human populations, determine these relationships prospectively, and investigate the potential role of differentially methylated sites with disease endpoints., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Pre-diabetes (pre-DM) is a strong predictor of diabetes (DM) over time. This study investigated how much of the recent increase in pre-DM identified among Alaska Native (AN) peoples living in urban southcentral Alaska may be due to changes in diagnostic methods. We used clinical and demographic data collected at baseline between 2004 and 2006 and at follow-up collected between 2015 and 2017 from the urban southcentral Alaska Education and Research Towards Health (EARTH) cohort. We used descriptive statistics and logistic regression to explore differences in demographic and clinical variables among the identified pre-DM groups. Of 388 participants in the follow-up study, 243 had A1c levels indicating pre-DM with only 20 demonstrating pre-DM also by fasting blood glucose (FBG). Current smoking was the sole predictor for pre-DM by A1c alone while abdominal obesity and elevated FBG-predicted pre-DM by A1c+FBG. No participants had an elevated FBG without an A1c elevation. A substantial portion of the rise in pre-DM found among urban southcentral AN peoples in the EARTH follow-up study was due to the addition of A1c testing. Pre-DM by A1c alone should be used to motivate behavioural changes that address modifiable risk factors, including smoking cessation, physical activity and weight management.

Background: American Indian (AI) communities are affected by uranium exposure from abandoned mines and naturally contaminated drinking water. Few studies have evaluated geographical differences across AI communities and the role of dietary exposures., Objective: We evaluated differences in urinary uranium levels by diet and geographical area among AI participants from the Northern Plains, the Southern Plains, and the Southwest enrolled in the Strong Heart Family Study (SHFS)., Methods: We used food frequency questionnaires to determine dietary sources related to urinary uranium levels for 1,682 SHFS participants in 2001-2003. We calculated adjusted geometric mean ratios (GMRs) of urinary uranium for an interquartile range (IQR) increase in self-reported food group consumption accounting for family clustering and adjusting for sociodemographic variables and other food groups. We determined the percentage of variability in urinary uranium explained by diet., Results: Median (IQR) urinary uranium levels were 0.027 (0.012, 0.057) μg/g creatinine. Urinary uranium levels were higher in Arizona (median 0.039 μg/g) and North Dakota and South Dakota (median 0.038 μg/g) and lower in Oklahoma (median 0.019 μg/g). The adjusted percent increase (95% confidence interval) of urinary uranium levels per IQR increase in reported food intake was 20% (5%, 36%) for organ meat, 11% (1%, 23%) for cereals, and 14% (1%, 29%) for alcoholic drinks. In analyses stratified by study center, the association with organ meat was specific to North Dakota and South Dakota participants. An IQR increase in consumption of fries and chips was inversely associated with urinary uranium levels -11% (-19%, -3%). Overall, we estimated that self-reported dietary exposures explained 1.71% of variability in urine uranium levels., Impact: Our paper provides a novel assessment of self-reported food intake and urinary uranium levels in a cohort of American Indian participants. We identify foods (organ meat, cereals, and alcohol) positively associated with urinary uranium levels, find that organ meat consumption is only associated with urine uranium in North Dakota and South Dakota, and estimate that diet explains relatively little variation in total urinary uranium concentrations. Our findings contribute meaningful data toward a more comprehensive estimation of uranium exposure among Native American communities and support the need for high-quality assessments of water and dust uranium exposures in SHFS communities., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: A growing body of research indicates that associations of ceramides and sphingomyelins with mortality depend on the chain length of the fatty acid acylated to the backbone sphingoid base. We examined associations of 8 ceramide and sphingomyelin species with mortality among an American Indian population., Methods and Results: The analysis comprised 2688 participants from the SHFS (Strong Heart Family Study). Plasma ceramide and sphingomyelin species carrying long-chain (ie, 16:0) and very-long-chain (ie, 20:0, 22:0, 24:0) saturated fatty acids were measured by sequential liquid chromatography and mass spectroscopy using samples from 2001 to 2003. Participants were followed for 18.8 years (2001-2020). Associations of ceramides and sphingomyelins with mortality were assessed using Cox models. The mean age of participants was 40.8 years. There were 574 deaths during a median 17.4-year follow-up. Ceramides and sphingomyelins carrying fatty acid 16:0 were positively associated with mortality. Ceramides and sphingomyelins carrying longer fatty acids were inversely associated with mortality. Per SD difference in each ceramide and sphingomyelin species, hazard ratios for death were: 1.68 (95% CI, 1.44-1.96) for ceramide-16 (Cer-16), 0.82 (95% CI, 0.71-0.95) for Cer-20, 0.60 (95% CI, 0.51-0.70) for Cer-22, 0.67 (95% CI, 0.56-0.79) for Cer-24, 1.80 (95% CI-1.57, 2.05) for sphingomyelin-16 (SM-16), 0.54 (95% CI, 0.47-0.62) for SM-20, 0.50 (95% CI, 0.44-0.57) for SM-22, and 0.59 (95% CI, 0.52-0.67) for SM-24., Conclusions: The direction/magnitude of associations of ceramides and sphingomyelins with mortality differs according to the length of the fatty acid acylated to the backbone sphingoid base., Registration: URL: https://www.clinicatrials.gov; Unique identifier: NCT00005134.

