Search

BackgroundPatients with chronic kidney disease (CKD) have dysfunctional high-density lipoprotein (HDL) particles as compared with the general population. Understanding the lipid composition of HDL may provide mechanistic insight. We tested associations of estimated glomerular filtration rate (eGFR) and albuminuria with relative HDL abundance of ceramides, sphingomyelins, and phosphatidylcholines in participants with CKD.MethodsWe studied 490 participants with CKD from the Seattle Kidney Study. HDL was isolated from plasma; targeted lipidomics was used to quantify the relative abundance of ceramides, sphingomyelins, and phosphatidylcholines per 10 µg of total HDL protein. We evaluated the associations of eGFR and albuminuria with levels of individual lipids and lipid classes (including 7 ceramides, 6 sphingomyelins, and 24 phosphatidylcholines) using multivariable linear regression, controlling for multiple comparisons via the false discovery rate.ResultsThe mean (SD) eGFR was 45 (24) mL/min/1.73 m2; the median (IQR[interquartile range]) albuminuria was 108 (16, 686) mg/g (12.2 [1.8, 77.6] mg/mmol) urine creatinine. After adjusting for demographics, past medical history, laboratory values, and medication use, eGFR was not associated with higher relative abundance of any class of lipids or individual lipids. Greater albuminuria was significantly associated with a higher relative abundance of total ceramides and moderate–long R-chain sphingomyelins, ceramides 22:0 and 24:1, hexosylceramide 16:0, sphingomyelin 16:0, and phosphatidylcholines 29:0, 30:1, and 38:2; the strongest association was for hexosylceramide 16:0 (increase per doubling of urine albumin to creatinine ratio 0.022 (95% CI, 0.012–0.032).ConclusionsGreater albuminuria was significantly associated with specific alterations in the lipid composition of HDL in participants with CKD.

American Indian (AI) communities experience persistent diabetes-related disparities, yet few nutrition interventions are designed for AI with type 2 diabetes or address socio-contextual barriers to healthy eating. We describe our process of adapting the evidence-based Cooking Matters® program for use by AI adults with type 2 diabetes in a rural and resource-limited setting in the North-Central United States. We conducted three focus groups with AI adults with diabetes to (i) identify Cooking Matters® adaptations and (ii) gather feedback on appropriateness of the adapted intervention using Barrera and Castro’s cultural adaptation framework. Transcripts were coded using an inductive, constant comparison approach. Queries of codes were reviewed to identify themes. Contextual considerations included limited access to grocery stores and transportation barriers, reliance on government food assistance and the intergenerational burden of diabetes. Adaptations to content and delivery included incorporating traditional and locally available foods; appealing to children or others in multigenerational households and prioritizing visual over written content. Our use of Barrera and Castro’s framework adds rigor and structure to the cultural adaptation process and increases the likelihood of future intervention success. Other researchers may benefit from using this framework to guide the adaptation of evidence-based interventions in AI communities.

Background and ObjectivesLittle is known about incidence of vascular and Alzheimer dementias in American Indians.MethodsWe conducted a large, heterogeneous, population-based, longitudinal cohort study of brain aging in community-dwelling American Indians aged 64–95 years from 11 tribes across 3 states, with neurologic examinations, 1.5T MRI, and extensive cognitive testing. Visit 1 in 2010–2013 (n = 817) and visit 2 in 2017–2019 (n = 403) included all willing, surviving participants. Standardized cognitive tests at both visits included Modified Mini-Mental Status Examination (MMSE), Wechsler Adult Intelligence Scale digit symbol coding (WAIS), Controlled Oral Word Association (COWA), and California Verbal Learning Test short form (CVLT). Test materials added at follow-up included Wide Range Achievement (reading) Test (WRAT) and National Alzheimer Coordinating Center Uniform Data Set cognitive battery (v3 form C2), including Montreal Cognitive Assessment (MoCA). MRI neuroradiologists coded infarcts, hemorrhages, white matter hyperintensities, sulcal atrophy, and ventricle enlargement.ResultsThe mean time between examinations was 6.7 years (SD 1.1, range 3.8–9.1 years). Years of formal education had modest correlation with WRAT reading score (r =0.45). Prevalence and incidence (respectively) of infarcts were 32% and 12.8/1,000 person-years (PYs) hemorrhages 6% and 4.4/1000 PY worsening sulci 74% and 19.0/1000 PY worsening ventricle 79% and 30.1/1000 PY worsening leukoaraiosis 44% and 26.1/1000 PY. Linear losses per year in cognitive scores were 0.6% MMSE, 1.2% WAIS, 0.6% COWA, and 2.2% CVLT. The mean MoCA scores were 18.9 (SD 4.3).DiscussionThese are the first data on longitudinal cognitive and imaging changes in American Indians and first reports of Alzheimer disease–related features. The mean scores in MoCA were similar or lower than standard cutoffs used to diagnose dementia in other racial/ethnic groups, suggesting that standardized cognitive tests may not perform well in this population. Test validation, adaptation, and score adjustment are warranted. Years of education were a poor proxy for premorbid function, suggesting novel methods for cognitive score contextualization is also needed in this population. Evaluation of selective survival suggests attrition from death, and frailty should be accounted for in causal analyses. Overall, these data represent a unique opportunity to examine neurology topics of critical importance to an understudied population.

