Atherosclerosis Risk In Communities Participants Research Articles

Atrial Fibrillation and Clonal Hematopoiesis in TET2 and ASXL1

Clonal hematopoiesis of indeterminate potential (CHIP) may contribute to the risk of atrial fibrillation (AF) through its association with inflammation and cardiac remodeling. To determine whether CHIP was associated with AF, inflammatory and cardiac biomarkers, and cardiac structural changes. This was a population-based, prospective cohort study in participants of the Atherosclerosis Risk in Communities (ARIC) study and UK Biobank (UKB) cohort. Samples were collected and echocardiography was performed from 2011 to 2013 in the ARIC cohort, and samples were collected from 2006 to 2010 in the UKB cohort. Included in this study were adults without hematologic malignancies, mitral valve stenosis, or previous mitral valve procedure from both the ARIC and UKB cohorts; additionally, participants without hypertrophic cardiomyopathy and congenital heart disease from the UKB cohort were also included. Data analysis was completed in 2023. CHIP (variant allele frequency [VAF] ≥2%), common gene-specific CHIP subtypes (DNMT3A, TET2, ASXL1), large CHIP (VAF ≥10%), inflammatory and cardiac biomarkers (high-sensitivity C-reactive protein, interleukin 6 [IL-6], IL-18, high-sensitivity troponin T [hs-TnT] and hs-TnI, N-terminal pro-B-type natriuretic peptide), and echocardiographic indices. Incident AF. A total of 199 982 adults were included in this study. In ARIC participants (4131 [2.1%]; mean [SD] age, 76 [5] years; 2449 female [59%]; 1682 male [41%]; 935 Black [23%] and 3196 White [77%]), 1019 had any CHIP (24.7%), and 478 had large CHIP (11.6%). In UKB participants (195 851 [97.9%]; mean [SD] age, 56 [8] years; 108 370 female [55%]; 87 481 male [45%]; 3154 Black [2%], 183 747 White [94%], and 7971 other race [4%]), 11 328 had any CHIP (5.8%), and 5189 had large CHIP (2.6%). ARIC participants were followed up for a median (IQR) period of 7.0 (5.3-7.7) years, and UKB participants were followed up for a median (IQR) period of 12.2 (11.3-13.0) years. Meta-analyzed hazard ratios for AF were 1.12 (95% CI, 1.01-1.25; P = .04) for participants with vs without large CHIP, 1.29 (95% CI, 1.05-1.59; P = .02) for those with vs without large TET2 CHIP (seen in 1340 of 197 209 [0.67%]), and 1.45 (95% CI, 1.02-2.07; P = .04) for those with vs without large ASXL1 CHIP (seen in 314 of 197 209 [0.16%]). Large TET2 CHIP was associated with higher IL-6 levels. Additionally, large ASXL1 was associated with higher hs-TnT level and increased left ventricular mass index. Large TET2 and ASXL1, but not DNMT3A, CHIP was associated with higher IL-6 level, indices of cardiac remodeling, and increased risk for AF. Future research is needed to elaborate on the mechanisms driving the associations and to investigate potential interventions to reduce the risk.

Abstract 4772: Metabolic phenotype, age acceleration, and obesity-related cancer risk in Women's Health Initiative and Atherosclerosis Risk in Communities cohorts

Abstract Introduction: While normal physiologic aging causes metabolic decline, metabolic dysregulation owing to excess nutrient intake, physical inactivity, and obesity may drive accelerated aging. However, the relationship of accelerated aging with metabolic dysfunction across different levels of BMI (i.e., metabolic obesity phenotype) and whether it may mediate the relationship with obesity-related cancer (ORC) risk is not well established. Methods: To test this hypothesis, we are leveraging existing blood-based DNA methylation (DNAm) data within the Women’s Health Initiative (WHI) and the Atherosclerosis Risk in Communities (ARIC) cohorts. Weight, height and blood pressure were measured by trained technicians in the respective cohorts and fasting blood glucose, triglycerides and HDL cholesterol were quatified by standard clinican assays. Metabolic obesity phenotypes are classified as metabolically healthy normal weight (MHNW), metabolically unhealthy normal weight (MUNW), metabolically healthy overweight/obese (MHO), and metabolically unhealthy overweight/obese (MUO) when defined by ATP III criteria. Age acceleration was measured as a residual from regressing pan-tissue Horvath’s DNAmAge on chronological age. Results: The mean baseline age was 64 ± 6.6 years and 54 ± 5.7 year among WHI and ARIC participants, respectively and the age acceleration was measured at an mean follow-up time of 16 years from baseline for WHI and 3.5 years from baseline for ARIC cohort. The outcome of interest, ORC incidence was observed among 474 participants of which 387 were women. The median time for cancer diagnosis from baseline was 25 year and from DNAm measurement was 18.6 years. Of the 4341 (70% women) participants included in the analysis, 23.9% were MHNW, 3.2% MUNW, 39% MHO, and 33.5% MUO. A 31.5% of MHNW, 40.4% of MUNW, 28.7% of MHO, and 35.2% of MUO showed age acceleration. MUNW (OR 1.47, 95% CI: 1.03-2.11) and MUO (OR 1.18, 95% CI: 1.00-1.40) individuals at baseline had increased odds of experiencing age acceleration at a follow-up visit. The risk of all ORC combined was significantly elevated among MUO (HR 1.63, 95% CI: 1.27-2.09) compared to MHNW. Age acceleration at the follow-up visit was not significantly associated with ORC risk (HR 0.91, 95% CI: 0.75-1.11). These analyses were not adjusted for confounders. Conclusions: MUNW and MUO individuals had increased odds of age acceleration at a follow-up visit. Furthermore, MUO individuals were at an elevated risk of ORC, compared to individuals with MHNW. Accelerated aging does not appear to mediate this association, as accelerated aging was not associated with ORC. Citation Format: Prasoona Karra, Garnet L. Anderson, Mary C. Playdon, Sheetal Hardikar, Aladdin Shadyab, Kari E. North, Anne E. Justice, Elizabeth A. Platz, Jan Bressler, Anna Prizment, Weihua Guan, Dominique S. Michaud, Eric A. Whitsel, Brock C. Christensen, Lucas A. Salas. Metabolic phenotype, age acceleration, and obesity-related cancer risk in Women's Health Initiative and Atherosclerosis Risk in Communities cohorts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4772.

