Atherosclerosis Risk In Communities Study Research Articles

Abstract P135: Effect of Cardiovascular Health Improvement at Midlife on Cardiovascular Event and Mortality Risk in Diabetes

Objective: This prospective cohort study examined the relationships between changes in CVH during midlife, as assessed by the Life's Simple 7, and risks of CVD events and all-cause mortality among individuals with diabetes and compared to individuals without diabetes. Methods: The study utilized data from the Atherosclerosis Risk in Communities Study, collected during visits 1 (1987-1989) and visit 3 (1993-1995) with a median follow-up of 23 years. Results: Among the final sample (N=8,741), 806 had diabetes (9.2%). Among participants with diabetes at baseline, 62.3% had consistently low CVH at both visits, 12.0% maintained moderate CVH, and 0.4% maintained favorable CVH. Meanwhile, 15.0% showed improvement, and 10.3% experienced a decline in CVH. Those who improved their CVH status had lower CVD event risks (HR=0.69; 95% CI: 0.50 to 0.93), as did those who maintained moderate CVH (HR=0.68; 95% CI: 0.50 to 0.94) or shifted from moderate to low CVH (HR=0.60; 95% CI: 0.41 to 0.88). These results were largely influenced by positive changes in blood pressure, cholesterol levels, physical activity, and smoking. Similar patterns were observed for all-cause mortality. In comparison to participants without diabetes who maintained a favorable CVH trajectory at midlife, those with diabetes consistently displayed higher risks of CVD events and mortality, regardless of their CVH trajectory (Figure 1). However, individuals with diabetes who maintained a favorable CVH trajectory at midlife had CVD event and mortality risks similar to those without diabetes who had consistently low CVH. Conclusions: For individuals with diabetes at midlife, achieving or maintaining ideal CVH levels through lifestyle factors may help reduce excess CVD events and mortality risk. Nonetheless, CVD risk in diabetes is not completely mitigated by favorable cardiovascular risk factor trajectories.

Abstract P316: Orthostatic Hypertension, Standing Hypertension, and Risk of Cardiovascular Disease

Background: There is substantial controversy over how to define orthostatic hypertension (OHTN), an increase in blood pressure (BP) after standing. Recent consensus statements combine both orthostatic and standing hypertension. This could be problematic if their individual associations with cardiovascular disease (CVD) differed as one phenotype would subsume the risk attributes of the other. Objectives: To compare the association between OHTN or standing HTN with CVD. Methods: The Atherosclerosis Risk in Communities Study measured supine and standing BP during visit 1 (1987-1989). OHTN was defined as a rise in SBP ≥20 mm Hg or DBP ≥10 mm Hg (standing minus supine BP). We also examined a new consensus statement definition of a rise of ≥20 mm Hg in SBP (systolic OHTN) and standing SBP of ≥140 mm Hg. We excluded participants with a history of CVD. We determined risk associations with incident CHD, heart failure, stroke, fatal CHD, and all-cause mortality using Cox models adjusted for CVD risk factors (see Table footnote). Results: Of 11,369 participants (56% female, 25% Black adults, mean age 54 years), 10% had OHTN, 20% had standing systolic HTN, and 1% had systolic OHTN with standing SBP ≥140 mm Hg. Over a range of 25-28 years of follow-up, OHTN was not significantly associated with any of the outcomes, while standing systolic HTN was significantly associated with all outcomes. In joint models comparing systolic OHTN and standing HTN, standing HTN was significantly associated with CVD and associations differed significantly from systolic OHTN (Table). Conclusions: Unlike OHTN, standing HTN was strongly associated with CVD and death. These differences in CVD risk raise important concerns about combining OHTN and standing HTN in a consensus definition.