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

To evaluate the association of nonesterified fatty acids (NEFA) with dysglycemia in older adults, NEFA levels were measured among participants in the Cardiovascular Health Study (United States; enrolled 1989–1993). Associations with insulin sensitivity and pancreatic β-cell function, and with incident type 2 diabetes mellitus (DM), were examined. The sample comprised 2,144 participants (aged 77.9 (standard deviation, 4.5) years). Participant data from the Cardiovascular Health Study visit in 1996–1997 was used with prospective follow-up through 2010. Fasting and postload NEFA showed significant associations with lower insulin sensitivity and pancreatic β-cell function, individually and on concurrent adjustment. Over median follow-up of 9.7 years, 236 cases of DM occurred. Postload NEFA were associated with risk of DM (per standard deviation, hazard ratio = 1.18, 95% confidence interval: 1.08, 1.29), but fasting NEFA were not (hazard ratio = 1.12, 95% confidence interval: 0.97, 1.29). The association for postload NEFA persisted after adjustment for putative intermediates, and after adjustment for fasting NEFA. Sex and body mass index modified these associations, which were stronger for fasting NEFA with DM in men but were accentuated for postload NEFA in women and among leaner individuals. Fasting and postload NEFA were related to lower insulin sensitivity and pancreatic β-cell function, but only postload NEFA were associated with increased DM. Additional study into NEFA metabolism could uncover novel potential targets for diabetes prevention in elders.

Introduction: Heart failure (HF) is a leading cause of death. Despite the high burden of CVD and diabetes affecting American Indian (AI) communities, studies of risk factors for HF and HF subtypes in AIs are lacking and critically needed to optimize prevention strategies. Hypothesis: We hypothesize that diabetes and diabetes-related complications are HF risk factors in AIs. Methods: A total of 3,066 Strong Heart Study (SHS) participants (mean age 56.3±8.1 years, 58% women, all free of CVD) recruited in 1989-91 were followed through 2017. A total of 489 participants developed HF (119 HFpEF, 68 HFmrEF, 98 HFrEF, 204 unclassified). We used Cox proportional hazards models to determine risk factors for HF and HF subtypes progressively adjusting for sociodemographic and traditional CV risk factors (Model 1) and additionally for glycated hemoglobin (HbA1c) and albuminuria (Model 2-main model). Results: HRs (95% CI) are shown in Table 1. Age, smoking status, BMI, hypertension treatment, diabetes status, HbA1c, and albuminuria were independently associated with overall HF (Model 2). Some associations differed across HF subtypes: male sex was associated with higher risk of HFrEF and potentially HFmrEF, whereas female sex was associated with higher risk of HFpEF. BMI was associated with HFpEF but not with HFmrEF and HFrEF. Higher HDL-cholesterol was negatively associated with risk of HFmrEF and HFrEF. Diabetes was consistently associated with all HF subtypes. HbA1c was significantly associated with HFmrEF and albuminuria was significantly associated with HpEF and HFrEF. The association with diabetes status was attenuated after adjustment for HbA1c and albuminuria for all forms of HF. Conclusion: Diabetes and diabetes-related complications are major risk factors for all forms of HF in the SHS. Indicators of HF risk differ across HF subtypes. Including measures of diabetes control (HbA1c) and target organ damage (albuminuria) in HF risk calculation improves risk prediction and could aid in targeting primary prevention interventions.

Background: Cadmium is a cardiotoxic divalent metal that accumulates in the liver and kidney. It resembles the essential metal zinc, replacing it in numerous enzymes and proteins. Zinc plays a major role in insulin function. Glucose dyshomeostasis increases the loss of zinc through the urine. Cadmium has been associated with peripheral artery disease and critical limb ischemia, conditions that lead to limb amputations. Chelation treatment with edetate disodium, an agent that facilitates the excretion of cadmium from the body, was beneficial for individuals with critical limb ischemia and diabetes in several small studies. This study evaluated the association of urinary levels of cadmium and zinc with amputations in a population with a high burden of diabetes from Arizona, Oklahoma, North Dakota and South Dakota. Hypothesis: We hypothesize that urinary cadmium and zinc levels are related to prevalent amputations in the SHS cohort. Methods: We included 2,724 participants from the Strong Heart Study, a population-based cohort study in 12 American Indian communities, recruited in 1989-1991 and followed for amputations through 1998-1999. Trained staff identified amputations of the lower extremity through visual examination at the baseline visit. We censored traumatic amputations. Baseline metal levels in spot urine samples were divided by urinary creatinine to account for urine dilution. Results: Mean age was 56.4 years, 41.5% participants were male, and 42% had diabetes. We identified a total of 35 (1.3%) amputations of the lower extremities during the study period. Median urinary levels were 0.97 μg/g for cadmium and 0.56 mg/g for zinc. Higher levels of urinary cadmium and zinc were positively associated with the presence of amputations. The odds ratios of prevalent amputations for an IQR of cadmium and zinc distribution were 1.54 (1.00, 2.38) and 2.24 (1.48, 3.39), respectively, in models adjusted for sociodemographic, lifestyle (tobacco and alcohol intake), and other factors (BMI, hypertension and diabetes status, HDL and LDL-cholesterol, and estimated glomerular filtration rate). The associations remained after further adjustment for fasting plasma glucose levels. Urinary cadmium and zinc levels were positively correlated (r=0.24, P Conclusions: Urinary cadmium and zinc were positively associated with the presence of lower extremity amputations in American Indian adults with a high burden of diabetes. These results support the current evidence of cadmium as a cardiometabolic risk factor, and the potential role of impaired zinc metabolism, reflected as increased urinary zinc excretion, in vascular complications of diabetes.