Importance: Persistent symptoms and disability following SARS-CoV-2 infection, known as post-COVID-19 condition or "long COVID," are frequently reported and pose a substantial personal and societal burden., Objective: To determine time to recovery following SARS-CoV-2 infection and identify factors associated with recovery by 90 days., Design, Setting, and Participants: For this prospective cohort study, standardized ascertainment of SARS-CoV-2 infection was conducted starting in April 1, 2020, across 14 ongoing National Institutes of Health-funded cohorts that have enrolled and followed participants since 1971. This report includes data collected through February 28, 2023, on adults aged 18 years or older with self-reported SARS-CoV-2 infection., Exposure: Preinfection health conditions and lifestyle factors assessed before and during the pandemic via prepandemic examinations and pandemic-era questionnaires., Main Outcomes and Measures: Probability of nonrecovery by 90 days and restricted mean recovery times were estimated using Kaplan-Meier curves, and Cox proportional hazards regression was performed to assess multivariable-adjusted associations with recovery by 90 days., Results: Of 4708 participants with self-reported SARS-CoV-2 infection (mean [SD] age, 61.3 [13.8] years; 2952 women [62.7%]), an estimated 22.5% (95% CI, 21.2%-23.7%) did not recover by 90 days post infection. Median (IQR) time to recovery was 20 (8-75) days. By 90 days post infection, there were significant differences in restricted mean recovery time according to sociodemographic, clinical, and lifestyle characteristics, particularly by acute infection severity (outpatient vs critical hospitalization, 32.9 days [95% CI, 31.9-33.9 days] vs 57.6 days [95% CI, 51.9-63.3 days]; log-rank P < .001). Recovery by 90 days post infection was associated with vaccination prior to infection (hazard ratio [HR], 1.30; 95% CI, 1.11-1.51) and infection during the sixth (Omicron variant) vs first wave (HR, 1.25; 95% CI, 1.06-1.49). These associations were mediated by reduced severity of acute infection (33.4% and 17.6%, respectively). Recovery was unfavorably associated with female sex (HR, 0.85; 95% CI, 0.79-0.92) and prepandemic clinical cardiovascular disease (HR, 0.84; 95% CI, 0.71-0.99). No significant multivariable-adjusted associations were observed for age, educational attainment, smoking history, obesity, diabetes, chronic kidney disease, asthma, chronic obstructive pulmonary disease, or elevated depressive symptoms. Results were similar for reinfections., Conclusions and Relevance: In this cohort study, more than 1 in 5 adults did not recover within 3 months of SARS-CoV-2 infection. Recovery within 3 months was less likely in women and those with preexisting cardiovascular disease and more likely in those with COVID-19 vaccination or infection during the Omicron variant wave.

Background: Dietary interventions are used for the treatment of hypertension. We evaluated the cost-efficacy of delivering boxes of healthy, culturally tailored foods and checks that can only be spent on produce in a Native American population., Methods: We conducted a group randomized controlled trial from 2018 to 2020 with N = 2 treatment counties and N = 2 control counties and a total of N = 160 Native American adults with baseline stage 1 or stage 2 hypertension. Participants in the intervention group received monthly boxes of food that adheres to the Dietary Approaches to Stop Hypertension diet as well as checks that could only be spent on produce for 6 months. We measured blood pressure and quality of life at baseline and at a 6-month follow-up in both intervention and control groups. We used ordered logistic regression to estimate the effect of treatment on probability of blood pressure improvements. We then conducted a cost-efficacy analysis., Results: We found that treatment was effective in reducing blood pressure in women with stage 1 hypertension at baseline. Based on this finding, we also estimate that this intervention satisfies normative cost-effectiveness thresholds, even when lifetime treatment is needed to preserve the impact, so long as treatment is only continued in those who respond to treatment., Conclusions: Direct delivery of healthy foods and checks that can only be spent on produce are a potentially cost-effective intervention for the management of hypertension among Native American women with stage 1 hypertension. Further research is needed to understand why we found an impact only for this group., (© 2024. The Author(s).)

The generalized estimating equations method (GEE) is commonly applied to analyze data obtained from family studies. GEE is well known for its robustness on misspecification of correlation structure. However, the unbalanced distribution of family sizes and complicated genetic relatedness structure within each family may challenge GEE performance. We focused our research on binary outcomes. To evaluate the performance of GEE, we conducted a series of simulations, on data generated adopting the kinship matrix (correlation structure within each family) from the Strong Heart Family Study (SHFS). We performed a fivefold cross-validation to further evaluate the GEE predictive power on data from the SHFS. A Bayesian modeling approach, with direct integration of the kinship matrix, was also included to contrast with GEE. Our simulation studies revealed that GEE performs well on a binary outcome from families having a relatively simple kinship structure. However, data with a binary outcome generated from families with complex kinship structures, especially with a large genetic variance, can challenge the performance of GEE.