Abstract P210: Incident Venous Thromboembolism and Subsequent Risk of Cardiovascular Outcomes: The Atherosclerosis Risk in Communities (ARIC) Study

Background: Venous thromboembolism (VTE) and atherothrombosis have different mechanisms of thrombosis formation. A few previous studies reported those having a VTE have greater risk of incident atherothrombotic disease. These studies have several limitations, such as inadequate adjustment for key confounders (e.g., obesity), selected study populations in clinical trials, and small sample size. Moreover, the links of VTE to heart failure (HF) and peripheral artery disease (PAD) are not well understood. Hypothesis: VTE is independently associated with a range of incident cardiovascular outcomes. Methods: In 12,988 ARIC participants without history of VTE or cardiovascular disease at baseline (1987-89), we quantified the association of VTE, as a time-varying exposure, with incident myocardial infarction (MI), stroke, HF, PAD (overall and its severe form, critical limb ischemia [CLI]) using multivariable Cox regression. We also considered unprovoked and provoked VTE separately. Results: Over a median follow-up of 25 years, 901 participants experienced incident VTE. In the same timeframe, there were 1,950 MI events, 1,247 stroke events, 2,981 HF events, and 516 PAD cases (including 207 CLI cases). Participants with VTE, compared to those without, had a higher risk of all cardiovascular outcomes ( Table ). The associations were particularly evident for incident PAD and CLI (adjusted HR 2.32 [95% CI 1.53, 3.52] and 3.44 [2.01, 5.88], respectively). Provoked VTE showed similar associations with all cardiovascular outcomes, whereas unprovoked VTE was significantly associated with MI, HF, and CLI only ( Table ). Conclusions: In this large community-based study, VTE was robustly associated with subsequent risk of different cardiovascular outcomes, independent of potential confounders. Patients with VTE should be considered at high risk of other cardiovascular outcomes and receive optimal preventive therapy for cardiovascular diseases, including atherosclerotic disease and HF.

Abstract MP33: Investigating the Link Between Glucose Patterns Assessed by Continuous Glucose Monitoring With Cognitive Impairment in Older Adults With Diabetes

Introduction: There are no studies in older adults with type 2 diabetes that examine the link between day-to-day glucose patterns and cognitive dysfunction. Continuous glucose monitoring (CGM) is a minimally invasive technology that can assess glucose every 1-15 minutes and characterize nuanced patterns in glucose. Hypothesis: CGM can provide a comprehensive picture of glycemic variability in people with cognitive dysfunction. Methods: We conducted a cross-sectional study of participants with diabetes in the Atherosclerosis Risk in Communities (ARIC) Study (Visit 9, 2021-2022). ARIC participants wore a CGM (Abbott Libre Pro) and underwent cognitive testing in three cognitive domains (memory, executive functioning, and language). Scores were standardized and averaged to give a global cognitive z-score. We compared HbA1c and clinically used CGM parameters (mean glucose, coefficient of variation, percent time in glucose range of 70-180 mg/dL, and percent time above 180 mg/dL) across quartiles of cognitive z-scores, adjusting for age and sex. We calculated p-values for trends from linear or quantile regression treating the median of cognitive Z-score in each quartile as a continuous variable. Results: We included 383 participants with diabetes (mean age, 83 years). Across categories of cognitive functioning, participants in the lowest cognitive functioning categories had significantly higher HbA1c, glucose variability, and less percent time spent with glucose in range (70-180 mg/dl) (Figure) . There was no clear trend in CGM mean glucose (p=0.15) (Figure, Panel B) . Conclusions: Cognitive dysfunction was associated with an increased burden of glycemic dysregulation assessed through CGM and HbA1c. Our results suggest CGM may be a useful complement to HbA1c for monitoring glycemic control in this population. Figure: Hemoglobin A1c (HbA1c) and continuous glucose monitoring (CGM) metrics across quartiles of cognitive Z-scores in older participants with diabetes in the ARIC Study (2021-2022)