Peer reviewed: True, Funder: University of New South Wales; FundRef: http://dx.doi.org/10.13039/501100001773, OBJECTIVE: To assess the prospective associations of circulating levels of omega 3 polyunsaturated fatty acid (n-3 PUFA) biomarkers (including plant derived α linolenic acid and seafood derived eicosapentaenoic acid, docosapentaenoic acid, and docosahexaenoic acid) with incident chronic kidney disease (CKD). DESIGN: Pooled analysis. DATA SOURCES: A consortium of 19 studies from 12 countries identified up to May 2020. STUDY SELECTION: Prospective studies with measured n-3 PUFA biomarker data and incident CKD based on estimated glomerular filtration rate. DATA EXTRACTION AND SYNTHESIS: Each participating cohort conducted de novo analysis with prespecified and consistent exposures, outcomes, covariates, and models. The results were pooled across cohorts using inverse variance weighted meta-analysis. MAIN OUTCOME MEASURES: Primary outcome of incident CKD was defined as new onset estimated glomerular filtration rate

Background: The prevalence of type 2 diabetes has dramatically increased in the past years. Increasing evidence supports that blood DNA methylation, the best studied epigenetic mark, is related to diabetes risk. Few prospective studies, however, are available. We studied the association of blood DNA methylation with diabetes in the Strong Heart Study. We used limma, Iterative Sure Independence Screening and Cox regression to study the association of blood DNA methylation with fasting glucose, HOMA-IR and incident type 2 diabetes among 1312 American Indians from the Strong Heart Study. DNA methylation was measured using Illumina's MethylationEPIC beadchip. We also assessed the biological relevance of our findings using bioinformatics analyses. Results: Among the 358 differentially methylated positions (DMPs) that were cross-sectionally associated either with fasting glucose or HOMA-IR, 49 were prospectively associated with incident type 2 diabetes, although no DMPs remained significant after multiple comparisons correction. Multiple of the top DMPs were annotated to genes with relevant functions for diabetes including SREBF1, associated with obesity, type 2 diabetes and insulin sensitivity; ABCG1, involved in cholesterol and phospholipids transport; and HDAC1, of the HDAC family. (HDAC inhibitors have been proposed as an emerging treatment for diabetes and its complications). Conclusions: Our results suggest that differences in peripheral blood DNA methylation are related to cross-sectional markers of glucose metabolism and insulin activity. While some of these DMPs were modestly associated with prospective incident type 2 diabetes, they did not survive multiple testing. Common DMPs with diabetes epigenome-wide association studies from other populations suggest a partially common epigenomic signature of glucose and insulin activity. The Strong Heart Study was supported by Grants from the National Heart, Lung, and Blood Institute (NHLBI) (contract numbers 75N92019D00027, 75N92019D00028, 75N92019D00029 and 75N92019D00030) and previous Grants (R01HL090863, R01HL109315, R01HL109301, R01HL109284, R01HL109282 and R01HL109319 and cooperative agreements: U01HL41642, U01HL41652, U01HL41654, U01HL65520 and U01HL65521) and by the National Institute of Environmental Health Sciences (Grant numbers R01ES021367, R01ES025216, P42ES033719, P30ES009089). ADR was supported by a fellowship from “la Caixa” Foundation (ID 100010434) (fellowship code “LCF/BQ/DR19/11740016”). MTP was supported by the Strategic Action for Research in Health sciences (PI15/00071) and CIBERCV, which are initiatives from Instituto de Salud Carlos III and the Spanish Ministry of Science and Innovation and co-funded with European Funds for Regional Development (FEDER), by the Third AstraZeneca Award for Spanish Young Researchers and by the State Agency for Research (PID2019-108973RB-C21). The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health (USA) or the National Health Institute Carlos III (Spain). The funders had no role in the planning, conducting, analysis, interpretation or writing of this study. Sí