Abstract P144: 1,5-Anhydroglucitol as a Marker of Hyperglycemic Excursions Defined by Continuous Glucose Monitoring in Older Adults

Background: Low levels (≤6 μg/mL) of serum 1,5-anhydroglucitol (1,5-AG) are thought to reflect periods of hyperglycemia. During periods of hyperglycemia, 1,5-AG competes with glucose for reabsorption in the kidney and is excreted in the urine, resulting in low serum concentrations of 1,5-AG. However, the performance of 1,5-AG to identify hyperglycemic excursions detected by continuous glucose monitoring (CGM) is unknown. Methods: We conducted a cross-sectional analysis of participants with diabetes in the Atherosclerosis Risk in Communities Study who wore a CGM sensor in 2021-2022 for up to 2 weeks. We evaluated the performance of 1,5-AG, modeled continuously and dichotomously (≤6 μg/mL, >6 μg/mL), to identify CGM derived metrics of hyperglycemia. Hyperglycemic excursions were defined as percent time spent with CGM glucose above 140 mg/dL, area under the curve (AUC) >140 mg/dL*minute, peak (maximum) CGM glucose, and the coefficient of variation (CV). Results: Among 322 participants with diabetes (mean age 83, 55% female), 22% had 1,5-AG≤6 μg/mL. The median CGM wear time was 13.9 days. The mean CGM glucose was 125 mg/dL (SD, 28) among those with 1,5-AG>6 μg/mL and 156 mg/dL (SD, 45) among those with 1,5-AG≤6 μg/mL. 1,5-AG was inversely associated with percent of time CGM glucose >140 mg/dL ( Figure ), AUC >140 mg/dL (Pearson correlation, r =-0.25), peak CGM glucose ( r =-0.41) and CV ( r =-0.25). Individuals with 1,5-AG≤6 μg/mL spent 5.5 hours more per day above 140 mg/dL compared to those with 1,5-AG>6 μg/mL. Conclusion: 1,5-AG is correlated with CGM-defined hyperglycemia. Low levels of 1,5-AG identify older adults with diabetes experiencing glycemic excursions.

Abstract 29: Effects of a Novel Structural Variant in Hemoglobin on Racial Differences in Hemoglobin A1c

Background: Studies have found higher hemoglobin A1c (HbA1c) at similar levels of glucose for adults who self-identify as Black vs. White, but the mechanism for this difference is poorly understood. Genetic variants that are more common in persons of African descent that affect hemoglobin (Hb) or red cell turnover may explain some of this difference. A recently discovered deletion in a non-coding region of the HBA2 gene is common in persons of African descent and may contribute to differences in Hb and HbA1c. Methods: We evaluated 5178 participants (mean age 56 years, 18% Black, 55% female) who attended Visit 2 (1990-1992) of the Atherosclerosis Risk in Communities Study without diagnosed diabetes and BMI <30 kg/m 2 . We compared the distributions of Hb and HbA1c in Black and White participants by the number of deletions in the HBA2 region (zero, one, or two). We used linear regression to evaluate the extent to which this genetic variant explained glucose-independent Black-White differences in HbA1c and Hb. Results: Deletions in the HBA2 region were common in Black participants (30% one, 4% two) but rare in White participants (1%: one, 0%: two). Mean Hb was lower in Black participants with one (-0.38 g/dL, p<0.001) and two deletions (-0.76 g/dL, p=0.002) and HbA1c was higher (one: +0.11%, p<0.001; two deletions: +0.13%, p=0.11) ( Figure ). Results were similar in White participants with one deletion (N=38), but non-significant. In a regression model adjusted for age, sex, fasting glucose, and BMI, the differences in HbA1c and Hb comparing Blacks vs White adults were +0.2% and -0.6 g/dL, respectively. Additional adjustment for HBA2 deletions explained 16% of the difference in HbA1c and 19% of the difference in Hb. Conclusions: A variation in the non-coding region of the HBA2 gene common in those with African ancestry results in significantly lower Hb and significantly higher HbA1c, partially explaining the small observed racial differences in HbA1c. Other undiscovered variants could more fully explain observed racial differences in HbA1c.

Galectin-3, Metabolic Risk, and Incident Heart Failure: The ARIC Study.

