Atherosclerosis Risk In Communities Cohort 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.

Self-Rated Health in Middle Age and Risk of Hospitalizations and Death: Recurrent Event Analysis of the ARIC Study.

Self-rated health is a simple measure that may identify individuals who are at a higher risk for hospitalization or death. To quantify the association between a single measure of self-rated health and future risk of recurrent hospitalizations or death. Atherosclerosis Risk in Communities (ARIC) study, a community-based prospective cohort study of middle-aged men and women with follow-up beginning from 1987 to 1989. We quantified the associations between initial self-rated health with risk of recurrent hospitalizations and of death using a recurrent events survival model that allowed for dependency between the rates of hospitalization and hazards of death, adjusted for demographic and clinical factors. Of the 14,937 ARIC cohort individuals with available self-rated health and covariate information, 34% of individuals reported "excellent" health, 47% "good," 16% "fair," and 3% "poor" at study baseline. After a median follow-up of 27.7years, 1955 (39%), 3569 (51%), 1626 (67%), and 402 (83%) individuals with "excellent," "good," "fair," and "poor" health, respectively, had died. After adjusting for demographic factors and medical history, a less favorable self-rated health status was associated with increased rates of hospitalization and death. As compared to those reporting "excellent" health, adults with "good," "fair," and "poor" health had 1.22 (1.07 to 1.40), 2.01 (1.63 to 2.47), and 3.13 (2.39 to 4.09) times the rate of hospitalizations, respectively. The hazards of death also increased with worsening categories of self-rated health, with "good," "fair," and "poor" health individuals experiencing 1.30 (1.12 to 1.51), 2.15 (1.71 to 2.69), and 3.40 (2.54 to 4.56) times the hazard of death compared to "excellent," respectively. Even after adjusting for demographic and clinical factors, having a less favorable response on a single measure of self-rated health taken in middle age is a potent marker of future hospitalizations and death.

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 WP241: Migraine Associated Risk of Stroke Score

Background: Migraine with aura is a risk factor for ischemic stroke. We refined the migraine with aura risk score (MARS) to create the migraine associated risk of stroke score (MARS Plus) making it applicable to migraine with and without aura. The expanded risk score includes vascular risk factors, migraine characteristics, and medications used in migraine patients. Methods: We prospectively evaluated participants in Atherosclerosis Risk in Communities Cohort (ARIC) with history of migraine. In this population, we tested the association of potential risk factors for ischemic stroke using a Cox proportional-hazards model. The coefficient of each variable was divided by the lowest β value and rounded to the nearest integer. The sum of the weighted score of the reported risk factors was found and was categorized into two prognostic groups. Results: We assessed migraine characteristics (aura, migraine frequency and duration) and medications (ergot alkaloids, triptans, hormone replacement therapy, sympathomimetics and steroids) in addition to traditional risk factors. Based on the points derived from the significant factors we assigned age≥65 =2, non-white race=2, hypertension=3, diabetes=4, body mass index ≥30 =2, coronary artery disease =2, atrial fibrillation =3, alcohol use=1, steroids=3 and presence of aura=2 to total 24 points. Cut-off of MARS Plus ≥5 was considered high risk for ischemic stroke based on receiver operating characteristic (ROC) curve and Youden’s index (Figure). Of the 1485 migraineurs, 112 had an ischemic stroke. MARS Plus ≥5 revealed a hazard ratio of 4.29 (95% CI 2.86-6.45) as shown in the Kaplan-Meier Survival Curve. Conclusion: The new MARS Plus is used to predict ischemic stroke in patients with migraine with and without aura. This new risk score, in addition to generalizability, includes factors such as migraine characteristics and medications that may increase stroke risk.