Background De novo lipogenesis (DNL) is the primary metabolic pathway synthesizing fatty acids from carbohydrates, protein, or alcohol. Our aim was to examine associations of in vivo levels of selected fatty acids (16:0, 16:1n7, 18:0, 18:1n9) in DNL with incidence of type 2 diabetes (T2D). Methods and findings Seventeen cohorts from 12 countries (7 from Europe, 7 from the United States, 1 from Australia, 1 from Taiwan; baseline years = 1970–1973 to 2006–2010) conducted harmonized individual-level analyses of associations of DNL-related fatty acids with incident T2D. In total, we evaluated 65,225 participants (mean ages = 52.3–75.5 years; % women = 20.4%–62.3% in 12 cohorts recruiting both sexes) and 15,383 incident cases of T2D over the 9-year follow-up on average. Cohort-specific association of each of 16:0, 16:1n7, 18:0, and 18:1n9 with incident T2D was estimated, adjusted for demographic factors, socioeconomic characteristics, alcohol, smoking, physical activity, dyslipidemia, hypertension, menopausal status, and adiposity. Cohort-specific associations were meta-analyzed with an inverse-variance-weighted approach. Each of the 4 fatty acids positively related to incident T2D. Relative risks (RRs) per cohort-specific range between midpoints of the top and bottom quintiles of fatty acid concentrations were 1.53 (1.41–1.66; p < 0.001) for 16:0, 1.40 (1.33–1.48; p < 0.001) for 16:1n-7, 1.14 (1.05–1.22; p = 0.001) for 18:0, and 1.16 (1.07–1.25; p < 0.001) for 18:1n9. Heterogeneity was seen across cohorts (I2 = 51.1%–73.1% for each fatty acid) but not explained by lipid fractions and global geographical regions. Further adjusted for triglycerides (and 16:0 when appropriate) to evaluate associations independent of overall DNL, the associations remained significant for 16:0, 16:1n7, and 18:0 but were attenuated for 18:1n9 (RR = 1.03, 95% confidence interval (CI) = 0.94–1.13). These findings had limitations in potential reverse causation and residual confounding by imprecisely measured or unmeasured factors. Conclusions Concentrations of fatty acids in the DNL were positively associated with T2D incidence. Our findings support further work to investigate a possible role of DNL and individual fatty acids in the development of T2D., Fumiaki Imamura and colleagues investigate the association between concentrations of fatty acid involved in de-novo lipogensis and incidence of Type 2 diabetes., Author summary Why was this study done? De novo lipogenesis (DNL) is a metabolic pathway involved in the endogenous synthesis of specific fatty acids, such as 16:0, 16:1n7, 18:0, and 18:1n9, and it is linked to the pathophysiology of cardiometabolic diseases, including type 2 diabetes (T2D). Circulating or tissue concentrations of these fatty acids have been investigated for the associations with T2D incidence in epidemiological research. However, published studies reported inconsistent associations inconsistently and were subject to publication bias. Summary evidence is not available to date for the associations between these fatty acids and T2D incidence. An integration of available cohort studies would increase statistical power and allow assessment of generalizability, standardization of analytical strategies, and evidence synthesis with the potential publication bias minimized. What did the researchers do and find? As a part of the Fatty Acids and Outcomes Research Consortium (FORCE), we conducted new individual-participant data analyses of 17 cohort studies of a total of 65,225 adults free of T2D at baseline, among whom 15,383 developed incident T2D over up to 20 years of follow-up. The cohort studies analyzed the associations between fatty acids (16:0, 16:1n7, 18:0, and 18:1n9) and the risk of developing T2D with standardized analytic strategy. In pooled analyses, each of the fatty acids was positively associated with a higher risk of developing T2D. The associations were independent of major risk factors for T2D, such as age, sex, race/ethnicity, socioeconomic characteristics, smoking status, physical activity, and obesity. What do these findings mean? The findings provide the first summary evidence to date for the positive relationships of concentrations of the DNL-related fatty acids with a risk of T2D, indicating the strong relevance of DNL and its determinants to the development of T2D. These fatty acids potentially reflect the status of DNL activity, which may be stimulated or suppressed by a combination of carbohydrate intake, alcohol intake, polyunsaturated fatty acid intake, and other lifestyle and clinical factors. Therefore, the current findings indicate the need for investigation into determinants and consequences of elevated concentrations of these fatty acids. Despite several advantages of our individual-level data analysis in this pooling project, the results cannot establish whether elevated concentrations of these fatty acids caused the development of T2D or whether underlying peripheral or hepatic insulin resistance, for example, may elevate both the fatty acid concentrations and the risk of T2D independently.

Background Few studies have assessed the associations of ceramides and sphingomyelins (SMs) with diabetes in humans. Objective We assessed associations of 15 circulating ceramides and SM species with incident diabetes in 2 studies. Methods The analysis included 435 American-Indian participants from the Strong Heart Study (nested case-control design for analyses; mean age: 57 y; 34% male; median time until diabetes 4.3 y for cases) and 1902 participants from the Strong Heart Family Study (prospective design for analyses; mean age: 37 y; 39% male; median 12.5 y of follow-up). Sphingolipid species were measured using stored plasma samples by sequential LC and MS. Using logistic regression and parametric survival models within studies, and an inverse-variance-weighted meta-analysis across studies, we examined associations of 15 ceramides and SM species with incident diabetes. Results There were 446 cases of incident diabetes across the studies. Higher circulating concentrations of ceramides containing stearic acid (Cer-18), arachidic acid (Cer-20), and behenic acid (Cer-22) were each associated with a higher risk of diabetes. The RRs for incident diabetes per 1 SD of each log ceramide species (μM) were 1.22 (95% CI: 1.09, 1.37) for Cer-18, 1.18 (95% CI: 1.06, 1.31) for Cer-20, and 1.20 (95% CI: 1.08, 1.32) for Cer-22. Although the magnitude of the risk estimates for the association of ceramides containing lignoceric acid (Cer-24) with diabetes was similar to those for Cer-18, Cer-20, and Cer-22 (RR = 1.13; 95% CI: 1.01, 1.26), the association was not statistically significant after correction for multiple testing (P = 0.007). Ceramides carrying palmitic acid (Cer-16), SMs, glucosyl-ceramides, or a lactosyl-ceramide were not associated with diabetes risk. Conclusions Higher concentrations of circulating Cer-18, Cer-20, and Cer-22 were associated with a higher risk of developing diabetes in 2 studies of American-Indian adults. This trial was registered at clinicaltrials.gov as NCT00005134.

