Atherosclerosis Risk In Communities Study Research Articles

Incidence and risk factors associated with atrioventricular block in the general population: the atherosclerosis risk in communities study and Cardiovascular Health Study

ObjectivesTo identify risk factors correlated with atrioventricular block (AVB) in the general population.MethodsParticipants in the Atherosclerosis Risk in Communities study (ARIC) and the Cardiovascular Health study (CHS) were enrolled. The presence of AVB was confirmed at an electrocardiogram (ECG) reading center using Minnesota ECG Classification. Cox proportional hazards models were performed to investigate potential risk factors of AVB, after adjustment for age, sex, race and traditional cardiovascular risk factors.ResultsDuring the 17 years of follow-up, a total of 731 high-degree AVB cases were identified. Age and sex-standardized rate of AVB was 2.79 and 2.35 per 1000 person-years in the white and the black population, respectively. With the increase of the geriatric population, the incidence of high-degree AVB will increase from 378,816 in 2020 to 535,076 in 2060, and most increment would occur among the elderly. Older age, male sex, the white race, overweight, comorbidities, declined forced vital capacity (FVC), elevated inflammation biomarkers, left bundle branch block and bifascicular block were independently associated with the incidence of high-degree AVB.ConclusionTo conclude, older age, male sex, white population, overweight, combined diabetes or chronic kidney disease, impaired FVC, elevated inflammation biomarkers, left bundle branch block and bifascicular block were independent predictors for high-degree AVB. The next 40 years would witness a dramatic increase in the incidence of high-degree AVB.

Serum metabolomic markers of artificially sweetened beverage consumption

BackgroundThe consumption of artificially sweetened beverages is on the rise. Use of artificial sweeteners has been associated with adverse health outcomes. There is a need to identify novel objective biomarkers of artificially sweetened beverages in order to improve dietary assessment and to provide insight into their metabolic impact. ObjectiveWe aim to identify serum metabolites that are associated with artificially sweetened beverage consumption. MethodsIn the Atherosclerosis Risk in Communities (ARIC) study, consumption of artificially sweetened beverages was assessed using a food frequency questionnaire and fasting serum samples were collected during the first study visit (1987-1989). Participants were categorized as "non-users" if they reported almost never consumption of artificially sweetened beverages, "moderate users" for 1 glass/month to 6 glasses/week, and "heavy users" for ≥1 glasses/day. Untargeted metabolomic profiling was conducted in two subgroups (subgroup 1: n=1,866, profiled in 2010; subgroup 2 profiled in 2014: n=2,072) and 360 metabolites were analyzed. In this secondary data analysis, multivariable linear regression models were used, adjusting for demographics, health behaviors, health status, and dietary factors. Analyses were conducted in each subgroup and results were meta-analyzed. ResultsIn a meta-analysis of 3,938 generally healthy participants (mean age 54 years, 60% women, 62% Black participants) from ARIC study visit 1, 11 serum metabolites were significantly associated with artificially sweetened beverage consumption. Heavier consumption of artificially sweetened beverages was associated with higher levels of 10 metabolites (saccharin, threonate, erythronate, glycerate, gluconate, mannitol, glucose, tryptophan betaine, trehalose, and N6-acetyllysine) and lower levels of glycocholenate sulfate. ConclusionWe found 11 serum metabolites related to artificially sweetened beverage intake, that consisted of known sugar substitutes, processed food additives, glucose-related compounds, and gut microbiome-related metabolites. These findings enhance our knowledge of the metabolic activity of artificial sweeteners and suggests new biomarkers for monitoring intake.

Six-year change in high-sensitivity cardiac troponin T with subsequent stroke risk in the general population

BackgroundThe association between change in high-sensitivity cardiac troponin T (hs-cTnT) and stroke risk in the general population remains unknown. We aimed to assess the association of a 6-year change in...

Association of left atrial function with frailty: The Atherosclerosis Risk in Communities (ARIC) study.