Background: Cardiovascular disease (CVD) is a leading cause of morbidity and mortality in American Indian people. In 2022, the American Heart Association developed the Life's Essential 8 goals to promote cardiovascular health (CVH) for Americans, composed of diet, physical activity, nicotine exposure, sleep, body mass index, blood lipids, blood pressure, and blood glucose. We examined whether achievement of Life's Essential 8 goals was associated with incident CVD among SHFS (Strong Heart Family Study) participants., Methods and Results: A total of 2139 SHFS participants without CVD at baseline were included in analyses. We created a composite CVH score based on achievement of Life's Essential 8 goals, excluding sleep. Scores of 0 to 49 represented low CVH, 50 to 69 represented moderate CVH, and 70 to 100 represented high CVH. Incident CVD was defined as incident myocardial infarction, coronary heart disease, congestive heart failure, or stroke. Cox proportional hazard models were used to examine the relationship of CVH and incident CVD. The incidence rate of CVD at the 20-year follow-up was 7.43 per 1000 person-years. Compared with participants with low CVH, participants with moderate and high CVH had a lower risk of incident CVD; the hazard ratios and 95% CIs for incident CVD for moderate and high CVH were 0.52 (95% CI, 0.40-0.68) and 0.25 (95% CI, 0.14-0.44), respectively, after adjustment for age, sex, education, and study site., Conclusions: Better CVH was associated with lower CVD risk which highlights the need for comprehensive public health interventions targeting CVH promotion to reduce CVD risk in American Indian communities.

Background: Although many studies on the association between dyslipidemia and cardiovascular disease (CVD) exist in older adults, data on the association among adolescents and young adults living with disproportionate burden of cardiometabolic disorders are scarce., Methods and Results: The SHFS (Strong Heart Family Study) is a multicenter, family-based, prospective cohort study of CVD in an American Indian populations, including 12 communities in central Arizona, southwestern Oklahoma, and the Dakotas. We evaluated SHFS participants, who were 15 to 39 years old at the baseline examination in 2001 to 2003 (n=1440). Lipids were measured after a 12-hour fast. We used carotid ultrasounds to detect plaque at baseline and follow-up in 2006 to 2009 (median follow-up=5.5 years). We identified incident CVD events through 2020 with a median follow-up of 18.5 years. We used shared frailty proportional hazards models to assess the association between dyslipidemia and subclinical or clinical CVD, while controlling for covariates. Baseline dyslipidemia prevalence was 55.2%, 73.6%, and 78.0% for participants 15 to 19, 20 to 29, and 30 to 39 years old, respectively. Approximately 2.8% had low-density lipoprotein cholesterol ≥160 mg/dL, which is higher than the recommended threshold for lifestyle or medical interventions in young adults of 20 to 39 years old. During follow-up, 9.9% had incident plaque (109/1104 plaque-free participants with baseline and follow-up ultrasounds), 11.0% had plaque progression (128/1165 with both baseline and follow-up ultrasounds), and 9% had incident CVD (127/1416 CVD-free participants at baseline). Plaque incidence and progression were higher in participants with total cholesterol ≥200 mg/dL, low-density lipoprotein cholesterol ≥160 mg/dL, or non-high-density lipoprotein cholesterol ≥130 mg/dL, while controlling for covariates. CVD risk was independently associated with low-density lipoprotein cholesterol ≥160 mg/dL., Conclusions: Dyslipidemia is a modifiable risk factor that is associated with both subclinical and clinical CVD, even among the younger American Indian population who have unexpectedly high rates of significant CVD events. Therefore, this population is likely to benefit from a variety of evidence-based interventions including screening, educational, lifestyle, and guideline-directed medical therapy at an early age.