Background Plasma ceramides and sphingomyelins have been independently linked to diabetes risk, glucose and insulin levels, and the risk of several cardiovascular (CVD) outcomes. However, whether individual ceramide and sphingomyelin species contribute to CVD risk among people with type 2 diabetes is uncertain. Our goal was to evaluate associations of 4 ceramide and 4 sphingomyelin species with incident CVD in a longitudinal population-based study among American Indians with diabetes. Methods This analysis included participants with prevalent type 2 diabetes from two cohorts: a prospective cohort of 597 participants in the Strong Heart Family Study (116 incident CVD cases; mean age: 49 years; average length of follow-up: 14 years), and a nested case–control sample of 267 participants in the Strong Heart Study (78 cases of CVD and 189 controls; mean age: 61 years; average time until incident CVD in cases: 3.8 years). The average onset of diabetes was 7 years prior to sphingolipid measurement. Sphingolipid species were measured using liquid chromatography and mass spectrometry. Cox regression and logistic regression were used to assess associations of sphingolipid species with incident CVD; results were combined across cohorts using inverse-variance weighted meta-analysis. Results There were 194 cases of incident CVD in the two cohorts. In meta-analysis of the 2 cohort results, higher plasma levels of Cer-16 (ceramide with acylated palmitic acid) were associated with higher CVD risk (HR per two-fold higher Cer-16: 1.85; 95% CI 1.05–3.25), and higher plasma levels of sphingomyelin species with a very long chain saturated fatty acid were associated with lower CVD risk (HR per two-fold higher SM-22: 0.48; 95% CI 0.26–0.87), although none of the associations met our pre-specified threshold for statistical significance of p = 0.006. Conclusions While replication of the findings from the SHS in other populations is warranted, our findings add to a growing body of research suggesting that ceramides, in particular Cer-16, not only are associated with higher diabetes risk, but may also be associated with higher CVD risk after diabetes onset. We also find support for the hypothesis that sphingomyelins with a very long chain saturated fatty acid are associated with lower CVD risk among adults with type 2 diabetes.

Introduction: Dyslipidemia is characterized by high levels of total cholesterol (TC), LDL cholesterol (LDL-C), triglycerides (TG), or low levels of HDL cholesterol (HDL-C) and is an established risk factor for subclinical and clinical cardiovascular disease (CVD) among adults. Although several investigations exist in older American Indian (AI) adults, the data on AI adolescents and young adults are scarce. Hypothesis: Dyslipidemia will be prevalent, and the incidence of subclinical and clinical CVD will be higher in young AI with than without baseline dyslipidemia. Methods: We evaluated AI participants from the SHFS, who were 14-39 years old at the baseline examination, 2001-2003 (n=1,436). To measure lipids, we drew blood after a 12-hour fast and defined dyslipidemia as any of the following: TC ≥ 200 mg/dL, LDL-C ≥ 100 mg/dL, TG ≥ 150 mg/dL, HDL-C < 40 mg/dL for men, HDL-C < 50mg/dL for women, non-HDL-C ≥ 130 mg/dL or taking lipid lowering medication. We used carotid ultrasound to detect atherosclerotic plaque at baseline and at the follow-up examination, 2006-2009. We identified CVD events through 2019 with a median follow-up of 17.8 years. We used log-rank tests to determine if the incidence of plaque or CVD events differed according to different categories of dyslipidemia. Results: Prevalence of dyslipidemia was 42%, 65%, and 73% for participants Conclusions: AI adolescents and young adults have an unexpectedly high prevalence of dyslipidemia, which leads to higher incident plaque and CVD events later in life. These data provide evidence for the benefits of lipid screening and intervention among this population.