Frailty is common in people with cardiovascular disease. Worse left atrial (LA) function is an independent risk factor for cardiovascular disease. However, whether worse LA function is associated with frailty is unclear. We included 3292 older adults from the Atherosclerosis Risk in Communities study who were non-frail at baseline (visit 5, 2011-2013) and had LA function (reservoir, conduit, and contractile strain) measured from two-dimensional speckle-tracking echocardiography. LA stiffness index was calculated as a ratio of E/e' to LA reservoir strain. Frailty was defined using the validated Fried frailty phenotype. Incident frailty was assessed between 2016 and 2019 during two follow-up visits. LA function was analyzed as quintiles. Multivariable logistic regression examined odds of incident frailty. Median (interquartile range [IQR]) age was 74 (71-77) years, 58% were female, and 214 (7%) participants developed frailty during a median (IQR) follow-up of 6.3 (5.6-6.8) years. After adjusting for baseline confounders and incident cardiovascular events during follow-up, the odds of developing frailty was 2.42 (1.26-4.66) times greater among participants in the lowest (vs highest) quintile of LA reservoir strain and 2.41 (1.11-5.22) times greater among those in the highest (vs lowest) quintile of LA stiffness index. Worse LA function was significantly associated with the development of exhaustion, but not the other components of the Fried frailty phenotype. Worse LA function is associated with higher incidence of frailty and exhaustion component independent of LA size and left ventricular function. Future studies are needed to elucidate the underlying mechanisms that drive the observed association.

Long-term longitudinal analysis of 4,187 participants reveals insights into determinants of clonal hematopoiesis

Clonal hematopoiesis of indeterminate potential (CHIP) is linked to diverse aging-related diseases, including hematologic malignancy and atherosclerotic cardiovascular disease (ASCVD). While CHIP is common among older adults, the underlying factors driving its development are largely unknown. To address this, we performed whole-exome sequencing on 8,374 blood DNA samples collected from 4,187 Atherosclerosis Risk in Communities Study (ARIC) participants over a median follow-up of 21 years. During this period, 735 participants developed incident CHIP. Splicing factor genes (SF3B1, SRSF2, U2AF1, and ZRSR2) and TET2 CHIP grow significantly faster than DNMT3A non-R882 clones. We find that age at baseline and sex significantly influence the incidence of CHIP, while ASCVD and other traditional ASCVD risk factors do not exhibit such associations. Additionally, baseline synonymous passenger mutations are strongly associated with CHIP status and are predictive of new CHIP clone acquisition and clonal growth over extended follow-up, providing valuable insights into clonal dynamics of aging hematopoietic stem and progenitor cells. This study also reveals associations between germline genetic variants and incident CHIP. Our comprehensive longitudinal assessment yields insights into cell-intrinsic and -extrinsic factors contributing to the development and progression of CHIP clones in older adults.

Sex Differences in Hypertension and Its Management Throughout Life.

The prevalence of hypertension and uncontrolled hypertension may differ by age and sex. We included participants in the Atherosclerosis Risk in Communities study at seven study visits over 33 years (visit 1: 15 636 participants; mean age, 54 years; 55% women), estimating sex differences in prevalence of hypertension (systolic blood pressure ≥130 mm Hg; diastolic blood pressure ≥80 mm Hg; or self-reported antihypertension medication use) and uncontrolled hypertension (systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg) using unadjusted and comorbidity-adjusted models. The prevalence of hypertension increased from 40% (ages, 43-46 years) to 93% (ages, 91-94 years). Within hypertensive individuals, the prevalence of uncontrolled hypertension was higher in men (33%) than women (23%) at ages 43 to 46 years but became higher in women than men starting at ages 61 to 64, with 56% of women and 40% men having uncontrolled hypertension at ages 91 to 94. This sex difference was not explained by differences in coronary heart disease, diabetes, body mass index, estimated glomerular filtration rate, number of antihypertension medications, classes of medications, or adherence to medications. In both sexes, uncontrolled hypertension was associated with a higher risk for chronic kidney disease progression (hazard ratio, 1.5 [1.2-1.9]; P=4.5×10-4), heart failure (hazard ratio, 1.6 [1.4-2.0]; P=8.1×10-7), stroke (hazard ratio, 2.1 [1.6-2.8]; P=1.8×10-8), and mortality (hazard ratio, 1.5 [1.3-1.6]; P=6.2×10-19). Sex differences in the prevalence of hypertension and uncontrolled hypertension vary by age, with the latter having implications for health throughout the life course.