It is unclear how metabolic syndrome (MetS) and diabetes affect Gal-3 (galectin 3) levels and the resulting implications for heart failure (HF) risk. We assessed relationships of MetS and diabetes with Gal-3, and their joint associations with incident HF. We included 8445 participants without HF (mean age, 63 years; 59% men; 16% Black race) at ARIC (Atherosclerosis Risk in Communities) study visit 4 (1996-1999). We categorized participants as having MetS only, MetS with diabetes, or neither, and by quartiles of MetS severity Z score. We assessed cross-sectional associations of metabolic risk categories with high Gal-3 level (≥75th percentile) using logistic regression. We used Cox regression to evaluate combined associations of metabolic risk categories and Gal-3 quartiles with HF. In cross-sectional analyses, compared with no MetS and no diabetes, MetS only (odds ratio [OR], 1.24 [95% CI, 1.10-1.41]) and MetS with diabetes (OR, 1.59 [95% CI, 1.32-1.92]) were associated with elevated Gal-3. Over a median follow-up of 20.5 years, there were 1749 HF events. Compared with individuals with neither diabetes nor MetS and with Gal-3 in the lowest quartile, the combination of MetS with diabetes and Gal-3 ≥75th percentile was associated with a 4-fold higher HF risk (hazard ratio, 4.35 [95% CI, 3.30-5.73]). Gal-3 provided HF prognostic information above and beyond MetS, NT-proBNP (N-terminal pro-B-type natriuretic peptide), high-sensitivity cardiac troponin T, and CRP (C-reactive protein) (ΔC statistic for models with versus without Gal-3: 0.003; P=0.004). MetS and diabetes are associated with elevated Gal-3. The HF risk significantly increased with the combination of greater metabolic risk and higher Gal-3.

Ankle-Brachial Index and Risk of Sudden Cardiac Death in the Community: The ARIC Study.

Sudden cardiac death (SCD) is a significant global public health problem accounting for 15% to 20% of all deaths. A great majority of SCD is associated with coronary heart disease, which may first be detected at autopsy. The ankle-brachial index (ABI) is a simple, noninvasive measure of subclinical atherosclerosis. The purpose of this study was to examine the relationship between ABI and SCD in a middle-aged biracial general population. Participants of the ARIC (Atherosclerosis Risk in Communities) study with an ABI measurement between 1987 and 1989 were included. ABI was categorized as low (≤0.90), borderline (0.90-1.00), normal (1.00-1.40), and noncompressible (>1.40). SCD was defined as a sudden pulseless condition presumed to be caused by a ventricular tachyarrhythmia in a previously stable individual and was adjudicated by a committee of cardiac electrophysiologists, cardiologists, and internists. Cox proportional hazards models were used to evaluate the associations between baseline ABI and incident SCD. Of the 15 081 participants followed for a median of 23.5 years, 556 (3.7%) developed SCD (1.96 cases per 1000 person-years). Low and borderline ABIs were associated with an increased risk of SCD (demographically adjusted hazard ratios [HRs], 2.27 [95% CI, 1.64-3.14] and 1.52 [95% CI, 1.17-1.96], respectively) compared with normal ABI. The association between low ABI and SCD remained significant after adjustment for traditional cardiovascular risk factors (HR, 1.63 [95% CI, 1.15-2.32]). Low ABI is independently associated with an increased risk of SCD in a middle-aged biracial general population. ABI could be incorporated into future SCD risk prediction models.

Posttraumatic Epilepsy and Dementia Risk

Although both head injury and epilepsy are associated with long-term dementia risk, posttraumatic epilepsy (PTE) has only been evaluated in association with short-term cognitive outcomes. To investigate associations of PTE with dementia risk. The Atherosclerosis Risk in Communities (ARIC) study initially enrolled participants from 1987 to 1989 and this prospective cohort study uses data through December 31, 2019, with a median follow-up of 25 years. Data were analyzed between March 14, 2023, and January 2, 2024. The study took place in 4 US communities in Minnesota, Maryland, North Carolina, and Mississippi. Of 15 792 ARIC study participants initially enrolled, 2061 were ineligible and 1173 were excluded for missing data, resulting in 12 558 included participants. Head injury was defined by self-report and International Classification of Diseases (ICD) diagnostic codes. Seizure/epilepsy was defined using ICD codes. PTE was defined as a diagnosis of seizure/epilepsy occurring more than 7 days after head injury. Head injury, seizure/epilepsy, and PTE were analyzed as time-varying exposures. Dementia was defined using cognitive assessments, informant interviews, and ICD and death certificate codes. Adjusted Cox and Fine and Gray proportional hazards models were used to estimate dementia risk. Participants had a mean (SD) age of 54.3 (5.8) years at baseline, 57.7% were female, 28.2% were of self-reported Black race, 14.4% were ultimately categorized as having head injury, 5.1% as having seizure/epilepsy, and 1.2% as having PTE. Over a median follow-up of 25 (25th to 75th percentile, 17-30) years, 19.9% developed dementia. In fully adjusted models, compared with no head injury and no seizure/epilepsy, PTE was associated with 4.56 (95% CI, 4.49-5.95) times the risk of dementia, while seizure/epilepsy was associated with 2.61 (95% CI, 2.21-3.07) times the risk and head injury with 1.63 (95% CI, 1.47-1.80) times the risk. The risk of dementia associated with PTE was significantly higher than the risk associated with head injury alone and with nontraumatic seizure/epilepsy alone. Results were slightly attenuated in models accounting for the competing risks of mortality and stroke, but patterns of association remained similar. In secondary analyses, the increased dementia risk associated with PTE occurring after first vs second head injury and after mild vs moderate/severe injury was similar. In this community-based cohort, there was an increased risk of dementia associated with PTE that was significantly higher than the risk associated with head injury or seizure/epilepsy alone. These findings provide evidence that PTE is associated with long-term outcomes and supports both the prevention of head injuries via public health measures and further research into the underlying mechanisms and the risk factors for the development of PTE, so that efforts can also be focused on the prevention of PTE after a head injury.