Abstract 12533: Heart Failure Diagnostic Classification Criteria in Hospitalized Patients Are Associated With Increased Mortality Risk: The Atherosclerosis Risk in Communities (ARIC) Study

Introduction: Multiple diagnostic HF classification have been used to identify heart failure (HF) events. Whether these classification criteria can be used for estimating prognosis is unknown. Research Question: This study compares multiple research-derived HF classification criteria for predicting mortality in the ARIC study cohort with validated hospitalized acute decompensated heart failure (ADHF) events. Methods: There were 1,954 ARIC cohort members with hospitalized HF events from 2005-2019, validated as ADHF by ARIC study classification/adjudication. These HF events were also classified as HF present/absent at the time of hospitalization by other HF classification criteria - Framingham, Modified Boston, NHANES, and Gothenburg. Hazard ratios (HRs) for all-cause mortality at 30 days, 1 year, and 5 years were calculated using logistic regression for all included HF classification criteria compared to ARIC, stratified by ejection fraction (EF), and adjusted for demographics and comorbidities. Results: For all ADHF events, Framingham, NHANES, and Gothenburg were prognostic for survival, but not modified Boston criteria (Table). ADHF patients who were also classified as HF by Framingham criteria had a 30% or more increased mortality at 30-day, 1-year, and 5-years regardless of EF, compared to those who were not classified as HF by Framingham (p<0.05). Framingham criteria were prognostic for 30-day survival for those with HFrEF, and also for 1-year and 5-year survival for those with HFpEF. Conclusion: The presence of HF as defined using different published criteria is associated with elevated risk of all-cause mortality. To our knowledge, this is a novel study comparing multiple research-derived HF classification criteria for clinical prognostication of mortality in ADHF. More studies are needed to assess the utility of these HF classification criteria for prognostication for HF morbidity and rehospitalization and by HF type.

Abstract 16776: Recurrent Admission of Acute Decompensated Heart Failure Among Patients With and Without PAD and Its Significance in the CKD Population: The ARIC Cohort Study

Introduction: Peripheral artery disease (PAD) and chronic kidney disease (CKD) are common comorbidities in patients with heart failure (HF). Importantly, CKD is associated with a greater risk of incident PAD and is a known risk factor for worse outcomes in HF patients. However, it is unclear whether the concomitant existence of PAD and CKD increases the risk of recurrent hospitalization for acute decompensated heart failure (ADHF). Methods: Since 2005, the Atherosclerosis Risk in Communities (ARIC) study has conducted hospital surveillance of ADHF with events verified by physician review. Demographics, comorbidities, laboratory data, and medications were abstracted from medical record by trained personnel. Hazard ratios of ADHF readmissions were analyzed using repeat-events Cox regression. Models were adjusted for age, race, sex, year and hospital of admission, coronary artery disease (CAD), COPD, and diabetes mellitus. CKD was defined by glomerular filtration rate [GFR] ≤60 mL/min/1.73m 2 . Results: From 2005-2018, there were 1049 index hospitalizations for ADHF (mean age 77 years, 66% white) with measured creatinine, who were discharged alive. Of these, 155 (15%) had a diagnosis of PAD and 66% had CKD stage 3a or worse (GFR ≤60 mL/min/1.73m 2 ). Patients with PAD had a greater prevalence of smoking, CAD, myocardial infarction, and stroke. The 1-year ADHF readmission rate tended to be higher in patients with PAD, irrespective of CKD stage, compared to those without PAD ( Figure 1 ). After adjustments, PAD was associated with greater hazards of 1-year ADHF readmissions, both in patients with CKD stage 3a or worse (HR, 1.71; 95% CI: 1.25 - 2.32) and without CKD (HR, 1.84; 95% CI: 1.07-3.15). Conclusion: Patients with ADHF and concomitant PAD have a higher prevalence of cardiovascular comorbidities and higher likelihood of 1-year ADHF readmission, irrespective of the CKD status. Focused strategies to prevent ADHF readmission in this high-risk group are warranted.

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.

Abstract 16832: Biomarker Enhanced Risk Prediction of Incident Heart Failure in Low-Risk Patients: The Atherosclerosis Risk in Communities (ARIC) Study