Semiparametric linear regression with an interval-censored covariate in the atherosclerosis risk in communities study

Semiparametric linear regression with an interval-censored covariate in the atherosclerosis risk in communities study

Multicohort Epigenome-Wide Association Study of All-Cause Cardiovascular Disease and Cancer Incidence: A Cardio-Oncology Approach

BackgroundEmerging evidence reveals a complex relationship between cardiovascular disease (CVD) and cancer, which share common risk factors and biological pathways. ObjectivesThe aim of this study was to evaluate common epigenetic signatures for CVD and cancer incidence in 3 ethnically diverse cohorts: Native Americans from the SHS (Strong Heart Study), European Americans from the FHS (Framingham Heart Study), and European Americans and African Americans from the ARIC (Atherosclerosis Risk In Communities) study. MethodsA 2-stage strategy was used that included first conducting untargeted epigenome-wide association studies for each cohort and then running targeted models in the union set of identified differentially methylated positions (DMPs). We also explored potential molecular pathways by conducting a bioinformatics analysis. ResultsCommon DMPs were identified across all populations. In a subsequent meta-analysis, 3 and 1 of those DMPs were statistically significant for CVD only and both cancer and CVD, respectively. No meta-analyzed DMPs were statistically significant for cancer only. The enrichment analysis pointed to interconnected biological pathways involved in cancer and CVD. In the DrugBank database, elements related to 1-carbon metabolism and cancer and CVD medications were identified as potential drugs for target gene products. In an additional analysis restricted to the 950 SHS participants who developed incident CVD, the C index for incident cancer increased from 0.618 (95% CI: 0.570-0.672) to 0.971 (95% CI: 0.963-0.978) when adjusting the models for the combined cancer and CVD DMPs identified in the other cohorts. ConclusionsThese results point to molecular pathways and potential treatments for precision prevention of CVD and cancer. Screening based on common epigenetic signatures of incident CVD and cancer may help identify patients with newly diagnosed CVD at increased cancer risk.

Psychosocial Health and the Association Between Cerebral Small Vessel Disease Markers With Dementia: The ARIC Study.

Associations between magnetic resonance imaging markers of cerebral small vessel disease (CSVD) and dementia risk in older adults have been established, but it remains unclear how lifestyle factors, including psychosocial health, may modify this association. Social support and social isolation were assessed among participants of the community-based ARIC (Atherosclerosis Risk in Communities) Study, via self-reported questionnaires (1990-1992). Following categorization of both factors, participants were classified as having strong or poor mid-life social relationships. At visit 5 (2011-2013), participants underwent 3T brain magnetic resonance imaging quantifying CSVD measures: white matter hyperintensity volume, microbleeds (subcortical), infarcts (lacunar), and white matter integrity (diffusion tensor imaging). Incident dementia cases were identified from the time of imaging through December 31, 2020 with ongoing surveillance. Associations between CSVD magnetic resonance imaging markers and incident dementia were evaluated using Cox proportional-hazard regressions adjusted for demographic and additional risk factors (from visit 2). Effect modification by mid-life social relationships was evaluated. Of the 1977 participants with magnetic resonance imaging, 1617 participants (60.7% women; 26.5% Black participants; mean age at visit 2, 55.4 years) were examined. In this sample, mid-life social relationships significantly modified the association between white matter hyperintensity volume and dementia risk (P interaction=0.001). Greater white matter hyperintensity volume was significantly associated with risk of dementia in all participants, yet, more substantially in those with poor (hazard ratio, 1.84 [95% CI, 1.49-2.27]) versus strong (hazard ratio, 1.26 [95% CI, 1.08-1.47]) mid-life social relationships. Although not statistically significant, subcortical microbleeds in participants with poor mid-life social relationships were associated with a greater risk of dementia, relative to those with strong social relationships, in whom subcortical microbleeds were no longer associated with elevated dementia risk. The elevated risk of dementia associated with CSVD may be reduced in participants with strong mid-life social relationships. Future studies evaluating psychosocial health through the life course and the mechanisms by which they modify the relationship between CSVD and dementia are needed.

Association Between Obesity and Risk of Total and Obesity-Related Cancer in People With Incident Cardiovascular Disease.