Melamine is a nephrotoxic industrial chemical. Diet is one source of melamine exposure, yet little work has examined the main dietary contributors, particularly among children. We evaluated associations of diet with urinary melamine and derivative concentrations among 123 children aged 4–6 years in the Global Alliance to Prevent Prematurity and Stillbirth cohort. Children’s diets on the day preceding urine collection were assessed using 24-h dietary recalls. Associations of meat, fruit, and grain intakes with melamine exposure were examined using multiple linear regression. Remaining food groups were examined in secondary analyses. Mean (SD) melamine, ammelide, and cyanuric acid concentrations were 6.1 (12.4), 1.9 (2.1), and 60.6 (221.2) ng/mL, respectively. The second tertile of red meat consumers had 98% (95% CI: 15%, 241%) greater melamine exposure than non-consumers, yet the highest consumers did not have increased exposure. Greater consumption of certain fruits was associated with lower urinary ammelide. The top yogurt consumers had 112% (95% CI: 29%, 247%) greater melamine exposure than non-consumers. Consumption of starchy vegetables excluding potatoes was associated with 139% (95% CI: 6%, 437%) greater urinary ammelide. These observed associations should be confirmed in future studies using larger samples and increased monitoring of non-dietary routes of exposure.

ImportanceTo our knowledge, no published studies have investigated the association of ambulatory activity with risk of death among young and middle-aged American Indian individuals. The burden of chronic disease and risk of premature death is higher among American Indian individuals than among the general US population, so better understanding of the association of ambulatory activity with risk of death is needed to inform public health messaging in tribal communities.ObjectiveTo examine the association of objectively measured ambulatory activity (ie, steps per day) with risk of death among young and middle-aged American Indian individuals.Design, Setting, and ParticipantsThe ongoing longitudinal Strong Heart Family Study (SHFS) is being conducted with participants aged 14 to 65 years in 12 rural American Indian communities in Arizona, North Dakota, South Dakota, and Oklahoma and includes up to 20 years of follow-up (February 26, 2001, to December 31, 2020). This cohort study included SHFS participants who had available pedometer data at baseline. Data analysis was performed on June 9, 2022.ExposuresObjectively measured ambulatory activity at baseline.Main Outcomes and MeasuresOutcomes of interest were total and cardiovascular-related mortality. Mixed-effects Cox proportional hazards regression was used to estimate hazard ratios for risk of death, with entry at the time of the pedometer assessment and time at risk until death or the latest adjudicated date of follow-up.ResultsA total of 2204 participants were included in this study. Their mean (SD) age was 41.0 (16.8) years; 1321 (59.9%) were female and 883 (40.1%) were male. During a mean follow-up of 17.0 years (range, 0-19.9 years), 449 deaths occurred. Compared with participants in the lowest quartile of steps per day (Conclusions and RelevanceIn this cohort study, American Indian individuals who took at least 3126 steps/d had a lower risk of death compared with participants who accumulated fewer steps per day. These findings suggest that step counters are an inexpensive tool that offers an opportunity to encourage activity and improve long-term health outcomes.

Rates of cardiovascular disease (CVD) among American Indians (AI) have been increasing. Although we have observed an association between atherosclerosis and CVD in older adults, the potential association among young AI is unclear. Therefore, we aim to describe the prevalence of atherosclerosis among young AI and determine its association with CVD and all-cause mortality.We evaluated AI participants from the Strong Heart Family Study (SHFS), who were40 years old and CVD free at the baseline examination, 2001-2003 (n = 1376). We used carotid ultrasound to detect baseline atherosclerotic plaque. We identified CVD events and all-cause mortality through 2019, with a median follow-up of 17.8 years. We used shared frailty Cox Proportional Hazards models to assess the association between atherosclerosis and time to CVD event or all-cause mortality, while controlling for covariates. Among 1376 participants, 71 (5.2%) had atherosclerosis at baseline. During follow-up, 120 (8.7%) had CVD events and 104 (7.6%) died from any cause. CVD incidence was higher in participants who had baseline atherosclerosis (13.51/1000 person-years) than in those who did not (4.95/1000 person-years, p = 0.0003). CVD risk and all-cause mortality were higher in participants with atherosclerosis, while controlling for covariates (CVD HR = 1.85, 95%CI = 1.02-3.37, p = 0.0420; all-cause mortality HR = 2.04, 95%CI = 1.07-3.89, p = 0.0291).Among young AI, atherosclerosis was independently associated with incident CVD and all-cause mortality later in life. Thus, atherosclerosis begins early in life and interventions in adolescents and young adults to slow the progression of disease could prevent or delay CVD events later in life.

Introduction: Rates of cardiovascular disease (CVD) among American Indians (AI) have been increasing. Subclinical atherosclerosis is typically detected later in life and may develop into clinical CVD. Although investigators have established the association in older adults, the burden of subclinical atherosclerosis and its relation to CVD risk among AI youth is unclear. Hypothesis: Subclinical atherosclerosis will be prevalent and the risk of CVD will be higher in AI with atherosclerotic plaque in adolescence and early adulthood. Methods: We evaluated AI participants from the SHFS, who were 14-39 years old, CVD free, and had a carotid ultrasound at the baseline examination, 2001-2003 (n=1,376). We used carotid ultrasound to detect baseline atherosclerotic plaque. We identified fatal and/or non-fatal CVD events through the end of 2019 with a median follow-up of 17.8 years. We used shared frailty Cox Proportional Hazards models to assess the association between subclinical atherosclerosis and time to CVD events, while controlling for covariates. Results: Among 1,376 participants, 71 (5.2%) had atherosclerotic plaque at baseline. During follow-up, 120 (8.7%) participants had a fatal or non-fatal CVD event. CVD incidence was higher in participants with baseline plaque (13.51/1,000 person-years) than in those without (4.95/1,000 person-years, p=0.0003, Figure 1). Risk of CVD was higher in participants with baseline plaque compared to those without, while controlling for age and obesity (CVD HR=1.85, 95% CI=1.02-3.37, p=0.0420). Conclusions: AI adolescents and young adults have an unexpectedly high prevalence of atherosclerotic plaque, which is independently associated with incident CVD later in life. Thus, atherosclerosis begins early in life and interventions in adolescents and young adults to slow the progression of disease could prevent or delay CVD events later in life.