Background: Identifying lipidomic markers of diet quality is needed to inform the development of biomarkers of diet, and to understand the mechanisms driving the diet- coronary heart disease (CHD) association., Objectives: This study aimed to identify lipidomic markers of diet quality and examine whether these lipids are associated with incident CHD., Methods: Using liquid chromatography-mass spectrometry, we measured 1542 lipid species from 1694 American Indian adults (aged 18-75 years, 62% female) in the Strong Heart Family Study. Participants were followed up for development of CHD through 2020. Information on the past year diet was collected using the Block Food Frequency Questionnaire, and diet quality was assessed using the Alternative Healthy Eating Index-2010 (AHEI). Mixed-effects linear regression was used to identify individual lipids cross-sectionally associated with AHEI. In prospective analysis, Cox frailty model was used to estimate the hazard ratio (HR) of each AHEI-related lipid for incident CHD. All models were adjusted for age, sex, center, education, body mass index, smoking, alcohol drinking, level of physical activity, energy intake, diabetes, hypertension, and use of lipid-lowering drugs. Multiple testing was controlled at a false discovery rate of <0.05., Results: Among 1542 lipid species measured, 71 lipid species (23 known), including acylcarnitine, cholesterol esters, glycerophospholipids, sphingomyelins and triacylglycerols, were associated with AHEI. Most of the identified lipids were associated with consumption of ω-3 (n-3) fatty acids. In total, 147 participants developed CHD during a mean follow-up of 17.8 years. Among the diet-related lipids, 10 lipids [5 known: cholesterol ester (CE)(22:5)B, phosphatidylcholine (PC)(p-14:0/22:1)/PC(o-14:0/22:1), PC(p-38:3)/PC(o-38:4)B, phosphatidylethanolamine (PE)(p-18:0/20:4)/PE(o-18:0/20:4), and sphingomyelin (d36:2)A] were associated with incident CHD. On average, each standard deviation increase in the baseline level of these 5 lipids was associated with 17%-23% increased risk of CHD (from HR: 1.17; 95% CI: 1, 1.36; to HR: 1.23; 95% CI: 1.05, 1.43)., Conclusions: In this study, lipidomic markers of diet quality in American Indian adults are found. Some diet-related lipids are associated with risk of CHD beyond established risk factors., (Copyright © 2023 American Society for Nutrition. Published by Elsevier Inc. All rights reserved.)

Background: Dyslipidemia is an independent risk factor for coronary heart disease (CHD). Standard lipid panel cannot capture the complexity of the blood lipidome (ie, all molecular lipids in the blood). To date, very few large-scale epidemiological studies have assessed the full spectrum of the blood lipidome on risk of CHD, especially in a longitudinal setting., Methods and Results: Using an untargeted liquid chromatography-mass spectrometry, we repeatedly measured 1542 lipid species from 1835 unique American Indian participants who attended 2 clinical visits (≈5.5 years apart) and followed up to 17.8 years in the Strong Heart Family Study (SHFS). We first identified baseline lipid species associated with risk of CHD, followed by replication in a European population. The model adjusted for age, sex, body mass index, smoking, hypertension, diabetes, low-density lipoprotein cholesterol, estimated glomerular filtration rate, education, and physical activity at baseline. We then examined the longitudinal association between changes in lipid species and changes in cardiovascular risk factors during follow-up. Multiple testing was controlled by the false discovery rate. We found that baseline levels of multiple lipid species (eg, phosphatidylcholines, phosphatidylethanolamines, and ceramides) were associated with the risk of CHD and improved the prediction accuracy over conventional risk factors in American Indian people. Some identified lipids in American Indian people were replicated in European people. Longitudinal changes in multiple lipid species (eg, acylcarnitines, phosphatidylcholines, and triacylglycerols) were associated with changes in cardiovascular risk factors., Conclusions: Baseline plasma lipids and their longitudinal changes over time are associated with risk of CHD. These findings provide novel insights into the role of dyslipidemia in CHD.

Background: Chronic lead exposure is associated with both subclinical and clinical cardiovascular disease. We evaluated whether declines in blood lead were associated with changes in systolic and diastolic blood pressure in adult American Indian participants from the SHFS (Strong Heart Family Study)., Methods and Results: Lead in whole blood was measured in 285 SHFS participants in 1997 to 1999 and 2006 to 2009. Blood pressure and measures of cardiac geometry and function were obtained in 2001 to 2003 and 2006 to 2009. We used generalized estimating equations to evaluate the association of declines in blood lead with changes in blood pressure; cardiac function and geometry measures were considered secondary. Mean blood lead was 2.04 μg/dL at baseline. After ≈10 years, mean decline in blood lead was 0.67 μg/dL. In fully adjusted models, the mean difference in systolic blood pressure comparing the highest to lowest tertile of decline (>0.91 versus <0.27 μg/dL) in blood lead was -7.08 mm Hg (95% CI, -13.16 to -1.00). A significant nonlinear association between declines in blood lead and declines in systolic blood pressure was detected, with significant linear associations where blood lead decline was 0.1 μg/dL or higher. Declines in blood lead were nonsignificantly associated with declines in diastolic blood pressure and significantly associated with declines in interventricular septum thickness., Conclusions: Declines in blood lead levels in American Indian adults, even when small (0.1-1.0 μg/dL), were associated with reductions in systolic blood pressure. These findings suggest the need to further study the cardiovascular impacts of reducing lead exposures and the importance of lead exposure prevention.