Cardiovascular disease (CVD) and cancer frequently co-occur due to shared risk factors such as obesity, which is linked to CVD and 14 cancer types. This study explores whether CVD pathophysiologies, combined with obesity, increase cancer risk, impacting clinical management. Data from the ARIC (Atherosclerosis Risk in Communities) study, spanning 28 years, were analyzed. The cohort included 5127 participants with incident CVD (myocardial infarction, stroke, heart failure, coronary heart disease), of whom 1511 developed a first primary cancer. Follow-up began at CVD diagnosis after Visit 1. Obesity was assessed using body mass index, waist circumference, and waist-to-hip ratio. Incidence rate differences between obesity groups were adjusted for age, sex, and center, whereas the obesity-cancer association was estimated using Fine-Gray regression adjusted for shared risk factors including smoking. Cancer incidence in obese individuals with CVD (body mass index: rate differences=226.6/100 000 person-years) was higher than in those with normal weight. Although obesity was not linked to overall cancer after adjusting for shared risk factors, it was nominally associated with obesity-related cancers. Specifically, women with CVD and obesity had increased obesity-related cancer risk (body mass index: hazard ratio, 1.67 [95% CI, 1.17-2.31]). No significant associations were found in men, even after excluding prostate cancer. This study suggests that obesity is linked to higher obesity-related cancer risk in women with incident CVD, independent of shared risk factors. Further research is needed to eliminate residual confounding, understand sex differences, and explore how CVD pathophysiologies and obesity together influence cancer risk.

Ultra-Processed Food Consumption and Risk of Incident Hypertension in US Middle-Aged Adults.

Consumption of ultra-processed food, which is manufactured food that is high in additives and sparse in intact foods, is adversely associated with cardiovascular health, primarily in non-US study populations. We aimed to estimate the association between ultra-processed food consumption and incident hypertension in middle-aged adults in the United States. We included 8923 ARIC (Atherosclerosis Risk in Communities) study participants who were hypertension free at baseline and had complete dietary, covariate, and hypertension data from visit 1 (1987-1989). Over a median (25th, 75th percentile) follow-up of 13 (6-21) years, 79% of participants developed hypertension. Participants in the highest quartile of ultra-processed food consumption had 15% higher risk of incident hypertension than those in the lowest quartile (hazard ratio [HR], 1.15 [95% CI, 1.08-1.23]). Participants in the highest quartile of consumption of sugar-sweetened beverages, red and processed meat, and margarine had 16% (HR, 1.16 [95% CI, 1.08-1.24]; p-trend <0.001), 10% (HR, 1.10 [95% CI, 1.03-1.19]; P trend = 0.005), and 6% (HR, 1.06 [95% CI, 0.99, 1.45]; P trend = 0.045) higher risk of incident hypertension, respectively, when compared with the lowest quartiles of consumption. Each additional serving of minimally or unprocessed food was associated with a 2% lower risk of incident hypertension (HR, 0.98 [95% CI, 0.98, 0.99], P<0.001). High consumption of ultra-processed foods, specifically of sugar-sweetened beverages, red and processed meat, and margarine, was associated with a higher incidence of hypertension, whereas minimally or unprocessed food consumption was associated with lower hypertension risk.

Validation of candidate protein biomarkers previously identified by genetic instruments for prostate cancer risk: A prospective cohort analysis of directly measured protein levels in the ARIC study.

Multiple novel protein biomarkers have been shown to be associated with prostate cancer risk using genetic instruments. This study aimed to externally validate the associations of 30 genetically predicted candidate proteins with prostate cancer risk using aptamer-based levels in US Black and White men in the Atherosclerosis Risk in Communities (ARIC) study. Plasma protein levels were previously measured by SomaScan® using the blood collected in 1990-1992. Among 4864 eligible participants, we ascertained 667 first primary prostate cancer cases through 2015. Hazard ratios (HRs) of prostate cancer and 95% confidence intervals (CIs) were estimated using Cox proportional hazards regression for tertiles of each protein. We adjusted for age, race, and other risk factors. Of the 30 proteins and considering a nominal p trend < 0.05, two were positively associated with prostate cancer risk-RF1ML (tertile 3 vs. 1: HR = 1.23; 95% CI 1.02-1.48; p trend = 0.037) and TPST1 (1.28, 95% CI 1.06-1.55; p trend = 0.0087); two were inversely associated-ATF6A (HR = 0.80, 95% CI 0.65-0.98; p trend = 0.028) and SPINT2 (HR = 0.74, 95% CI 0.61-0.90; p trend = 0.0025). One protein, KDEL2, which was nonlinearly associated (test-for-linearity: p < 0.01) showed a statistically significant lower risk in the second tertile (HR = 0.79, 95% CI 0.65-0.95). Of these five, four proteins-ATF6A, KDEL2, RF1ML, and TPST1-were consistent in the direction of association with the discovery studies. This study validated some pre-diagnostic protein biomarkers of the risk of prostate cancer.