Abstract P166: Social Isolation and Social Support Are Associated With Self-Rated Health and Heart Failure Outcomes in the Atherosclerosis Risk in Communities (ARIC) Study

Introduction: Social isolation (SI) and social support (SS) are associated with incidence of heart failure (HF). Few studies investigate how SI, SS, and subtypes of SS (appraisal, belonging, self-esteem, and tangible) measured before HF are related to morbidity and mortality after HF. Objective: Assess whether SI, SS, and subtypes of SS are associated with self-rated health trajectories and HF outcomes among participants with incident HF hospitalizations, and if results differ by sex or race. Methods: We included 2967 ARIC participants (51% female, 27% Black, mean age 59 (SD 6) years) with incident HF hospitalization after Visit 2 (1990-1992). We identified incident HF hospitalization as ICD-9 code 428 in any position and physician adjudicated events; on average HF occurred 17 (SD 8) years after Visit 2. We measured predefined SI categories and tertiles of SS at Visit 2 using the 10-item Lubben Social Network Scale and the 16-item Interpersonal Support Evaluation List, which were assessed as separate exposures. We assessed associations with trajectories of annually measured self-rated health in the 4 years prior to and after incident HF hospitalization, measured by the probability of being in excellent/good self-rated health (0-100% scale), using linear mixed effects models. We calculated hazard ratios (HR) and 95% confidence intervals (CIs) for associations with time to first all-cause rehospitalization and all-cause mortality using Cox proportional hazard models. Models were adjusted for age, sex, race-center, employment status, years of education, prior use of mental health medications, and time between Visit 2 and HF. Results: Over mean follow-up of 5 (SD 5) years after initial HF hospitalization, 90% of participants experienced rehospitalization and there were 2378 deaths. Low overall SS had a 5.8% (95% CI 7.8%, 3.8%) lower probability of excellent/good self-rated health over time than high SS; associations of subtypes of SS with this outcome were similar. Low belonging SS was associated with greater days to first rehospitalization (HR 0.85; 95% CI 0.79, 0.96) compared to the highest tertile, however belonging SS was not associated with mortality (HR 1.05; 95% CI 0.95, 1.17). Low tangible SS was associated with greater mortality among White (HR 1.14; 95% CI 1.01, 1.28) but not Black participants (HR 0.95; 95% CI 0.78, 1.16), compared to the highest tertile. Being socially isolated/high risk for SI was associated with greater hazard of all-cause mortality among females (HR 1.57; 95% CI 1.20, 2.06) but not males (HR 0.95; 95% CI 0.75, 1.19), compared to low SI. Conclusions: SI and SS measured before HF were relevant to HF outcomes, but relevance may vary by sex and race. In particular, greater SI was only associated with greater mortality among females, and lower tangible SS with greater mortality among White participants only. Belonging support was associated with some HF outcomes but not others.

Associations Between Mid-Life Psychosocial Measures and Estimated Late Life Amyloid Burden: The Atherosclerosis Risk in Communities (ARIC)-PET Study.

Psychosocial factors are modifiable risk factors for Alzheimer's disease (AD). One mechanism linking psychosocial factors to AD risk may be through biological measures of brain amyloid; however, this association has not been widely studied. To determine if mid-life measures of social support and social isolation in the Atherosclerosis Risk in Communities (ARIC) Study cohort are associated with late life brain amyloid burden, measured using florbetapir positron emission tomography (PET). Measures of social support and social isolation were assessed in ARIC participants (visit 2: 1990-1992). Brain amyloid was evaluated with florbetapir PET standardized uptake value ratios (SUVRs; visit 5: 2012-2014). Among 316 participants without dementia, participants with intermediate (odds ratio (OR), 0.47; 95% CI, 0.25-0.88), or low social support (OR, 0.43; 95% CI, 0.22-0.83) in mid-life were less likely to have elevated amyloid SUVRs, relative to participants with high social support. Participants with moderate risk for social isolation in mid-life (OR, 0.32; 95% CI, 0.14-0.74) were less likely to have elevated amyloid burden than participants at low risk for social isolation. These associations were not significantly modified by sex or race. Lower social support and moderate risk of social isolation in mid-life were associated with lower odds of elevated amyloid SUVR in late life, compared to participants with greater mid-life psychosocial measures. Future longitudinal studies evaluating mid-life psychosocial factors, in relation to brain amyloid as well as other health outcomes, will strengthen our understanding of the role of these factors throughout the lifetime.