Chronic kidney disease is a leading cause of death and disability globally and impacts individuals of African ancestry (AFR) or with ancestry in the Americas (AMS) who are under-represented in genome-wide association studies (GWASs) of kidney function. To address this bias, we conducted a large meta-analysis of GWASs of estimated glomerular filtration rate (eGFR) in 145,732 AFR and AMS individuals. We identified 41 loci at genome-wide significance (p < 5 × 10 -8 ), of which two have not been previously reported in any ancestry group. We integrated fine-mapped loci with epigenomic and transcriptomic resources to highlight potential effector genes relevant to kidney physiology and disease, and reveal key regulatory elements and pathways involved in renal function and development. We demonstrate the varying but increased predictive power offered by a multi-ancestry polygenic score for eGFR and highlight the importance of population diversity in GWASs and multi-omics resources to enhance opportunities for clinical translation for all., Competing Interests: Declaration of interests P.N. reports investigator-initiated research grants from Allelica, Apple, Amgen, Boston Scientific, Genentech/Roche, and Novartis, personal fees from Allelica, Apple, AstraZeneca, Blackstone Life Sciences, Eli Lilly & Co, Foresite Labs, Genentech/Roche, GV, HeartFlow, Magnet Biomedicine, and Novartis, scientific advisory board membership of Esperion Therapeutics, Preciseli, and TenSixteen Bio, scientific co-founder of TenSixteen Bio, equity in MyOme, Preciseli, and TenSixteen Bio, and spousal employment at Vertex Pharmaceuticals, all unrelated to the present work. M.B.L. has received speaker and advisory fees from Otsuka, Reata, Bayer, and Sanofi Genzyme. G.P. has received speaker and advisory fees from Amgen, Bayer, Novartis, and Sanofi, and has received research grants from Bayer and Sanofi. L.M.R. is a consultant for the TOPMed Administrative Coordinating Center (through Westat)., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: To examine the associations of dietary Mg intake with inflammatory biomarkers (C-reactive protein (CRP) and interleukin 6 (IL-6)), and the interaction of dietary Mg intake with single nucleotide polymorphism (SNP) rs3740393, a SNP related to Mg metabolism and transport, on CRP and IL-6 among American Indians (AIs)., Methods: This cross-sectional study included AI participants (n = 1,924) from the Strong Heart Family Study (SHFS). Mg intake from foods and dietary supplements was ascertained using a 119-item Block food frequency questionnaire, CRP and IL-6 were measured from blood, and SNP rs3740393 was genotyped using MetaboChip. Generalized estimating equations were used to examine associations of Mg intake, and the interaction between rs3740393 and dietary Mg, with CRP and IL-6., Results: Reported Mg intake was not associated with CRP or IL-6, irrespective of genotype. A significant interaction (p-interaction = 0.018) was observed between Mg intake and rs3740393 on IL-6. Among participants with the C/C genotype, for every 1 SD higher in log-Mg, log-IL-6 was 0.04 (95% CI: -0.10 to 0.17) pg/mL higher. Among participants with the C/G genotype, for every 1 SD higher in log-Mg, log-IL-6 was 0.08 (95% CI: -0.21 to 0.05) pg/mL lower, and among participants with the G/G genotype, for every 1 SD higher in log-Mg, log-IL-6 was 0.19 (95% CI: -0.38 to -0.01) pg/mL lower., Conclusions: Mg intake may be associated with lower IL-6 with increasing dosage of the G allele at rs3740393. Future research is necessary to replicate this finding and examine other Mg-related genes that influence associations of Mg intake with inflammation., Competing Interests: The authors have declared that no competing interests exist., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

Background: Inorganic arsenic (As) may increase the risk of cardiovascular disease (CVD) and all-cause mortality through accelerated aging, which can be estimated using epigenetic-based measures., Objectives: We evaluated three DNA methylation-based aging measures (PhenoAge, GrimAge, DunedinPACE) (epigenetic aging measures) as potential mediators of the previously reported association of As exposure with CVD incidence, CVD mortality, and all-cause mortality in the Strong Heart Study (SHS), an epidemiological cohort of American Indian adults., Methods: Blood DNA methylation and urinary As levels were measured in 2,323 SHS participants (41.5% men, mean age of 55 years old). PhenoAge and GrimAge values were calculated using a residual-based method. We tested the association of urinary As with epigenetic aging measures using linear regression, the association of epigenetic aging measures with the three health outcomes using additive hazards models, and the mediation of As-related CVD incidence, CVD mortality, and all-cause mortality by epigenetic aging measures using the product of coefficients method., Results: SHS participants with higher vs. lower urinary As levels had similar PhenoAge age, older GrimAge age, and faster DunedinPACE. An interquartile range increase in urinary As was associated with higher of PhenoAge age acceleration [ mean difference  ( 95 %  confidence interval ) = 0.48 (0.17, 0.80) years], GrimAge age acceleration [0.80 (0.60, 1.00) years], and DunedinPACE [0.011 (0.005, 0.018)], after adjusting for age, sex, center location, genetic components, smoking status, and body mass index. Of the 347 incident CVD events per 100,000 person-years associated with a doubling in As exposure, 21.3% (9.1, 57.1) and 22.6% (9.5, 56.9), were attributable to differences in GrimAge and DunedinPACE, respectively., Discussion: Arsenic exposure was associated with older GrimAge and faster DunedinPACE measures of biological age. Furthermore, accelerated biological aging measured from DNA methylation accounted for a relevant fraction of As-associated risk for CVD, CVD mortality, and all-cause mortality in the SHS, supporting the role of As in accelerated aging. Research of the biological underpinnings can contribute to a better understanding of the role of aging in arsenic-related disease. https://doi.org/10.1289/EHP11981.