CKD Prevalence and Incidence in Older Adults Using Estimated GFR With Different Filtration Markers: The Atherosclerosis Risk in Communities Study

The prevalence of chronic kidney disease (CKD) is known to increase with age; however, creatinine may be a less reliable filtration marker in older adults. Few studies have investigated the prevalence and progression of CKD using different filtration markers for estimating glomerular filtration rate (GFR). A prospective observational cohort study. 6,393 White and African American participants aged 65-100 years from the Atherosclerosis Risk in Communities Study (ARIC) at Visit 5, followed longitudinally at Visits 6 and7. The eGFR was estimated either by creatinine (eGFRcr), cystatin C (eGFRcys), creatinine and cystatin C (eGFRcr-cys), or using creatinine, cystatin C, and β-2-microglobulin (eGFRcr-cys-b2m). CKD progression was defined as 30% decline in eGFR at follow-up visits. Logistic regression models, adjusted for sex, race and study center, diabetes, blood pressure, body mass index, prevalent cardiovascular disease, and heart failure. At Visit 5, the mean age in the study population was 75.8 years, and the mean eGFR ranged from 71.2 to 61.2mL/min/1.73m2 using eGFRcr or eGFRcys, respectively. The proportion with eGFR<60mL/min/1.73m2 was lowest with eGFRcr and highest with eGFRcys for all age groups, and prevalence increased with age for allmarkers. For example, the prevalence of eGFRcr<60mL/min/1.73m2 in ages 70-74 years ranged from 15% to 21% and in ages 85-89 years ranged from 38% to 46% at the different visits. The proportion with a 30% eGFR decline over a mean of 8 years in people who were originally aged 65-69 years ranged from 9% (eGFRcr)-18% (eGFRcys). More people with eGFRcr≥60mL/min/1.73m2 were reclassified to<60mL/min/1.73m2 when using eGFRcys (33%) compared with eGFRcr-cys (12%) or eGFRcr-cys-b2m (18%). The proportion with 30% eGFR decline was lowest with eGFRcr and highest with eGFRcys, with greater incidence in older age groups for all markers. No direct measurement of GFR. Not all participants survived or attended subsequent follow-up visits. The prevalence and progression of CKD increase with age, but estimates vary with the filtration marker used. The eGFRcr gave the lowest estimate of CKD at 15% for people aged 65-69 years at Visit 5 while eGFRcys gave the highest estimates of CKD at 26% for that same population.

Neighborhood Socioeconomic Disadvantage Across the Life Course and Premature Mortality

There are consistent data demonstrating that socioeconomic disadvantage is associated with risk of premature mortality, but research on the relationship between neighborhood socioeconomic factors and premature mortality is limited. Most studies evaluating the association between neighborhood socioeconomic status (SES) and mortality have used a single assessment of SES during middle to older adulthood, thereby not considering the contribution of early life neighborhood SES. To investigate the association of life course neighborhood SES and premature mortality. This cohort study included Black and White participants of the multicenter Atherosclerosis Risk in Communities Study, a multicenter study conducted in 4 US communities: Washington County, Maryland; Forsyth County, North Carolina; Jackson, Mississippi; and the northwestern suburbs of Minneapolis, Minnesota. Participants were followed up for a mean (SD) of 18.8 (5.7) years (1996-2020). Statistical analysis was performed from March 2023 through May 2024. Participants' residential addresses during childhood, young adulthood, and middle adulthood were linked with US Census-based socioeconomic indicators to create summary neighborhood SES scores for each of these life epochs. Neighborhood SES scores were categorized into distribution-based tertiles. Premature death was defined as all-cause mortality occurring before age 75 years. Multivariable-adjusted Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% CIs. Among 12 610 study participants, the mean (SD) age at baseline was 62.6 (5.6) years; 3181 (25.2%) were Black and 9429 (74.8%) were White; and 7222 (57.3%) were women. The lowest, compared with the highest tertile, of neighborhood SES score in middle adulthood was associated with higher risk of premature mortality (HR, 1.28; 95% CI, 1.07-1.54). Similar associations were observed for neighborhood SES in young adulthood among women (HR, 1.25; 95% CI, 1.00-1.56) and neighborhood SES in childhood among White participants (HR, 1.25; 95% CI, 1.01-1.56). Participants whose neighborhood SES remained low from young to middle adulthood had an increased premature mortality risk compared with those whose neighborhood SES remained high (HR, 1.25; 95% CI, 1.05-1.49). In this study, low neighborhood SES was associated with premature mortality. The risk of premature mortality was greatest among individuals experiencing persistently low neighborhood SES from young to middle adulthood. Place-based interventions that target neighborhood social determinants of health should be designed from a life course perspective that accounts for early-life socioeconomic inequality.