Background: Primary prevention strategies to reduce heart failure (HF) burden are urgently warranted. The Pooled Cohort equations to Prevent HF (PCP-HF) risk score is a validated risk tool that integrates readily available parameters obtained in primary care setting to estimate the 10-year risk for incident HF. Although PCP-HF performs well for high-risk individuals, the model’s predictive utility for low-risk individuals may potentially be enhanced by integration of biomarkers. Methods: In this study, the PCP-HF risk score was derived from data collected at visit 5 (2011-2013) of the ARIC cohort study and its 5-year predictive accuracy was investigated using surveillance data up to 2019. Participants with <10% PCP-HF risk probability of incident HF were classified as low-risk. Incremental improvement in predicting incident HF by including laboratory and imaging-based biomarkers in the low-risk population was analyzed by logistic regression, by calculating the area under the curve (AUC) from receiver operating characteristics. Results: Of 4980 study participants with 5 years of follow up, 47% had a low PCP-HF risk score (mean age 73 years, 71% women, 32% Black). Of these, 3% developed HF within 5 years. Compared to those with a high PCP-HF risk score, individuals with low PCP-HF risk score were younger, more often female and Black; had lower left ventricular (LV) mass index and left atrial volume index, higher magnitude of LV global longitudinal strain, and lower levels of NT-proBNP and hs-TnT. On further analysis, the model incorporating laboratory and imaging-based biomarkers exhibited greater predictive accuracy for incident HF compared to the original PCP-HF risk score in this low-risk population (AUC: 0.85 vs 0.62). Conclusion: The integration of laboratory and imaging-based biomarkers with the PCP-HF risk score enhances the predictive accuracy of risk modeling for incident HF, especially in individuals identified as low-risk by the 10-year risk prediction tool.

Novel Size-Based High-Density Lipoprotein Subspecies and Incident Vascular Events.

Background High-density lipoprotein (HDL) particle concentration likely outperforms HDL cholesterol in predicting atherosclerotic cardiovascular events. Whether size-based HDL subspecies explain the atheroprotective associations of HDL particle concentration remains unknown. Our objective was to assess whether levels of specific size-based HDL subspecies associate with atherosclerotic cardiovascular disease in a multiethnic pooled cohort and improve risk prediction beyond traditional atherosclerotic cardiovascular disease risk factors. Methods and Results Seven HDL size-based subspecies were quantified by nuclear magnetic resonance (LP4 algorithm; H1=smallest; H7=largest) among participants without prior atherosclerotic cardiovascular disease in ARIC (Atherosclerosis Risk in Communities), MESA (Multi-Ethnic Study of Atherosclerosis), PREVEND (Prevention of Renal and Vascular Endstage Disease), and DHS (Dallas Heart Study) cohorts (n=15 371 people). Multivariable Cox proportional hazards models were used to evaluate the association between HDL subspecies and incident myocardial infarction (MI) or ischemic stroke at follow-up (average 8-10 years) adjusting for HDL cholesterol and risk factors. Improvement in risk prediction was assessed via discrimination and reclassification analysis. Within the pooled cohort (median age 57 years; female 54%; Black 22%) higher H1 (small) and H4 (medium) concentrations were inversely associated with incident MI (hazard ratio [HR]/SD, H1 0.88 [95% CI, 0.81-0.94]; H4 0.89 [95% CI, 0.82-0.97]). H4 but not H1 improved risk prediction indices for incident MI. Increasing H2 and H4 were inversely associated with improved risk prediction indices for composite end point of stroke, MI, and cardiovascular death (HR/SD, H2 0.94 [95% CI, 0.88-0.99]; H4 0.91 [95% CI, 0.85-0.98]). Levels of the large subspecies (H6 and H7) were not associated with any vascular end point. Conclusions Two of 7 HDL size-based subspecies modestly improved risk prediction for MI and composite vascular end points in a large multiethnic pooled cohort. These findings support assessment of precise HDL subspecies for future studies regarding clinical utility.

Circulating Proteins and Mortality in CKD: A Proteomics Study of the AASK and ARIC Cohorts