Serum Metabolomic Markers of Protein-Rich Foods and Incident CKD: Results From the Atherosclerosis Risk in Communities Study

Rationale & ObjectiveWhile urine excretion of nitrogen estimates total protein intake, biomarkers of specific dietary protein sources have been sparsely studied. Using untargeted metabolomics, this study aimed to identify serum metabolomic markers of six protein-rich foods and to examine whether dietary protein-related metabolites are associated with incident chronic kidney disease (CKD). Study DesignProspective cohort study. Setting & Participants3,726 participants from the Atherosclerosis Risk in Communities (ARIC) study without CKD at baseline. ExposureDietary intake of six protein-rich foods (fish, nuts, legumes, red and processed meat, eggs, poultry), serum metabolites. OutcomesIncident CKD [eGFR <60 mL/min/1.73 m2 with ≥25% eGFR decline relative to visit 1, hospitalization or death related to CKD, or end-stage kidney disease. Analytical ApproachMultivariable linear regression models estimated cross-sectional associations between protein-rich foods and serum metabolites. C-statistics assessed the metabolites’ ability to improve discrimination of highest versus lower three quartiles of intake of protein-rich foods beyond covariates (demographics, clinical factors, health behaviors, and intake of nonprotein food groups). Cox regression models identified prospective associations between protein-related metabolites and incident chronic kidney disease (CKD). ResultsThirty significant associations were identified between protein-rich foods and serum metabolites (fish, n=8; nuts, n=5; legumes, n=0; red and processed meat, n=5; eggs, n=3; poultry, n=9). Metabolites collectively significantly improved discrimination of high intake of protein-rich foods compared to covariates alone (difference in C-statistics=0.033, 0.051, 0.003, 0.024, and 0.025 for fish, nuts, red and processed meat, eggs, and poultry-related metabolites, respectively; p<1.00 x 10-16 for all). Dietary intake of fish was positively associated with 1-docosahexaenoylglycerophosphocholine (22:6n3), which was inversely associated with incident CKD (HR 0.82, 95% CI 0.75-0.89, p=7.81×10-6). LimitationsResidual confounding and sample storage duration. ConclusionsWe identified candidate biomarkers of fish, nuts, red and processed meat, eggs, and poultry. A fish-related metabolite, 1-docosahexaenoylglycerophosphocholine (22:6n3), was associated with lower risk of CKD.

A Deep Patient-Similarity Learning Framework for the Assessment of Diastolic Dysfunction in Elderly Patients.