Background: Fine particulate matter (PM 2.5 ) exposure is a known risk factor for numerous adverse health outcomes, with varying estimates of component-specific effects. Populations with compromised health conditions such as diabetes can be more sensitive to the health impacts of air pollution exposure. Recent trends in PM 2.5 in primarily American Indian- (AI-) populated areas examined in previous work declined more gradually compared to the declines observed in the rest of the US. To further investigate components contributing to these findings, we compared trends in concentrations of six PM 2.5 components in AI- vs. non-AI-populated counties over time (2000-2017) in the contiguous US., Methods: We implemented component-specific linear mixed models to estimate differences in annual county-level concentrations of sulfate, nitrate, ammonium, organic matter, black carbon, and mineral dust from well-validated surface PM 2.5 models in AI- vs. non-AI-populated counties, using a multi-criteria approach to classify counties as AI- or non-AI-populated. Models adjusted for population density and median household income. We included interaction terms with calendar year to estimate whether concentration differences in AI- vs. non-AI-populated counties varied over time., Results: Our final analysis included 3108 counties, with 199 (6.4%) classified as AI-populated. On average across the study period, adjusted concentrations of all six PM 2.5 components in AI-populated counties were significantly lower than in non-AI-populated counties. However, component-specific levels in AI- vs. non-AI-populated counties varied over time: sulfate and ammonium levels were significantly lower in AI- vs. non-AI-populated counties before 2011 but higher after 2011 and nitrate levels were consistently lower in AI-populated counties., Conclusions: This study indicates time trend differences of specific components by AI-populated county type. Notably, decreases in sulfate and ammonium may contribute to steeper declines in total PM 2.5 in non-AI vs. AI-populated counties. These findings provide potential directives for additional monitoring and regulations of key emissions sources impacting tribal lands., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

BACKGROUND. The confounder-corrected chemical shift-encoded MRI (CSE-MRI) sequence used to determine proton density fat fraction (PDFF) for hepatic fat quantification is not widely available. As an alternative, hepatic fat can be assessed by a two-point Dixon method to calculate signal fat fraction (FF) from conventional T1-weighted in- and opposed-phase (IOP) images, although signal FF is prone to biases, leading to inaccurate quantification. OBJECTIVE. The purpose of this study was to compare hepatic fat quantification by use of PDFF inferred from conventional T1-weighted IOP images and deep-learning convolutional neural networks (CNNs) with quantification by use of two-point Dixon signal FF with CSE-MRI PDFF as the reference standard. METHODS. This study entailed retrospective analysis of data from 292 participants (203 women, 89 men; mean age, 53.7 ± 12.0 [SD] years) enrolled at two sites from September 1, 2017, to December 18, 2019, in the Strong Heart Family Study (a prospective population-based study of American Indian communities). Participants underwent liver MRI (site A, 3 T; site B, 1.5 T) including T1-weighted IOP MRI and CSE-MRI (used to reconstruct CSE PDFF and CSE R2* maps). With CSE PDFF as reference, a CNN was trained in a random sample of 218 (75%) participants to infer voxel-by-voxel PDFF maps from T1-weighted IOP images; testing was performed in the other 74 (25%) participants. Parametric values from the entire liver were automatically extracted. Per-participant median CNN-inferred PDFF and median two-point Dixon signal FF were compared with reference median CSE-MRI PDFF by means of linear regression analysis, intraclass correlation coefficient (ICC), and Bland-Altman analysis. The code is publicly available at github.com/kang927/CNN-inference-of-PDFF-from-T1w-IOP-MR. RESULTS. In the 74 test-set participants, reference CSE PDFF ranged from 1% to 32% (mean, 11.3% ± 8.3% [SD]); reference CSE R2* ranged from 31 to 457 seconds -1 (mean, 62.4 ± 67.3 seconds -1 [SD]). Agreement metrics with reference to CSE PDFF for CNN-inferred PDFF were ICC = 0.99, bias = -0.19%, 95% limits of agreement (LoA) = (-2.80%, 2.71%) and for two-point Dixon signal FF were ICC = 0.93, bias = -1.11%, LoA = (-7.54%, 5.33%). CONCLUSION. Agreement with reference CSE PDFF was better for CNN-inferred PDFF from conventional T1-weighted IOP images than for two-point Dixon signal FF. Further investigation is needed in individuals with moderate-to-severe iron overload. CLINICAL IMPACT. Measurement of CNN-inferred PDFF from widely available T1-weighted IOP images may facilitate adoption of hepatic PDFF as a quantitative bio-marker for liver fat assessment, expanding opportunities to screen for hepatic steatosis and nonalcoholic fatty liver disease.