Proteomics could provide pathophysiologic insight into the increased risk of mortality in patients with chronic kidney disease (CKD). This study aimed to investigate associations between the circulating proteome and all-cause mortality among patients with CKD. Observational cohort study. Primary analysis in 703 participants in the African American Study of Kidney Disease and Hypertension (AASK) and validation in 1,628 participants with CKD in the Atherosclerosis Risk in Communities (ARIC) study who attended visit5. Circulating proteins. All-cause mortality. Among AASK participants, we evaluated the associations of 6,790 circulating proteins with all-cause mortality using multivariable Cox proportional hazards models. Proteins with significant associations were further studied in ARIC Visit 5 participants with CKD. In the AASK cohort, the mean age was 54.5 years, 271 (38.5%) were women, and the mean measured glomerular filtration rate (GFR) was 46mL/min/1.73m2. The median follow-up was 9.6 years, and 7 distinct proteins were associated with all-cause mortality at the Bonferroni-level threshold (P<0.05 of the 6,790) after adjustment for demographics and clinical factors, including baseline measured estimated GFR and proteinuria. In the ARIC visit 5 cohort, the mean age was 77.2 years, 903 (55.5%) were women, the mean estimated GFR was 54mL/min/1.73m2 and median follow-up was 6.9 years. Of the 7 proteins found in AASK, 3 (β2-microglobulin, spondin-1, and N-terminal pro-brain natriuretic peptide) were available in the ARIC data, with all 3 significantly associated with death in ARIC. Possibility of unmeasured confounding. Cause of death was not known. Using large-scale proteomic analysis, proteins were reproducibly associated with mortality in 2 cohorts of participants with CKD. Patients with chronic kidney disease (CKD) have a high risk of premature death, with various pathophysiological processes contributing to this increased risk of mortality. This observational cohort study aimed to investigate the associations between circulating proteins and all-cause mortality in patients with CKD using large-scale proteomic analysis. The study analyzed data from the African American Study of Kidney Disease and Hypertension (AASK) study and validated the findings in the Atherosclerosis Risk in Communities (ARIC) Study. A total of 6,790 circulating proteins were evaluated in AASK, and 7 proteins were significantly associated with all-cause mortality. Three of these proteins (β2-microglobulin, spondin-1, and N-terminal pro-brain natriuretic peptide (BNP)) were also measured in ARIC and were significantly associated with death. Additional studies assessing biomarkers associated with mortality among patients with CKD are needed to evaluate their use in clinical practice.

Bidirectional Association Between Frailty and Cardiac Structure and Function: The Atherosclerosis Risk in Communities Study.

Background Frailty and heart failure frequently coexist in late life. Limited data exist regarding the longitudinal associations of frailty and subclinical cardiac dysfunction. We aim to quantify the association of frailty with longitudinal changes in cardiac function and of cardiac function with progression in frailty status in older adults. Methods and Results Participants in the Atherosclerosis Risk in Communities cohort underwent frailty assessments at Visit 5 (V5; 2011-2013), V6 (2016-2017), and V7 (2018-2019), and echocardiographic assessments at V5 and V7. We assessed the association between frailty status at V5 and changes in frailty status from V5 to V7 and changes in cardiac function over 6 years. We then evaluated the association of cardiac function measured at Visit 5 with progression in frailty status over 4 years. Multivariable regression models adjusted for demographics and comorbidities. Among 2574 participants free of heart failure at V5 and V7 (age 74±4 years at V5 and 81±4 years at V7), 3% (n=83) were frail. Frailty at V5 was associated with greater left atrial volume index and E/e' ratio at V5 and 7. Participants who transitioned from robust at V5 to frail at V7 demonstrated greater increases in left ventricular mass index, left atrial volume index, and E/e' over the same period. Among 1648 robust participants at Visit 5, greater left ventricular mass index and mean wall thickness, lower tissue Doppler imaging e', and higher E/e' ratio at Visit 5 were associated with progression in frailty status. Conclusions Among robust, older adults free of heart failure, progression in frailty and subclinical left ventricular remodeling and diastolic dysfunction are interrelated.

Proteomic cardiovascular risk assessment in chronic kidney disease.

Chronic kidney disease (CKD) is widely prevalent and independently increases cardiovascular risk. Cardiovascular risk prediction tools derived in the general population perform poorly in CKD. Through large-scale proteomics discovery, this study aimed to create more accurate cardiovascular risk models. Elastic net regression was used to derive a proteomic risk model for incident cardiovascular risk in 2182 participants from the Chronic Renal Insufficiency Cohort. The model was then validated in 485 participants from the Atherosclerosis Risk in Communities cohort. All participants had CKD and no history of cardiovascular disease at study baseline when ∼5000 proteins were measured. The proteomic risk model, which consisted of 32 proteins, was superior to both the 2013 ACC/AHA Pooled Cohort Equation and a modified Pooled Cohort Equation that included estimated glomerular filtrate rate. The Chronic Renal Insufficiency Cohort internal validation set demonstrated annualized receiver operating characteristic area under the curve values from 1 to 10 years ranging between 0.84 and 0.89 for the protein and 0.70 and 0.73 for the clinical models. Similar findings were observed in the Atherosclerosis Risk in Communities validation cohort. For nearly half of the individual proteins independently associated with cardiovascular risk, Mendelian randomization suggested a causal link to cardiovascular events or risk factors. Pathway analyses revealed enrichment of proteins involved in immunologic function, vascular and neuronal development, and hepatic fibrosis. In two sizeable populations with CKD, a proteomic risk model for incident cardiovascular disease surpassed clinical risk models recommended in clinical practice, even after including estimated glomerular filtration rate. New biological insights may prioritize the development of therapeutic strategies for cardiovascular risk reduction in the CKD population.