Abstract TMP79: Magnetic Resonance Imaging Elements Predict Incident Intracerebral Hemorrhage

Introduction: Incident intracerebral hemorrhage (ICH) is an uncommon medical event that can lead to devastating outcomes, including death. Small vessel disease (SVD), as measured by cerebral microbleeds (CMBs) and white matter hyperintensities (WMH), has been associated with risk factors and might be a predictor of incident ICH. CMBs result from irregularities in brain vessel structure due to chronic hypertension and cerebral amyloid angiopathy. These microhemorrhages are a possible risk factor for ICH. Methods: A cohort of ARIC (Atherosclerosis Risk in Communities) participants underwent 3T MRI at visit 5 (2011-2013). CMBs were assessed using a T2* gradient echo. CMBs are homogenous hypointense lesions ≤10 mm in diameter. WMH volumes were derived from FLAIR images using an automated program to measure the volumetric burden of leukoaraiosis. During 10 years of follow-up, incident ICH was noted in 7 (0.4%) out of 1,656 participants were dichotomized based on the presence of CMB and the median of WMH volume. Results: ARIC subjects (n=1656, mean age=76±5 years; 40% men; 26% African American race) underwent MRI. CMBs were present in 385 (23.25%) patients out of 1656. ICH occurred in 0.16% and 1.30% of patients without CMBs and with CMBs, respectively. Kaplan Meier (KM) survival analysis between CMBs and ICH was significant (logrank p=0.002). Cox Regression yielded a significant crude hazards ratio (HR 8.7, 95% CI 1.7-44.7, p=0.010). Adjustment for age, gender, race, and hypertension was also significant (HR 9.9, 95% CI 1.9-52.0, p=0.07). KM survival analysis between WMH median (11.68 cm 3 ) and ICH was significant (logrank p=0.006). Figure 1 displays the KM curves of those with and without CMBs and the incidence of ICH as well as those below and above WMH median and incidence of ICH. Conclusion: CMBs and WMH detected by MRI appear to be an important predictor for the occurrence of incident ICH. Further research is needed to observe if MRI could be used to screen subjects at high-risk for elevated risk of incident ICH.

Factors Associated With Fatigue in Persons With Atrial Fibrillation in the Atherosclerosis Risk in Communities (ARIC) Study.

Atrial fibrillation (AF) is a common cardiac arrhythmia affecting over 6 million people in the U.S. Fatigue is a frequent symptom of AF, yet no underlying biological mechanisms have been identified in AF-related fatigue as in other chronic conditions such as cancer or HIV fatigue (inflammation, tissue injury). We aimed to identify biomarkers and correlates of AF-fatigue in ARIC participants. Participants with AF from ARIC visit 5 (2011-2013) were included in the study. Multiple linear regression was used to estimate the association of high sensitivity troponin (hs-TnT), N-terminal fragment B-type natriuretic peptide (NT-proBNP) and high sensitivity C-reactive protein (hsCRP) levels with self-reported fatigue (SF-12 and PROMIS Fatigue Scale), depressive symptoms (Center for Epidemiological Studies Depression survey), and physical functioning (Short Physical Performance Battery) scores. All biomarkers underwent natural-log transformation. There were 446 participants (mean age: 78y ± 5; 44% women). In adjusted analyses, NT-proBNP was associated with AF-fatigue (β: 0.11, 95% CI: 0.03, 0.19), increased depressive symptoms (β: 0.44, 95% CI: 0.19, 0.70), and decreased physical function (β: -0.48, 95% CI: -0.72, -0.23). Hs-TnT was also associated with elevated AF-fatigue (β: 0.24, 95% CI: 0.09, 0.39) along with decreased physical function (β: -1.19, 95% CI: -1.64, -0.75). No significant associations were found with hsCRP and fatigue. Increased levels of cardiac injury biomarkers, depressive symptoms, and decreased physical function were associated with AF-fatigue. Inflammation was not associated with AF-fatigue; other physiological pathways, such as cardiac overload or myocardial injury may be more relevant in AF-fatigue.

Abstract 13124: Better Prognostic Value of Single Time Coronary Artery Calcium Score Over the 30-y Averaged Pooled Cohort Equation in Older Adults: The Atherosclerosis Risk in Communities (ARIC) Study

Background: Cardiovascular disease (CVD) risk prediction in the 75-and-older population is challenging in part because traditional risk factors at older age may not reflect the risk factor profile over the life course. In this regard, coronary artery calcium (CAC) can be considered an integrated biomarker of exposure to CVD risk factors. However, the predictive value of a single time point CAC at older age vs. the cumulative exposure of traditional risk factors over three decades is unknown. Methods: In 1,875 ARIC participants (age 75-94 years) without a history of coronary heart disease (CHD), stroke, and heart failure (HF) at Visit 7 (2018-2019), we assessed the association of Visit 7 CAC vs. a weighted average of Pooled Cohort Equation (PCE) calculated 10-year atherosclerotic CVD (ASCVD) risk from Visit 1 (1987-89) to Visit 7 with the risk of ASCVD (CHD or stroke), HF, and all-cause mortality using adjusted Cox models. Risk prediction improvement was assessed using Harrel’s C-statistics. Results: The median CAC was 221 (IQI 35-743), and the median averaged PCE score was 15.0% (IQI 10.4%-21.2%). Over a median follow-up of 2.1 (IQI 1.7-2.5) years, there were 48 ASCVD events, 36 HF events, and 85 deaths. A higher CAC score was associated with a higher risk of ASCVD and HF, even after adjusting for averaged PCE (adjusted hazard ratio 3.33 [95% CI 1.53, 7.26] and 5.57 [1.95, 15.89] for CAC 1000+ vs. 0-99, respectively), but not all-cause mortality ( Table ). In contrast, averaged PCE was not associated with ASCVD or HF independent of CAC. However, averaged PCE showed robust associations with all-cause mortality. Notably, the addition of CAC to averaged PCE significantly improved risk prediction of HF, whereas adding averaged PCE to CAC did not significantly improve the risk prediction for any adverse outcome. Conclusions: The present study shows that a single time point CAC outperforms 30-y cumulative exposure of PCE for ASCVD and HF prediction in the 75-and-older population.