Anemia, Iron Deficiency, and Cause-Specific Mortality: The Atherosclerosis Risk in Communities Study.

Anemia is a risk factor for all-cause mortality in older adults. Iron deficiency may also be associated with adverse outcomes, independent of its role in causing anemia. This study tested the hypotheses that anemia, and low ferritin among non-anemic participants, were associated with all-cause and cause-specific mortality in a community-based cohort of older adults. Fasting blood was obtained from 5,070 ARIC participants (median age: 75 years) in 2011-2013. Anemia was defined by hemoglobin concentrations &lt;12 g/dL in women and &lt;13 g/dL in men. We classified 4,020 non-anemic participants by quartiles of plasma ferritin, measured by the SomaScan proteomics platform. Cox proportional hazards regression was used. Mortality was ascertained via phone calls with proxies as part of twice-yearly cohort follow-up, surveillance of local hospital discharge indexes, state death records, and linkage to the National Death Index. Of the total participants, 21% had anemia at baseline. Over a median of 7.5 years, there were 1,147 deaths, including 357 due to cardiovascular disease (CVD), 302 to cancer, and 132 to respiratory disease. Compared to those with normal hemoglobin, participants with anemia had a higher risk of all-cause mortality (hazard ratio 1.81 [95% CI: 1.60-2.06]), and mortality due to CVD (1.77 [1.41-2.22]), cancer (1.81 [1.41-2.33]), and respiratory disease (1.72 [1.18-2.52]) in demographics-adjusted models. In fully adjusted models, associations with all-cause mortality (1.37 [1.19-1.58]) and cause-specific mortality were attenuated. In non-anemic participants, lower ferritin levels were not associated with all-cause or cause-specific mortality, though associations were observed among participants with lesser evidence of inflammation (CRP below the median level of 1.9 mg/L) and for cancer mortality in men only. Anemia is common among older adults and is associated with all-cause mortality, as well as mortality due to CVD, cancer, and respiratory disease. Our results do not provide evidence that iron deficiency, independent of anemia, is associated with mortality in this population.

Plasma proteins associated with plant-based diets: Results from the Atherosclerosis Risk in Communities (ARIC) study and Framingham Heart Study (FHS)