Introduction: Findings on MRI of vascular brain injury, such as brain infarcts and white matter hyperintensities, are chronic manifestation of atherosclerosis. A gut-microbiome-generated metabolite, trimethylamine N-oxide (TMAO), is an independent predictor of clinical cardiovascular events. However, no study has examined associations between TMAO and subclinical vascular brain injury in the general population. Hypothesis: TMAO levels are positively associated with evidence of progressive subclinical vascular brain injury on serial MRI scans with incident brain infarcts and white matter worsening. Methods: The Cardiovascular Health Study (CHS) is a community-based prospective cohort study in adults aged >65 years. Plasma TMAO was measured using mass spectrometry from samples collected in 1992-1993 and 1996-1997. Brain MRI was performed at 1991-1994 and again at 1997-1999. White matter was graded on a 10-point scale, higher being worse, and white matter worsening (WMW) was defined by an increase of least one point comparing initial and follow up scans. In these analyses, participants with prior TIA or stroke were excluded. Those with serum TMAO and both MRI scans were included: n=1196 for incident brain infarct and n=1553 for white matter worsening. Logistic regression was used for the association of baseline TMAO levels and incident brain infarcts, and Poisson regression, for the change in TMAO levels and WMW. Models were adjusted for age, sex, race, alcohol use, intake of meat and vegetable, and vascular risk factors. Results: Between the two MRI scans, 191(15.9%) participants had subclinical incident brain infarcts, and 423 (27.2%) participants had WMW. Comparing the highest vs. lowest quartile, the first TMAO were not significantly associated with incident brain infarcts: odds ratio 0.78 (95% CI: 0.49 to 1.25). Again comparing the highest vs. lowest quartile, changes in TMAO were not associated with WMW: 1.08 (0.77 to 1.51). Conclusions: Baseline and changes in plasma TMAO levels were not associated with findings of subclinical vascular brain injury on MRI in older US adults. The associations of TMAO with the adverse clinical events seen in prior clinical samples of patients were not seen at the subclinical level in our population-based study.

OBJECTIVE Comprehensive assessment of alterations in lipid species preceding type 2 diabetes (T2D) is largely unknown. We aimed to identify plasma molecular lipids associated with risk of T2D in American Indians. RESEARCH DESIGN AND METHODS Using untargeted liquid chromatography–mass spectrometry, we repeatedly measured 3,907 fasting plasma samples from 1,958 participants who attended two examinations (∼5.5 years apart) and were followed up to 16 years in the Strong Heart Family Study. Mixed-effects logistic regression was used to identify lipids associated with risk of T2D, adjusting for traditional risk factors. Repeated measurement analysis was performed to examine the association between change in lipidome and change in continuous measures of T2D, adjusting for baseline lipids. Multiple testing was controlled by false discovery rate at 0.05. RESULTS Higher baseline level of 33 lipid species, including triacylglycerols, diacylglycerols, phosphoethanolamines, and phosphocholines, was significantly associated with increased risk of T2D (odds ratio [OR] per SD increase in log2-transformed baseline lipids 1.50–2.85) at 5-year follow-up. Of these, 21 lipids were also associated with risk of T2D at 16-year follow-up. Aberrant lipid profiles were also observed in prediabetes (OR per SD increase in log2-transformed baseline lipids 1.30–2.19 for risk lipids and 0.70–0.78 for protective lipids). Longitudinal changes in 568 lipids were significantly associated with changes in continuous measures of T2D. Multivariate analysis identified distinct lipidomic signatures differentiating high- from low-risk groups. CONCLUSIONS Lipid dysregulation occurs many years preceding T2D, and novel molecular lipids (both baseline level and longitudinal change over time) are significantly associated with risk of T2D beyond traditional risk factors. Our findings shed light on the mechanisms linking dyslipidemia to T2D and may yield novel therapeutic targets for early intervention tailored to American Indians.