Abstract 13089: Plasma Proteomics and Risk of Incident Ischemic Stroke: Meta-Analysis of the Atherosclerosis Risk in Communities (ARIC) Study and the Cardiovascular Health Study (CHS)

Background: Proteomic profiling can screen large numbers of proteins to discover novel biomarkers related to ischemic stroke. However, prior studies have used a targeted approach or assessed a limited number of proteins (<1300). Using data from the Atherosclerosis Risk in Communities (ARIC) study and the Cardiovascular Health Study (CHS), we examined the prospective association between 4954 plasma protein targets and incident ischemic stroke. Methods: Participants free of prevalent stroke at the time of proteomic profiling were included. Proteomics data were obtained from the 1990-92 exam in ARIC and the 1992-93 exam in CHS. Plasma proteins were quantified using the aptamer-based SOMAScan platform. Ischemic stroke events were ascertained and adjudicated through 2019 in ARIC and June 30, 2015 in CHS. Cox proportional hazards models adjusting for demographics, ischemic stroke risk factors, and estimated glomerular filtration rate were used. ARIC and CHS results were combined using fixed-effects meta-analysis. A Bonferroni-corrected p<1.01e-5 was considered significant. Results: Median follow-up time in ARIC and CHS were 25 and 12 years, respectively. Among 10,856 ARIC participants (mean age 57 years, 56% female, 23% Black), 890 had an incident ischemic stroke. Among 3,283 CHS participants (mean age 74 years, 62% female, 18% Black), 507 had an incident ischemic stroke. In the meta-analysis, 44 proteins were significantly associated with incident ischemic stroke, of which 32 have not been previously reported ( Figure ). Of the 32, amyloid-like protein and kit ligand were the most strongly associated with ischemic stroke; each SD increment in log 2 (amyloid-like protein) and log 2 (kit ligand) were associated with 20% and 19% lower risk of ischemic stroke. Conclusion: In a meta-analysis of two community-based cohorts, we identified 32 novel protein associations with incident ischemic stroke. Further research is needed to determine causal associations.

Abstract 12449: Association of Left Atrial Function With Mitral Regurgitation Progression: Atherosclerosis Risk in Communities Study

Background: Left atrial (LA) enlargement and atrial fibrillation (AF) are associated with functional mitral regurgitation (MR). It is unknown whether lower (worse) LA function is associated with MR progression, independent of LA size, in individuals without AF. Hypothesis: We hypothesized that lower LA function was associated with higher odds of MR progression. Aims: To evaluate the association of echocardiographic-based LA function with MR progression in the Atherosclerosis Risk in Communities (ARIC) Study, a community-based cohort. Methods: We included 2,444 ARIC participants (mean age, 73.8 ± 4.4 years, 42% male, 21% Black) who underwent 2D-echocardiogram at visits 5 (2011-2013) and 7 (2018-2019) and excluded those with AF, heart failure, and heart valve surgery at visit 5. Based on American College of Cardiology/American Heart Association guidelines, MR was graded as stages A-D. MR progression was defined as new onset of MR at visit 7, any increase in MR stage, or mitral valve surgery for MR between visit 5 and 7. LA function was measured using strain analysis and included reservoir, conduit, and contractile strain. Logistic regression models were used for the analysis. Results: After mean follow up of 6.5 ± 2.4 years, MR progression occurred in 504 (21%) participants. As shown in the table, lower reservoir strain was associated with higher odds of MR progression (OR [95% CI] per SD decrement, 1.16 [1.003, 1.34]) after adjusting for demographics, clinical risk factors, LA size and LV mass and function. LA conduit and contractile strain were not significantly associated with MR progression. Conclusion: Lower LA function is associated with higher odds of MR progression, independent of LA size, in individuals without AF. More research is needed to clarify the mechanism to identify novel prevention strategies for MR progression.