Background & AimsPlant-based diets are associated with a lower risk of chronic diseases. Large-scale proteomics can identify objective biomarkers of plant-based diets, and can improve our understanding of the pathways that link plant-based diets to health outcomes. This study investigated the plasma proteome of four different plant-based diets [overall plant-based diet (PDI), provegetarian diet, healthful plant-based diet (hPDI), and unhealthful plant-based diet (uPDI)] in the Atherosclerosis Risk in Communities (ARIC) Study and replicated the findings in the Framingham Heart Study (FHS) Offspring cohort. MethodsARIC Study participants at visit 3 (1993-1995) with completed food frequency questionnaire (FFQ) data and proteomics data were divided into internal discovery (n=7,690) and replication (n=2,543) data sets. Multivariable linear regression was used to examine associations between plant-based diet indices (PDIs) and 4,955 individual proteins in the discovery sample. Then, proteins that were internally replicated in the ARIC Study were tested for external replication in FHS (n=1,358). Pathway overrepresentation analysis was conducted for diet-related proteins. C-statistics were used to predict if the proteins improved prediction of plant-based diet indices beyond participant characteristics. ResultsIn ARIC discovery, a total of 837 diet-protein associations (PDI=233; provegetarian=182; hPDI=406; uPDI=16) were observed at false discovery rate (FDR) <0.05. Of these, 453 diet-protein associations (PDI=132; provegetarian=104; hPDI=208; uPDI=13) were internally replicated. In FHS, 167/453 diet-protein associations were available for external replication, of which 8 proteins (PDI=1; provegetarian=0; hPDI=8; uPDI=0) replicated. Complement and coagulation cascades, cell adhesion molecules, and retinol metabolism were over-represented. C-C motif chemokine 25 for PDI and 8 proteins for hPDI modestly but significantly improved the prediction of these indices individually and collectively (P value for difference in C-statistics<0.05 for all tests) ConclusionsUsing large-scale proteomics, we identified potential candidate biomarkers of plant-based diets, and pathways that may partially explain the associations between plant-based diets and chronic conditions.

Derivation and Validation of ICD-10 Codes for Identifying Incident Stroke

Claims data with International Statistical Classification of Diseases, Tenth Revision (ICD-10) codes are routinely used in clinical research. However, the use of ICD-10 codes to define incident stroke has not been validated against expert-adjudicated outcomes in the US population. To develop and validate the accuracy of an ICD-10 code list to detect incident stroke events using Medicare inpatient fee-for-service claims data. This cohort study used data from 2 prospective population-based cohort studies, the Atherosclerosis Risk in Communities (ARIC) study and the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, and included participants aged 65 years or older without prior stroke who had linked Medicare claims data. Stroke events in the ARIC and REGARDS studies were identified via active surveillance and adjudicated by expert review. Medicare-linked ARIC data (2016-2018) were used to develop a list of ICD-10 codes for incident stroke detection. The list was validated using Medicare-linked REGARDS data (2016-2019). Data were analyzed from September 1, 2022, through September 30, 2023. Stroke events detected in Medicare claims vs expert-adjudicated stroke events in the ARIC and REGARDS studies. The main outcomes were sensitivity and specificity of incident stroke detection using ICD-10 codes. In the ARIC study, there were 110 adjudicated incident stroke events among 5194 participants (mean [SD] age, 80.1 [5.3] years) over a median follow-up of 3.0 (range, 0.003-3.0) years. Most ARIC participants were women (3160 [60.8%]); 993 (19.1%) were Black and 4180 (80.5%) were White. Using the primary diagnosis code on a Medicare billing claim, the ICD-10 code list had a sensitivity of 81.8% (95% CI, 73.3%-88.5%) and a specificity of 99.1% (95% CI, 98.8%-99.3%) to detect incident stroke. Using any diagnosis code on a Medicare billing claim, the sensitivity was 94.5% (95% CI, 88.5%-98.0%) and the specificity was 98.4% (95% CI, 98.0%-98.8%). In the REGARDS study, there were 140 adjudicated incident strokes among 6359 participants (mean [SD] age, 75.8 [7.0] years) over a median follow-up of 4.0 (range, 0-4.0) years. More than half of the REGARDS participants were women (3351 [52.7%]); 1774 (27.9%) were Black and 4585 (72.1%) were White. For the primary diagnosis code, the ICD-10 code list had a sensitivity of 70.7% (95% CI, 63.2%-78.3%) and a specificity of 99.1% (95% CI, 98.9%-99.4%). For any diagnosis code, the ICD-10 code list had a sensitivity of 77.9% (95% CI, 71.0%-84.7%) and a specificity of 98.9% (95% CI, 98.6%-99.2%). These findings suggest that ICD-10 codes could be used to identify incident stroke events in Medicare claims with moderate sensitivity and high specificity.