Age-related changes in cardiac structure and function are well recognized and make the clinical determination of abnormal LV diastolic function (LVDD) particularly challenging in the elderly. We investigated whether a deep neural network (DeepNN) model[70] of LVDD, previously validated in a younger cohort, can be implemented in an older population to predict incident heart failure (HF). A previously developed DeepNN was tested on 5,596 older participants (66-90 years; 57% female; 20% black) from the Atherosclerosis Risk in Communities study. The association of DeepNN predictions with HF or all-cause death for the American College of Cardiology Foundation/American Heart Association Stage A/B (n = 4,054) and Stage C/D (n = 1,542) subgroups was assessed. The DeepNN-predicted High-Risk compared to the Low-Risk phenogroup demonstrated an increased incidence of HF and death for both Stage A/B and Stage C/D (log-rank p < 0.0001 for all). In multivariable analyses, the High-Risk phenogroup remained an independent predictor of HF and death in both Stages A/B (adjusted hazard ratio (HR) [95% confidence interval], 6.52[4.20-10.13] and 2.21(1.68-2.91), both p < 0.0001) and Stage C/D (6.51[4.06-10.44] and 1.03(1.00-1.06), both p < 0.0001) respectively. In addition, DeepNN showed incremental value over the 2016 ASE/EACVI guidelines (Net reclassification index, 0.5[CI:0.4-0.6], p < 0.001; C-statistic improvement, DeepNN [0.76] vs. ASE/EACVI [0.70], p < 0.001) overall and maintained across stage-groups. Despite training with a younger cohort, a deep patient-similarity-based learning framework for assessing LVDD provides a robust prediction of all-cause death and incident HF for older patients.

Abstract 72: Association Between Stroke Subtype and Post-Stroke Cognitive Decline: A Pooled Cohort Analysis of Four Cohorts

Introduction: Associations between stroke subtype and post-stroke cognitive decline are unclear. We determined if post-stroke cognitive trajectories differed between 1) hemorrhagic vs. ischemic stroke and 2) ischemic stroke subtypes. Methods: We identified 1,150 eligible dementia-free individuals with incident stroke (93% ischemic, 7% hemorrhagic, 50% women, 31% Black, median age, 65) from 4 cohort studies from 1971-2019: Atherosclerosis Risk in Communities Study, Cardiovascular Health Study, Framingham Offspring Study, and Reasons for Geographic and Racial Differences in Stroke. Of the ischemic strokes, 22% were small-vessel occlusion, 8% large artery atherosclerosis, 21% cardioembolic, and 49% cryptogenic/other determined etiology. Linear mixed-effects models were used to estimate longitudinal changes in cognition after incident stroke. Global cognition (primary outcome), executive function, and memory were harmonized across studies and standardized as T-scores (mean [SD], 50 [10]); a 1-point difference represents a 0.1-SD difference in cognition. Median (IQR) follow-up was 5.9 (3.2, 9.2) years. Results: Survivors of ischemic stroke had significant declines in global cognition, executive function, and memory (Table). For example, global cognition declined -0.35 points/year (95%CI, -0.43, -0.26); P &lt;0.001. Initial post-stroke cognitive scores and post-stroke cognitive trajectories did not differ between hemorrhagic and ischemic stroke, except for lower initial post-stroke memory scores (adjusted difference, -1.39 points; 95% CI, -2.77, -0.01; P =0.049). Survivors of small-vessel occlusions had significant declines in global cognition, executive function, and memory (Table). Initial post-stroke cognitive scores and post-stroke cognitive trajectories did not differ by ischemic stroke subtype. Conclusions: Our results suggest that stroke survivors experience long-term post-stroke cognitive decline regardless of subtype.

Familial Hypercholesterolemia Variant and Cardiovascular Risk in Individuals With Elevated Cholesterol