Abstract 18509: NT-proBNP Trajectories and Heart Failure Risk Associations in Middle to Older Ages in Adulthood: The Atherosclerosis Risk in Communities (ARIC) Study

Background: NT-proBNP is a powerful marker of heart failure (HF) risk. NT-proBNP levels increase with age; however, the impact of distinct longitudinal trajectories of NT-proBNP on future HF risk with aging is largely unexplored. Hypothesis: Middle-aged adults with higher baseline concentrations and steeper increases of NT-proBNP through older ages have greater HF risk. Methods: We performed a prospective analysis of 12,124 ARIC participants with 2 or more serial NT-proBNP measurements from Visits 2 through 6, without HF at baseline or HF events between the NT-proBNP assessments. We constructed linear mixed models to evaluate NT-proBNP trajectories for males and females. We defined 4 trajectories, using sex-specific medians to define high versus low: low baseline/low slope, low baseline/high slope, high baseline/low slope, high baseline/high slope. We used Kaplan Meier survival curves and multivariable Cox regression to evaluate the HF risk associations of different NT-proBNP trajectories. Results: The mean age was 57 years with 56% women and 23% Black adults, BMI 27. The median baseline NT-proBNP concentrations were 62 and 36 pg/mL and the average NT-proBNP slopes were 4.6% and 7.2% increase/year for women and men, respectively. Black individuals were more likely to have lower baseline levels, whereas those with diabetes, obesity, or prevalent coronary heart disease had higher slopes. Over a median 22-year follow-up, 2,772 HF events occurred. There was a stepwise increase in HF risk with higher baseline levels and slopes of NT-proBNP, with individuals with the high baseline/high slope NT-proBNP trajectory having a HR for HF of 3.70 (95% CI 3.26-4.20) compared to those with low baseline-low slope ( Figure ). Conclusions: Higher baseline concentrations and steeper increases of NT-proBNP with aging are associated with greater HF risk. Identifying and addressing modifiable determinants of NT-proBNP trajectories with aging may have implications for HF prevention.

Abstract 12181: Association of Left Atrial Function With Vascular Brain Injury: The Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS)

Background: Lower (worse) left atrial (LA) function is associated with higher dementia risk. It is unclear whether lower LA function is associated with vascular brain injury on brain MRI, an established correlate for higher dementia risk. Using data from the Atherosclerosis Risk in Communities (ARIC) study, we assessed the cross-sectional association between LA function measures and brain MRI markers of vascular brain injury (cerebral microbleeds, brain infarcts). Hypothesis: Participants with lower LA function will be more likely to have presence of > 1 cerebral microbleed or brain infarct. Methods: ARIC participants who had both an echocardiogram and brain MRI at visit 5 (2011-13) were included. We excluded those with prevalent dementia, stroke, or atrial fibrillation. LA function measures were obtained from 2D-echocardiograms and assessed in quartiles (highest quartile was the reference). Brain MRI measures were assessed as the presence or absence of > 1 cerebral microbleed or brain infarct. Logistic regression was used. Results: Of the 1502 participants (mean [SD] age 76 [5], 60% female, 27% Black) in this analysis, 345 (23%) and 351 (23%) had > 1 cerebral microbleed or brain infarct present. Compared to the highest quartile, lower LA reservoir and conduit strain quartiles were associated with higher odds of cerebral microbleeds. LA contractile strain was not associated with cerebral microbleeds. Compared to the highest quartile, the lowest LA conduit strain quartile, but not reservoir strain, was associated with higher odds of brain infarcts. LA contractile strain was inversely associated with brain infarcts. Conclusion: In this community-based cohort, lower LA function was cross-sectionally associated with cerebral microbleeds and brain infarcts. The inverse relationship with LA contractile strain may be due to contractile function compensating for a decrease in early diastolic filling. Prospective studies are needed to confirm these findings.

Omega-3 Polyunsaturated Fatty Acids are not associated with Peripheral Artery Disease in a Meta-Analysis from the Multi-Ethnic Study of Atherosclerosis and Atherosclerosis Risk in Communities Study Cohorts

BackgroundResearch suggests omega-3 polyunsaturated fatty acids (PUFAs) exert favorable effects on several biological processes involved in the development and progression of atherosclerotic cardiovascular disease (ASCVD). However, studies examining the relationship between omega-3 PUFAs and peripheral artery disease (PAD) are scarce. ObjectivesWe evaluated the associations between omega-3 PUFAs and incident PAD in a meta-analysis of the Multi-Ethnic Study of Atherosclerosis (MESA) and Atherosclerosis Risk in Communities (ARIC) study cohorts. MethodsOmega-3 PUFAs eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were measured at baseline for all MESA (n = 6495) and Minnesota ARIC participants (n = 3612). Incident clinical PAD events (MESA n = 106; ARIC n = 149) identified primarily through ICD discharge codes were assessed through follow-up of each cohort. Associations between omega-3 PUFAs (EPA, DHA, and EPA+DHA) and incident PAD were modeled in MESA and ARIC as quartiles and continuously using Cox proportional hazards regression, respectively. A fixed-effects meta-analysis was conducted to evaluate associations in the 2 cohorts combined. ResultsIn the fully adjusted model, in 10,107 participants, no significant associations were observed between EPA, DHA, or EPA+DHA, and incident PAD modeled as quartiles or continuously for either MESA or ARIC cohorts separately or in the meta-analysis after a follow-up of approximately 15 y. ConclusionThis study is consistent with previous literature indicating that the beneficial effects of omega-3 PUFAs on the markers of ASCVD may not translate to a clinically meaningful decrease in PAD risk.