Circulating Magnesium and Risk of Major Adverse Cardiac Events among Patients with Atrial Fibrillation in the ARIC Cohort.

Background: Serum magnesium (Mg) has been reported to be inversely associated with the risk of atrial fibrillation (AF), coronary artery disease (CAD), and major adverse cardiovascular events (MACE). The association between serum Mg and the risk of MACE, heart failure (HF), stroke, and all-cause mortality among patients with AF has not been evaluated. Objective: We aim to examine whether higher serum Mg is associated with a lower risk of MACE, heart failure (HF), stroke, and all-cause mortality among patients with AF. Methods: We evaluated prospectively 413 participants of the Atherosclerosis Risk in Communities (ARIC) Study with a diagnosis of AF at the time of Mg measurement participating in visit 5 (2011-2013). Serum Mg was modeled in tertiles and as a continuous variable in standard deviation units. Endpoints (HF, MI, stroke, cardiovascular (CV) death, all-cause mortality, and MACE) were identified and modeled separately using Cox proportional hazard regression adjusting for potential confounders. Results: During a mean follow-up of 5.8 years, there were 79 HFs, 34 MIs, 24 strokes, 80 CV deaths, 110 MACEs, and 198 total deaths. After adjustment for demographic and clinical variables, participants in the second and third tertiles of serum Mg had lower rates of most endpoints, with the strongest inverse association for the incidence of MI (HR 0.20, 95% CI 0.07, 0.61) comparing top to bottom tertile. Serum Mg modeled linearly as a continuous variable did not show clear associations with endpoints except MI (HR 0.50, 95% CI 0.31, 0.80). Due to the limited number of events, the precision of most estimates of association was relatively low. Conclusions: Among patients with AF, higher serum Mg was associated with a lower risk of developing incident MI and, to a lesser extent, other CV endpoints. Further studies in larger patients with AF cohorts are needed to evaluate the role of serum Mg in preventing adverse CV outcomes in these patients.

Abstract P236: Neighborhood Socioeconomic Status and Functional Status Impairment in Late-Life: The Atherosclerosis Risk in Communities (ARIC) Study

Introduction: Neighborhood characteristics and physical activity levels may impact physical function. The present study examined the relationship between neighborhood socioeconomic status (NSES) and functional status impairment among older men and women and examined whether this relationship differed by physical activity. Hypothesis: Compared to those with high levels of NSES, participants with low NSES will have higher odds of functional impairment in late life. This association will be modified by physical activity. Methods: We constructed an aggregate measure of NSES using census-based indicators of wealth, education, and occupation and quantified distribution-based tertiles of low, middle, and high NSES among ARIC cohort participants in Visit 5 (2011-2013). We used the Rosow-Breslau scale to ascertain functional status (range 0-4; functional impairment defined as a score&lt;4) during the 2016 annual telephone interview. Multivariable logistic regression was used to examine the association between NSES tertiles and functional status impairment adjusting for age, race, ARIC center, and sex. We tested for effect modification by AHA-defined physical activity (categorized as poor, intermediate, ideal based on weekly minutes of moderate-to-vigorous physical activity). We also tested for effect modification by sex, race, and age. Results: Among 4,439 participants (mean age: 75 (SD 5) years, 22% Black, 55% female), 1,788 (40%) had functional status impairment. In analyses adjusted for sex, race, and age, the odds of functional impairment among participants with low NSES were 1.86 (95% CI: 1.60, 2.16) times the odds of functional impairment among those with high NSES. There was evidence of effect measure modification by race (p=0.06) and age (p=0.07). In White participants, the odds of functional status impairment among participants with low NSES was 1.99 (95% CI: 1.69, 2.35) times the odds of functional impairment among those with high NSES. This association was attenuated in Black participants (OR: 1.38, 95% CI: 0.96, 2.00). In participants less than 74 years, the odds of functional status impairment among participants with low NSES was 2.17 (95% CI: 1.73, 2.72) times the odds of functional impairment among those with high NSES. This association was attenuated in participants 74 years and older (OR: 1.64, 95% CI: 1.34, 1.99). There was no evidence of effect modification by physical activity (p=0.20) nor sex (p=0.65). Conclusions: Low NSES is modestly associated with functional status impairment in older adulthood. This association appeared stronger in Whites compared to Blacks, and in those younger than 74 years.