Background and Aims: Dyslipidemia is an independent risk factor for atherosclerosis and atherosclerotic cardiovascular disease (ASCVD). To date, a comprehensive assessment of individual lipid species associated with atherosclerosis is lacking in large-scale epidemiological studies, especially in a longitudinal setting. We investigated the association of circulating lipid species and its longitudinal changes with carotid atherosclerosis., Methods: Using liquid chromatograph-mass spectrometry, we repeatedly measured 1542 lipid species in 3687 plasma samples from 1918 unique American Indians attending two visits (mean ∼5 years apart) in the Strong Heart Family Study. Carotid atherosclerotic plaques were assessed by ultrasonography at each visit. We identified lipids associated with prevalence or progression of carotid plaques, adjusting age, sex, BMI, smoking, hypertension, diabetes, and eGFR. Then we examined whether longitudinal changes in lipids were associated with changes in cardiovascular risk factors. Multiple testing was controlled at false discovery rate (FDR) < 0.05., Results: Higher levels of sphingomyelins, ether-phosphatidylcholines, and triacylglycerols were significantly associated with prevalence or progression of carotid plaques (odds ratios ranged from 1.15 to 1.34). Longitudinal changes in multiple lipid species (e.g., acylcarnitines, phosphatidylcholines, triacylglycerols) were associated with changes in cardiometabolic traits (e.g., BMI, blood pressure, fasting glucose, eGFR). Network analysis identified differential lipid networks associated with plaque progression., Conclusions: Baseline and longitudinal changes in multiple lipid species were significantly associated with carotid atherosclerosis and its progression in American Indians. Some plaque-related lipid species were also associated with risk for CVD events., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Altered DNA methylation (DNAm) might be a biological intermediary in the pathway from smoking to lung cancer. In this study, we investigated the contribution of differential blood DNAm to explain the association between smoking and lung cancer incidence. Blood DNAm was measured in 2321 Strong Heart Study (SHS) participants. Incident lung cancer was assessed as time to event diagnoses. We conducted mediation analysis, including validation with DNAm and paired gene expression data from the Framingham Heart Study (FHS). In the SHS, current versus never smoking and pack-years single-mediator models showed, respectively, 29 and 21 differentially methylated positions (DMPs) for lung cancer with statistically significant mediated effects (14 of 20 available, and five of 14 available, positions, replicated, respectively, in FHS). In FHS, replicated DMPs showed gene expression downregulation largely in trans, and were related to biological pathways in cancer. The multimediator model identified that DMPs annotated to the genes AHRR and IER3 jointly explained a substantial proportion of lung cancer. Thus, the association of smoking with lung cancer was partly explained by differences in baseline blood DNAm at few relevant sites. Experimental studies are needed to confirm the biological role of identified eQTMs and to evaluate potential implications for early detection and control of lung cancer., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Ana Navas-Acien reports financial support was provided by National Heart Lung and Blood Institute. Ana Navas-Acien reports financial support was provided by National Institute of Environmental Health Sciences. Daniel Levy reports financial support was provided by National Institutes of Health. Arce Domingo-Relloso reports financial support was provided by La Caixa Foundation. Maria Tellez-Plaza reports financial support provided by AstraZeneca Spain, the Instituto de Salud Carlos III and the Spanish Ministry of Science and Innovation and co-funded with European Funds for Regional Development., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Sphingolipids are a family of circulating lipids with regulatory and signaling roles that are strongly associated with both eGFR and cardiovascular disease. Patients with chronic kidney disease (CKD) are at high risk for cardiovascular events, and have different plasma concentrations of certain plasma sphingolipids compared to patients with normal kidney function. We hypothesize that circulating sphingolipids partially mediate the associations between eGFR and cardiovascular events., Methods: We measured the circulating concentrations of 8 sphingolipids, including 4 ceramides and 4 sphingomyelins with the fatty acids 16:0, 20:0, 22:0, and 24:0, in plasma from 3,463 participants in a population-based cohort (Cardiovascular Health Study) without prevalent cardiovascular disease. We tested the adjusted mediation effects by these sphingolipids of the associations between eGFR and incident cardiovascular disease via quasi-Bayesian Monte Carlo method with 2,000 simulations, using a Bonferroni correction for significance., Findings: The mean (±SD) eGFR was 70 (±16) mL/min/1.73 m 2 ; 62% of participants were women. Lower eGFR was associated with higher plasma ceramide-16:0 and sphingomyelin-16:0, and lower ceramides and sphingomyelins-20:0 and -22:0. Lower eGFR was associated with risk of incident heart failure and ischemic stroke, but not myocardial infarction. Five of eight sphingolipids partially mediated the association between eGFR and