Sleep apnea, hypoxia, and late-onset epilepsy: the Atherosclerosis Risk in Communities study.

Sleep apnea is associated with unexplained epilepsy in older adults in small studies. We sought to determine the relationship between sleep apnea and additional sleep characteristics and late-onset epilepsy (LOE), adjusting for comorbidities, using data from the large, prospective Atherosclerosis Risk in Communities (ARIC) Study cohort. We used Medicare claims to identify cases of LOE in ARIC participants. We used polysomnography data from 1309 ARIC participants who also participated in the Sleep Heart Health Study in 1995-1998, and demographic and comorbidity data from ARIC. Later risk of LOE was evaluated using survival analysis with a competing risk of death. We also used survival analysis in 2672 ARIC participants to identify the association between self-reported obstructive sleep apnea (2011-2013), and the risk of subsequent LOE. Late-midlife oxygen desaturation to less than 80% during sleep was associated with subsequent development of LOE, adjusted subhazard ratio 3.28 (1.18-9.08), but the apnea-hypopnea index was not related. Participant report of diagnosis of sleep apnea in 2011-2013 was also associated with subsequent LOE, adjusted subhazard ratio 2.59 (1.24-5.39). Sleep apnea and oxygen saturation nadir during sleep are associated with LOE, independently of hypertension and other comorbidities. These potentially modifiable risk factors could have large clinical implications for LOE.

Association of Plasma Aβ42/Aβ40 Ratio and Late-Onset Epilepsy: Results From the Atherosclerosis Risk in Communities Study.

The objective of this study was to determine the relationship between plasma β-amyloid (Aβ), specifically the ratio of 2 Aβ peptides (the Aβ42/Aβ40 ratio, which correlates with increased accumulation of Aβ in the CNS), and late-onset epilepsy (LOE). We used Medicare fee-for-service claims codes from 1991 to 2018 to identify cases of LOE among 1,424 Black and White men and women enrolled in the Atherosclerosis Risk in Communities (ARIC) study cohort. The Aβ42/Aβ40 ratio was calculated from plasma samples collected from ARIC participants in 1993-1995 (age 50-71 years) and 2011-2013 (age 67-90 years). We used survival analysis accounting for the competing risk of death to determine the relationship between late-life plasma Aβ42/Aβ40, and its change from midlife to late life, and the subsequent development of epilepsy. We adjusted for demographics, the apolipoprotein e4 genotype, and comorbidities, including stroke, dementia, and head injury. A low plasma ratio of 2 Aβ peptides, the Aβ42/Aβ40 ratio, correlates with low CSF Aβ42/Aβ40 and with increased accumulation of Aβ in the CNS. Decrease in plasma Aβ42/Aβ40 ratio from midlife to late life, but not an isolated measurement of Aβ42/Aβ40, was associated with development of epilepsy in later life. For every 50% reduction in Aβ42/Aβ40, there was a 2-fold increase in risk of epilepsy (adjusted subhazard ratio 2.30, 95% CI 1.27-4.17). A reduction in plasma Aβ42/Aβ40 is associated with an increased risk of subsequent epilepsy. Our observations provide a further validation of the link between Aβ, hyperexcitable states, and LOE.

Prediabetes, intervening diabetes and subsequent risk of dementia: the Atherosclerosis Risk in Communities (ARIC) study.

The aim of this work was to evaluate whether the association of prediabetes with dementia is explained by the intervening onset of diabetes. Among participants of the Atherosclerosis Risk in Communities (ARIC) study we defined baseline prediabetes as HbA1c 39-46 mmol/mol (5.7-6.4%) and subsequent incident diabetes as a self-reported physician diagnosis or use of diabetes medication. Incident dementia was ascertained via active surveillance and adjudicated. We quantified the association of prediabetes with dementia risk before and after accounting for the subsequent development of diabetes among ARIC participants without diabetes at baseline (1990-1992; participants aged 46-70 years). We also evaluated whether age at diabetes diagnosis modified the risk of dementia. Among 11,656 participants without diabetes at baseline, 2330 (20.0%) had prediabetes. Before accounting for incident diabetes, prediabetes was significantly associated with the risk of dementia (HR 1.12 [95% CI 1.01, 1.24]). After accounting for incident diabetes, the association was attenuated and non-significant (HR 1.05 [95% CI 0.94, 1.16]). Earlier age of onset of diabetes had the strongest association with dementia: HR 2.92 (95% CI 2.06, 4.14) for onset before 60 years; HR 1.73 (95% CI 1.47, 2.04) for onset at 60-69 years; and HR 1.23 (95% CI 1.08, 1.40) for onset at 70-79 years. Prediabetes is associated with dementia risk but this risk is explained by the subsequent development of diabetes. Earlier age of onset of diabetes substantially increases dementia risk. Preventing or delaying progression of prediabetes to diabetes will reduce dementia burden.