Abstract P256: Psychosocial Risk Factors Are Associated With Lower Cardiovascular Health, Measured by Life’s Essential 8, in the Atherosclerosis Risk in Communities (ARIC) Study

Introduction: Psychosocial factors (social isolation, social support, trait anger, and depressive symptoms) are associated with cardiovascular disease risk factors and incidence; few studies investigate whether they are associated with cardiovascular health (CVH), and none with a new definition of CVH, Life’s Essential 8 (LE8) published by the American Heart Association (AHA). Hypothesis: Cross-sectional associations of psychosocial factors and CVH will be inverse, and will be modified by sex and race. Methods: We included 11,674 ARIC cohort participants (58% women; 23% Black; mean age 57 (standard deviation (SD): 6) years) who attended Visit 2 (1990-1992) and had complete data. All psychosocial factors and the following LE8 components were measured at Visit 2: nicotine exposure, sleep, body mass index, blood lipids, blood glucose, and blood pressure. Physical activity and diet were measured at Visit 1 (1987-1989). Psychosocial factors were categorized per standard convention or by tertiles. LE8 was scored per the AHA definition (0-100 range). Associations of each psychosocial factor with continuous LE8 score were assessed using multivariable linear regressions. Results: Mean LE8 score was 61 (SD: 15). Poorer scores on psychosocial factor assessments were associated with lower LE8 scores, with the largest magnitude of association for depressive symptoms (Figure). Participants with high levels of depressive symptoms had an LE8 score 8 points lower than those with low levels of depressive symptoms. Stratum-specific estimates and p-values for interaction terms suggested no modification by sex; however psychosocial factors were associated with approximately a 1 point lower LE8 score in White participants than in Black participants. Conclusion: Poorer psychosocial health factors were associated with lower CVH among middle-aged men and women in ARIC. Future work could investigate whether psychosocial factors modify the relationship between CVH and incident cardiovascular disease.

Abstract P543: Longitudinal Change in Perceived Loneliness Among Older Adults During the COVID-19 Pandemic: The Atherosclerosis Risk in Communities (ARIC) Study

Introduction: We and others observed that social distancing enforced early in the COVID-19 pandemic led to an increase in loneliness, a social condition associated with adverse mental and physical health outcomes. Here, we examine longitudinal changes in perceived loneliness over the first two years of the COVD-19 pandemic among older adults participating in the Atherosclerosis Risk in Communities (ARIC) Study. Hypothesis: Perceived loneliness decreased over the course of the pandemic. Methods: The UCLA 3-item Loneliness questionnaire, which assesses lack of companionship, feeling left out, and feeling isolated, to classify level of perceived loneliness, was administered to ARIC participants in March-October 2020 and again in August 2020-March 2022 as part of the Colllaborative Cohort of Cohorts for COVID-19 Research (C4R). Prepandemic measures (Jan-March 2020) were available in a subset. For each item, response categories “hardly ever”, “some of the time” and “often” were scored from 1 to 3, respectively, and added to create a final score ranging from 3 to 9 (higher scores indicating greater loneliness). T-tests were used to compare mean loneliness score values between the measurement periods. Mixed effects linear regression models were fit to examine predictors of change in the loneliness score. Results: Among 2,335 ARIC cohort participants with repeat assessments of loneliness during the COVID-19 pandemic (mean age 82.4 (SD 4.4) years, 64.8% female, 18.5% Black), mean perceived loneliness score decreased from 4.40 (SD 1.51) to 3.78 (SD 1.25) (p-value &lt;0.01) over median follow-up of 10.7 (SD 3.8) months. In 516 participants with pre-pandemic measures, the mean perceived loneliness score was 3.63 (SD 1.13). In analyses adjusted for age, the decrease in the loneliness score during the pandemic was greater by 0.65 (95% CI: 0.46, 0.84) units among Black, as compared to White participants. Male sex was likewise associated with a 0.89 (95% CI: 0.77, 1.02) unit decrease in the loneliness score. No differences were observed by educational attainment, age, or levels of the Area Deprivation Index. Conclusion: Despite reporting greater loneliness during the first six months of the COVID-19 pandemic compared to the time prior to the pandemic, older adults reported similar levels of perceived loneliness in the second year of the pandemic compared to pre-pandemic levels. In particular, Black race and and male sex were associated with greater reductions in loneliness over the pandemic period. These results suggest that older adults were psychologically resilient with respect to the extreme social changes associated with the COVID-19 pandemic.