Chest Symptoms and Long-Term Risk of Incident Cardiovascular Disease

BackgroundWe sought to evaluate the associations of chest pain and dyspnea with the long-term risk of cardiovascular disease including coronary disease, heart failure, atrial fibrillation, and stroke. MethodsIn 13,200 participants without cardiovascular disease in the Atherosclerosis Risk in Communities study (1987-1989), chest pain was categorized into definite angina, possible angina, non-anginal chest pain, and no chest pain using the Rose questionnaire. Dyspnea was categorized into grades 3-4, 2, 1, and 0 by the modified Medical Research Council scale. The associations of chest pain and dyspnea with incident myocardial infarction, heart failure, atrial fibrillation, and stroke over a median follow-up of ∼27 years were quantified with multivariable Cox models. ResultsDefinite angina and possible angina were associated with myocardial infarction (adjusted hazard ratios [HR] 1.80 [95%CI 1.45-2.13] and 1.65 [1.27-2.15]). Although lesser magnitude than myocardial infarction, both definite and possible angina were associated with heart failure. For atrial fibrillation, possible angina showed higher HR than definite angina. Dyspnea showed similar HRs for myocardial infarction and heart failure in grades 3-4 (2.00 [1.61-2.49] and 1.94 [1.62-2.32]). Stroke was least associated with chest symptoms. Chest pain and dyspnea significantly improved the discrimination of cardiovascular disease except stroke, beyond traditional risk factors. ConclusionsIn individuals without cardiovascular disease, chest pain and dyspnea were independently associated with incident cardiovascular disease for about 3 decades, suggesting the need for evaluating chest pain from a broader perspective of cardiovascular disease beyond coronary disease and the importance of dyspnea for cardiovascular risk assessment including myocardial infarction.

Age of Diabetes Diagnosis and Lifetime Risk of Dementia: The Atherosclerosis Risk in Communities (ARIC) Study.

The impact of age of diabetes diagnosis on dementia risk across the life course is poorly characterized. We estimated the lifetime risk of dementia by age of diabetes diagnosis. We included 13,087 participants from the Atherosclerosis Risk in Communities Study who were free from dementia at age 60 years. We categorized participants as having middle age-onset diabetes (diagnosis <60 years), older-onset diabetes (diagnosis 60-69 years), or no diabetes. Incident dementia was ascertained via adjudication and active surveillance. We used the cumulative incidence function estimator to characterize the lifetime risk of dementia by age of diabetes diagnosis while accounting for the competing risk of mortality. We used restricted mean survival time to calculate years lived without and with dementia. Among 13,087 participants, there were 2,982 individuals with dementia and 4,662 deaths without dementia during a median follow-up of 24.1 (percentile 25-percentile 75, 17.4-28.3) years. Individuals with middle age-onset diabetes had a significantly higher lifetime risk of dementia than those with older-onset diabetes (36.0% vs. 31.0%). Compared with those with no diabetes, participants with middle age-onset diabetes also had a higher cumulative incidence of dementia by age 80 years (16.1% vs. 9.4%) but a lower lifetime risk (36.0% vs. 45.6%) due to shorter survival. Individuals with middle age-onset diabetes developed dementia 4 and 1 years earlier than those without diabetes and those with older-onset diabetes, respectively. Preventing or delaying diabetes may be an important approach for reducing dementia risk throughout the life course.

Patterns of cognitive domain abnormalities enhance discrimination of dementia risk prediction: The ARIC study.

The contribution of neuropsychological assessments to risk assessment for incident dementia is underappreciated. We analyzed neuropsychological testing results in dementia-free participants in the Atherosclerosis Risk in Communities (ARIC) study. We examined associations of index domain-specific neuropsychological test performance with incident dementia using cumulative incidence curves and Cox proportional hazards models. Among 5296 initially dementia-free participants (mean [standard deviation] age of 75.8 [5.1] years; 60.1% women, 22.2% Black) over a median follow-up of 7.9 years, the covariate-adjusted hazard ratio varied substantially depending on the pattern of domain-specific performance and age, in an orderly manner from single domain language abnormalities (lowest risk) to single domain executive or memory abnormalities, to multidomain abnormalities including memory (highest risk). By identifying normatively defined cognitive abnormalities by domains based on neuropsychological test performance, there is a conceptually orderly and age-sensitive spectrum of risk for incident dementia that provides valuable information about the likelihood of progression. Domain-specific cognitive profiles carry enhanced prognostic value compared to mild cognitive impairment. Single-domain non-amnestic cognitive abnormalities have the most favorable prognosis. Multidomain amnestic abnormalities have the greatest risk for incident dementia. Patterns of domain-specific risks are similar by sex and race.