Longitudinal Changes in Left Ventricular Diastolic Function in Late Life: The ARIC Study

BackgroundThere is limited data regarding longitudinal changes of diastolic function in the very old, who are at the highest risk for heart failure (HF). ObjectivesThis study aims to quantify intraindividual longitudinal changes of diastolic function over 6 years in late life. MethodsThe authors studied 2,524 older adult participants in the prospective community-based ARIC (Atherosclerosis Risk In Communities) study who underwent protocol-based echocardiography at study visits 5 (2011-2013) and 7 (2018-2019). The primary diastolic measures were tissue Doppler e′, E/e′ ratio, and left atrial volume index (LAVI). ResultsMean age was 74 ± 4 years at visit 5 and 80 ± 4 at visit 7, 59% were women, and 24% were Black. At visit 5, mean e′septal was 5.8 ± 1.4 cm/s, E/e′septal 11.7 ± 3.5, and LAVI 24.3 ± 6.7 mL/m2. Over a mean of 6.6 ± 0.8 years, e′septal decreased by 0.6 ± 1.4 cm/s, E/e′septal increased by 3.1 ± 4.4, and LAVI increased by 2.3 ± 6.4 mL/m2. The proportion with 2 or more abnormal diastolic measures increased from 17% to 42% (P < 0.001). Compared with participants free of cardiovascular (CV) risk factors or diseases at visit 5 (n = 234), those with prevalent CV risk factors or diseases but without prevalent or incident HF (n = 2,150) demonstrated greater increases in E/e′septal and LAVI. Increases of E/e′septal and LAVI were both associated with the development of dyspnea between visits in analyses adjusted for CV risk factors. ConclusionsDiastolic function generally deteriorates over 6.6 years in late life, particularly among persons with CV risk factors, and is associated with development of dyspnea. Further studies are necessary to determine if risk factor prevention or control will mitigate these changes.

38 Plasma proteomic signature of motoric cognitive risk syndrome

OBJECTIVES/GOALS: Motoric cognitive risk (MCR) is a pre-dementia syndrome characterized by slow gait and subjective cognitive complaints. In the Atherosclerosis Risk in Communities (ARIC) study, we aim to (1) identify plasma proteins and protein modules associated with MCR and (2) compare the proteomic signature of MCR to that of mild cognitive impairment (MCI). METHODS/STUDY POPULATION: Nondemented ARIC participants were classified by MCR status (yes/no) according to a memory questionnaire and 4-meter walk. MCI status (yes/no) was classified by expert diagnosis using standardized criteria. We measured 4,877 proteins in plasma collected at ARIC Visit 5 (late-life) and Visit 2 (midlife) utilizing the SomaScan4 proteomic assay. Multivariable logistic regression”adjusted for demographic variables, kidney function, cardiovascular risk factors, and APOE4 status”related each protein to MCR at late-life. An FDR corrected P RESULTS/ANTICIPATED RESULTS: Proteome-wide association study among 4076 ARIC participants (mean age=75; 58% women, 17% Black, 4% MCR+, 21% MCI+; MCR+ and MCI+ groups overlapped) at late-life identified 26 MCR-associated proteins involved in metabolism, vascular/visceral smooth muscle, and extracellular matrix organization. At an uncorrected P DISCUSSION/SIGNIFICANCE: This proteomic characterization of MCR identifies novel plasma proteins and networks, both distinct from and overlapping with those of MCI, thus highlighting the partially divergent mechanisms underlying these pre-dementia syndromes. These findings may be leveraged toward dementia prognostication and targeted therapeutic approaches.

The association of peripheral neuropathy detected by monofilament testing with risk of falls and fractures in older adults.

In persons with diabetes, annual screening for peripheral neuropathy (PN) using monofilament testing is the standard of care. However, PN detected by monofilament testing is common in older adults, even in the absence of diabetes. We aimed to assess the association of PN with risk of falls and fractures in older adults. We included participants in the Atherosclerosis Risk in Communities (ARIC) Study who underwent monofilament testing at visit 6 (2016-2017). Incident falls and fractures were identified based on ICD-9 and ICD-10 codes from active surveillance of all hospitalizations and linkage to Medicare claims. We used Cox models to assess the association of PN with falls and fractures (combined and as separate outcomes) after adjusting for demographics and risk factors for falls. There were 3617 ARIC participants (mean age 79.4 [SD 4.7] years, 40.8% male, and 21.4% Black adults), of whom 1242 (34.3%) had PN based on monofilament testing. During a median follow-up of 2.5 years, 371 participants had a documented fall, and 475 participants had a documented fracture. The incidence rate (per 1000 person-years) for falls or fractures for participants with PN versus those without PN was 111.1 versus 74.3 (p < 0.001). The age-, sex-, and race-adjusted 3-year cumulative incidence of incident fall or fracture was significantly higher for participants with PN versus those without PN (26.5% vs. 18.4%, p < 0.001). After adjusting for demographics, PN remained independently associated with falls and fractures (HR 1.48, 95% CI 1.26, 1.74). Results were similar for models including traditional risk factors for falls, when falls and fractures were analyzed as separate outcomes, and after adjustment for competing risk of death. PN, as measured by monofilament testing, is common in older adults and associated with risk of falls and fracture. Screening with monofilament testing may be warranted to identify older adults at high risk for falls.