Previous studies consistently report that diet quality is inversely associated with risk of cardiovascular disease (CVD) and type 2 diabetes. However, few studies have assessed the association of diet quality with serum lipoproteins, an intermediate marker of cardio-metabolic health, or assessed whether type 2 diabetes modifies these associations. This study assessed associations of diet quality (evaluated using the Alternative Healthy Eating Index (AHEI)), and the interaction of diet quality with diabetes, on total cholesterol (TC), triglycerides (TG), low-density lipoprotein (LDL-C), high-density lipoprotein (HDL-C), apolipoprotein A (apoA1), and apolipoprotein B (apoB) among American Indians (AIs). Participants comprised AIs who participated in the Strong Heart Family Study (SHFS)—a study of CVD and its risk factors in 12 AI communities. Generalized estimated equations (GEEs) were used to examine the following associations: (1) the cross-sectional associations of diet quality (as determined by AHEI) with serum lipoproteins (n = 2200); and (2) the prospective associations of the AHEI measured at baseline with serum lipoproteins (n = 1899). In cross-sectional analyses, associations of AHEI with TC (p

Background Diet plays a key role in development of diabetes, and there has been recent interest in better understanding the association of dairy food intake with diabetes. Objective This study examined the associations of full-fat and low-fat dairy food intake with incident diabetes among American Indians-a population with a high burden of diabetes. Methods The study included participants from the Strong Heart Family Study (SHFS), a family-based study of cardiovascular disease in American Indians, free of diabetes at baseline (2001-2003) (n = 1623). Participants were 14-86-y-old at baseline and 60.8% were female. Dairy food intake was assessed using a Block food frequency questionnaire. Incident diabetes was defined using American Diabetes Association criteria. Parametric survival models with a Weibull distribution were used to evaluate the associations of full-fat and low-fat dairy food intake with incident diabetes. Serving sizes were defined as 250 mL for milk and 42.5 g for cheese. Results We identified 277 cases of diabetes during a mean follow-up of 11 y. Reported intake of dairy foods was low [median full-fat dairy food intake: 0.11 serving/1000 kcal; median low-fat dairy food intake: 0.03 serving/1000 kcal]. Participants who reported the highest full-fat dairy food intake had a lower risk of diabetes compared to those who reported the lowest full-fat food dairy intake [HR (95% CI): 0.79 (0.59, 1.06); P-trend = 0.03, comparing extreme tertiles, after adjustment for age, sex, site, physical activity, education, smoking, diet quality, and low-fat dairy food intake]. Low-fat dairy food intake was not associated with diabetes. Conclusions American Indians who participated in the SHFS reported low dairy food intake. Participants who reported higher full-fat dairy food intake had a lower risk of diabetes than participants who reported lower intake. These findings may be of interest to populations with low dairy food intake.

Non-caloric artificial sweeteners (NAS) are marketed as healthier alternatives to sugar, but the relationship between consumption of NAS and development of diabetes is unclear. This study assessed the associations of diet soda and NAS consumption with (1) early markers of insulin and glucose homeostasis (cross-sectionally) and (2) incident diabetes (over an average of 8 years of follow-up) among American Indians, a population with high rates of obesity. The study population included Strong Heart Family Study participants without cardiovascular disease or diabetes who participated in the 2007–2009 study exam (n = 1359). Diet soda and NAS consumption were assessed using a Block food frequency questionnaire and supplemental NAS questionnaire at the study exam. Fasting plasma glucose and insulin were measured during the study exam after a 12-h overnight fast. Participants were followed for incident diabetes through December 2017 using a single phone interview and medical record review; diabetes was identified by self-report and confirmed by documentation in medical records. Associations of diet soda and NAS consumption with fasting insulin, glucose, and incident diabetes were assessed using generalized estimating equations (fasting insulin and glucose analyses) and parametric survival models with Weibull distributions (incident diabetes analyses). Just under half of participants reported regularly consuming diet soda (40%) or using NAS to sweeten their beverages (41%). During an average 8 years of follow-up, we identified 98 cases of incident diabetes. After correction for multiple comparisons, there were no statistically significant associations of reported diet soda and NAS consumption with fasting insulin, fasting glucose, or incident diabetes. Although reported consumption of diet soda and NAS were high, neither were associated with diabetes risk.

Objective:Perceptions of social-contextual food environments and associated factors that influence food purchases are understudied in American Indian (AI) communities. The purpose of the present study was to: (i) understand the perceived local food environment; (ii) investigate social-contextual factors that influence family food-purchasing choices; and (iii) identify diet intervention strategies.Design:This qualitative study consisted of focus groups with primary household shoppers and key-informant interviews with food retailers, local government food assistance programme directors and a dietitian. An inductive, constant comparison approach was used to identify major themes.Setting:A large AI reservation community in the north-central USA.Participants:Four focus groups (n 31) and seven key-informant interviews were conducted in February and May 2016.Results:Perceptions of both the higher cost of healthy foods and limited access to these foods influenced the types of foods participants purchased. Dependence on government assistance programmes and the timing of benefits also contributed to the types of foods purchased. Participants described purchasing foods based on the dietary needs and preferences of their children. Suggestions for improving the purchase and consumption of healthy foods included: culturally relevant and family-centred cooking classes and workshops focused on monthly food budgeting. Participants also emphasized the importance of involving the entire community in healthy eating initiatives.Conclusions:Cost and access were the major perceived barriers to healthy eating in this large rural AI community. Recommended interventions included: (i) family-friendly and culturally relevant cooking classes; (ii) healthy food-budgeting skills training; and (iii) approaches that engage the entire community.

BACKGROUND AND AIM: Chronic low-dose exposure to uranium (U) through diet is not well characterized in the US. American Indian (AI) participants in the Strong Heart Family Study (SHFS) have higher ...