Abstract TMP105: Migraine With Aura Risk Score, Medication Use And Composite Cardiovascular

Background: The migraine with aura risk score (MARS) was developed to predict the risk of ischemic stroke in patients with migraine with aura. Certain medications (estrogen replacement therapy-ERT, triptans and ergot alkaloids) have been postulated to increase cardiovascular risk. We tested if MARS or medications increased risk of ischemic stroke, cardiovascular event, and death. Methods: Migraine with aura patients (N=430) in the Atherosclerosis Risk in Communities Cohort were considered in this study. Those who had events prior to being evaluated were excluded leaving 420 patients. MARS was calculated at visit 3 (1993-1995) and patients were stratified as low (≤2) and high (≥3) risk groups. Medication uses were recorded on the same visit. Results: Of the 420 patients with a history of migraine with aura (age, mean±standard deviation=58.5±5.5, 349 female, 344 white), 49 patients had an ischemic stroke, 79 had a cardiovascular event, and 192 died during a 25-year follow-up period. The high-risk group was noted to have hazards ratio (HR) of 4.41 (95% CI 2.45-7.94) for ischemic stroke, 5.89 (95% CI 3.69-9.38) for cardiovascular event, and 3.56 (95% CI 2.66-4.79) for death, compared with the low-risk group. HR for composite events was 3.60 (95% CI 2.73-4.75). Kaplan-Meier Survival curves are depicted below (Logrank p&lt;0.0001). Among medications only ERT (used in 34%) was associated with a significantly lower risk of composite events (HR 0.63, 95% CI 0.47-0.84), no significant difference for triptans (used in 1%) or ergot alkaloids (used in 4%). Conclusion: MARS≥3 increased the risk of composite events. Triptans and ergot alkaloids were not associated with increased risks and ERT was associated with a lower risk of composite events. The MARS finding needs validation in an external dataset and medication effects need confirmation in a randomized clinical trial.

Carotid ultrasonography improves residual risk stratification in guidelines-defined high cardiovascular risk patients

Abstract Background The clinical value of carotid atherosclerosis markers for residual risk stratification in high atherosclerotic cardiovascular disease (ASCVD) risk patients is not established. Purpose In the present study we aimed to derive and validate optimal values of markers of carotid subclinical atherosclerosis improving risk stratification in guidelines-defined high ASCVD risk patients. Methods We consecutively analysed high or very high ASCVD risk patients from a cardiovascular (CV) prevention registry (n=751, derivation cohort) and from the Atherosclerosis Risk in Communities (ARIC) study (n=2,897, validation cohort). Baseline ASCVD risk was defined using the 2021 European Society of Cardiology (ESC) guidelines (clinical ESCrisk). Intima-media thickness (IMT) excluding plaque, average maximal (avg.maxWT), maximal wall thickness (maxWT) and number of sites with carotid plaque were assessed. As endpoint of the study was defined the composite of CV death, acute myocardial infarction (MI) and revascularization after a median of 3.4 years in both cohorts and additionally for 16.7 years in the ARIC cohort. Results MaxWT &amp;gt;2.00mm and avg.maxWT &amp;gt;1.39mm provided incremental prognostic value, improved discrimination and correctly reclassified risk over the clinical ESCrisk both in the derivation and the validation cohort (p&amp;lt;0.05 for net reclassification index, integrated discrimination index and Delta Harrell's C index). MaxWT &amp;lt;0.9mm predicted very low probability of CV events (negative predictive value = 97% and 92% in the derivation and validation cohort, respectively). These findings were additionally confirmed for very long-term events in the validation cohort. Conclusion Integration of carotid ultrasonography in guidelines-defined risk stratification may identify very high risk patients in need for further residual risk reduction or at very low probability Funding Acknowledgement Type of funding sources: None.