heart failure. The sphingolipids associated with the greatest proportion mediated were ceramide-16:0 (proportion mediated 13%, 95% CI 8-22%) and sphingomyelin-16:0 (proportion mediated 10%, 95% CI 5-17%). No sphingolipids mediated the association between eGFR and ischemic stroke., Interpretation: Plasma sphingolipids partially mediated the association between lower eGFR and incident heart failure. Altered sphingolipids metabolism may be a novel mechanism for heart failure in patients with CKD., Funding: This study was supported by T32 DK007467 and a KidneyCure Ben J. Lipps Research Fellowship (Dr. Lidgard). Sphingolipid measurements were supported by R01 HL128575 (Dr. Lemaitre) and R01 HL111375 (Dr. Hoofnagle) from the National Heart, Lung, and Blood Institute (NHLBI)., Competing Interests: Declaration of interests Dr. Zelnick reports a consultancy agreement with Veterans Medical Research Foundation, and serves as a Statistical Editor for the Clinical Journal of the American Society of Nephrology. Dr. Hoofnagle reports providing expert testimony for Kilpatrick Townsend and Stockton LLP; receipt of equipment and instrument support from Waters, Inc.; and serves as an Associate Editor for Clinical Chemistry., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Introduction: Native American communities suffer disproportionately from elevated metal exposures and increased risk for cardiovascular diseases and diabetes. DNA methylation is a sensitive biomarker of aging-related processes and novel epigenetic-based "clocks" can be used to estimate accelerated biological aging that may underlie increased risk. Metals alter DNA methylation, yet little is known about their individual and combined impact on epigenetic age acceleration. Our objective was to investigate the associations of metals on several DNA methylation-based aging measures in the Strong Heart Study (SHS) cohort., Methods: Blood DNA methylation data from 2,301 SHS participants was used to calculate age acceleration of epigenetic clocks (PhenoAge, GrimAge, DunedinPACE, Hannum, Horvath). Urinary metals [arsenic (As), cadmium (Cd), tungsten (W), zinc (Zn), selenium (Se), molybdenum (Mo)] were creatinine-adjusted and categorized into quartiles. We examined associations of individual metals through linear regression models and used Bayesian Kernel Machine Regression (BKMR) for the impact of the total metal mixture on epigenetic age acceleration., Results: The mixture of nonessential metals (W, As, Cd) was associated with greater GrimAge acceleration and DunedinPACE, while the essential metal mixture (Se, Zn, Mo) was associated with lower epigenetic age acceleration. Cd was associated with increased epigenetic age acceleration across all clocks and BKMR analysis suggested nonlinear associations between Se and DunedinPACE, GrimAge, and PhenoAge acceleration. No interactions between individual metals were observed. The associations between Cd, Zn, and epigenetic age acceleration were greater in never smokers in comparison to current/former smokers., Conclusion: Nonessential metals were positively associated with greater epigenetic age acceleration, with strongest associations observed between Cd and DunedinPACE and GrimAge acceleration. In contrast, essential metals were associated with lower epigenetic aging. Examining the influence of metal mixtures on epigenetic age acceleration can provide insight into metals and aging-related diseases., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Dyslipidemia is an important risk factor for hypertension and cardiovascular disease. Standard lipid panel cannot reflect the complexity of blood lipidome. The associations of individual lipid species with hypertension remain to be determined in large-scale epidemiological studies, especially in a longitudinal setting., Methods: Using liquid chromatography-mass spectrometry, we repeatedly measured 1542 lipid species in 3699 fasting plasma samples at 2 visits (1905 at baseline, 1794 at follow-up, ~5.5 years apart) from 1905 unique American Indians in the Strong Heart Family Study. We first identified baseline lipids associated with prevalent and incident hypertension, followed by replication of top hits in Europeans. We then conducted repeated measurement analysis to examine the associations of changes in lipid species with changes in systolic blood pressure, diastolic blood pressure, and mean arterial pressure. Network analysis was performed to identify lipid networks associated with the risk of hypertension., Results: Baseline levels of multiple lipid species, for example, glycerophospholipids, cholesterol esters, sphingomyelins, glycerolipids, and fatty acids, were significantly associated with both prevalent and incident hypertension in American Indians. Some lipids were confirmed in Europeans. Longitudinal changes in multiple lipid species, for example, acylcarnitines, phosphatidylcholines, fatty acids, and triacylglycerols, were significantly associated with changes in blood pressure measurements. Network analysis identified distinct lipidomic patterns associated with the risk of hypertension., Conclusions: Baseline plasma lipid species and their longitudinal changes are significantly associated with hypertension development in American Indians. Our findings shed light on the role of dyslipidemia in hypertension and may offer potential opportunities for risk stratification and early prediction of hypertension., Competing Interests: Disclosures None.