Association of Pulmonary Function With Late-Life Cardiac Function and Heart Failure Risk: The ARIC Study.

Background Pulmonary and cardiac functions decline with age, but the associations of pulmonary dysfunction with cardiac function and heart failure (HF) risk in late life is not known. We aimed to determine the associations of percent predicted forced vital capacity (ppFVC) and the ratio of forced expired volume in 1second (FEV1) to forced vital capacity (FVC; FEV1/FVC) with cardiac function and incident HF with preserved or reduced ejection fraction in late life. Methods and Results Among 3854 HF-free participants in the ARIC (Atherosclerosis Risk in Communities) cohort study who underwent echocardiography and spirometry at the fifth study visit (2011-2013), associations of FEV1/FVC and ppFVC with echocardiographic measures, cardiac biomarkers, and risk of HF, HF with preserved ejection fraction, and HF with reduced ejection fraction were assessed. Multivariable linear and Cox regression models adjusted for demographics, body mass index, coronary disease, atrial fibrillation, hypertension, and diabetes. Mean age was 75±5years, 40% were men, 19% were Black, and 61% were ever smokers. Mean FEV1/FVC was 72±8%, and ppFVC was 98±17%. In adjusted analyses, lower FEV1/FVC and ppFVC were associated with higher NT-proBNP (N-terminal pro-B-type natriuretic peptide; both P<0.001) and pulmonary artery pressure (P<0.004). Lower ppFVC was also associated with higher left ventricular mass, left ventricular filling pressure, and high-sensitivity C-reactive protein (all P<0.01). Lower FEV1/FVC was associated with a trend toward higher risk of incident HF with preserved ejection fraction (hazard ratio [HR] per 10-point decrease, 1.31; 95% CI, 0.98-1.74; P=0.07) and HF with reduced ejection fraction (HR per 10-point decrease, 1.24; 95% CI, 0.91-1.70; P=0.18), but these associations did not reach statistical significance. Lower ppFVC was associated with incident HF with preserved ejection fraction (HR per 10-unit decrease, 1.21; 95% CI, 1.04-1.41; P=0.013) but not with HF with reduced ejection fraction (HR per 10-unit decrease, 0.90; 95% CI, 0.76-1.07; P=0.24). Conclusions Subclinical reductions in FEV1/FVC and ppFVC differentially associate with cardiac function and HF risk in late life.

Carotid ultrasonography improves residual risk stratification in guidelines-defined high cardiovascular risk patients.

The clinical value of carotid atherosclerosis markers for residual risk stratification in high atherosclerotic cardiovascular disease (ASCVD) risk patients is not established. We aimed to derive and validate optimal values of markers of carotid subclinical atherosclerosis improving risk stratification in guidelines-defined high ASCVD risk patients. We consecutively analysed high or very high ASCVD risk patients from a cardiovascular (CV) prevention registry (n = 751, derivation cohort) and from the Atherosclerosis Risk in Communities (ARIC) study (n = 2,897, validation cohort). Baseline ASCVD risk was defined using the 2021 European Society of Cardiology guidelines (clinical ESCrisk). Intima-media thickness excluding plaque, average maximal (avg.maxWT), maximal wall thickness (maxWT) and number of sites with carotid plaque were assessed. As primary endpoint of the study was defined the composite of cardiac death, acute myocardial infarction and revascularization after a median of 3.4 years in both cohorts and additionally for 16.7 years in the ARIC cohort. MaxWT &gt; 2.00 mm and avg.maxWT &gt; 1.39 mm provided incremental prognostic value, improved discrimination and correctly reclassified risk over the clinical ESCrisk both in the derivation and the validation cohort (P &lt; 0.05 for net reclassification index, integrated discrimination index and Delta Harrell's C index). MaxWT &lt; 0.9 mm predicted very low probability of CV events (negative predictive value = 97% and 92% in the derivation and validation cohort, respectively). These findings were additionally confirmed for very long-term events in the validation cohort. Integration of carotid ultrasonography in guidelines-defined risk stratification may identify patients at very high-risk in need for further residual risk reduction or at very low probability for events.