Familial hypercholesterolemia (FH) is a genetic disorder that often results in severely high low-density lipoprotein cholesterol (LDL-C) and high risk of premature coronary heart disease (CHD). However, the impact of FH variants on CHD risk among individuals with moderately elevated LDL-C is not well quantified. To assess CHD risk associated with FH variants among individuals with moderately (130-189 mg/dL) and severely (≥190 mg/dL) elevated LDL-C and to quantify excess CHD deaths attributable to FH variants in US adults. A total of 21 426 individuals without preexisting CHD from 6 US cohort studies (Atherosclerosis Risk in Communities study, Coronary Artery Risk Development in Young Adults study, Cardiovascular Health Study, Framingham Heart Study Offspring cohort, Jackson Heart Study, and Multi-Ethnic Study of Atherosclerosis) were included, 63 of whom had an FH variant. Data were collected from 1971 to 2018, and the median (IQR) follow-up was 18 (13-28) years. Data were analyzed from March to May 2023. LDL-C, cumulative past LDL-C, FH variant status. Cox proportional hazards models estimated associations between FH variants and incident CHD. The Cardiovascular Disease Policy Model projected excess CHD deaths associated with FH variants in US adults. Of the 21 426 individuals without preexisting CHD (mean [SD] age 52.1 [15.5] years; 12 041 [56.2%] female), an FH variant was found in 22 individuals with moderately elevated LDL-C (0.3%) and in 33 individuals with severely elevated LDL-C (2.5%). The adjusted hazard ratios for incident CHD comparing those with and without FH variants were 2.9 (95% CI, 1.4-6.0) and 2.6 (95% CI, 1.4-4.9) among individuals with moderately and severely elevated LDL-C, respectively. The association between FH variants and CHD was slightly attenuated when further adjusting for baseline LDL-C level, whereas the association was no longer statistically significant after adjusting for cumulative past LDL-C exposure. Among US adults 20 years and older with no history of CHD and LDL-C 130 mg/dL or higher, more than 417 000 carry an FH variant and were projected to experience more than 12 000 excess CHD deaths in those with moderately elevated LDL-C and 15 000 in those with severely elevated LDL-C compared with individuals without an FH variant. In this pooled cohort study, the presence of FH variants was associated with a 2-fold higher CHD risk, even when LDL-C was only moderately elevated. The increased CHD risk appeared to be largely explained by the higher cumulative LDL-C exposure in individuals with an FH variant compared to those without. Further research is needed to assess the value of adding genetic testing to traditional phenotypic FH screening.

Associations Between Prior Head Injury, Physical Functioning, and Frailty in the Atherosclerosis Risk in Communities Study.

Older adults have the highest rates of head injury and are at the greatest risk for subsequent dysfunction, yet research on subsequent physical decline is limited. We sought to examine cross-sectional and prospective associations of head injury with physical functioning and frailty among older adults. A total of 5598 Atherosclerosis Risk in Communities Study participants from Visit 5 (2011-13) underwent assessments of physical functioning (Short Physical Performance Battery [SPPB], comprised of gait speed, chair stands, and balance) and frailty (defined using established criteria) were followed through Visit 7 (2018-19). Head injury was self-reported or based on ICD-9 codes. Adjusted linear and multinomial logistic regression models were used to estimate associations. Prospective models incorporated inverse probability of attrition weights to account for death or attrition. Participants were a mean age of 75 years, 58% were women, 22% were Black, and 27% had a prior head injury. Compared to individuals without head injury, individuals with head injury had worse physical functioning (SPPB total score, β-coefficient = -0.22, 95% CI: -0.35 to -0.09) and were more likely to be pre-frail (OR = 1.19, 95% CI: 1.04 to 1.35) or frail (OR = 1.40, 95% CI: 1.08 to 1.80) compared to robust. Prospectively, head injury was associated with a 0.02 m/s greater decline (95% CI: -0.04 to -0.01) in gait speed over a median of 5 years. Among baseline robust individuals (n = 1847), head injury was associated with increased odds of becoming pre-frail (OR = 1.32, 95% CI: 1.04 to 1.67) or frail (OR = 1.92, 95% CI: 1.05 to 3.51) compared to robust. Older adults with prior head injury had worse physical functioning and greater frailty at baseline and were more likely to become frail and walk slower over time, compared to individuals without head injury.

Plasma protein signatures of adult asthma.

Adult asthma is complex and incompletely understood. Plasma proteomics is an evolving technique that can both generate biomarkers and provide insights into disease mechanisms. We aimed to identify plasma proteomic signatures of adult asthma. Protein abundance in plasma was measured in individuals from the Agricultural Lung Health Study (ALHS) (761 asthma, 1095 non-case) and the Atherosclerosis Risk in Communities study (470 asthma, 10,669 non-case) using the SOMAScan 5K array. Associations with asthma were estimated using covariate adjusted logistic regression and meta-analyzed using inverse-variance weighting. Additionally, in ALHS, we examined phenotypes based on both asthma and seroatopy (asthma with atopy (n = 207), asthma without atopy (n = 554), atopy without asthma (n = 147), compared to neither (n = 948)). Meta-analysis of 4860 proteins identified 115 significantly (FDR<0.05) associated with asthma. Multiple signaling pathways related to airway inflammation and pulmonary injury were enriched (FDR<0.05) among these proteins. A proteomic score generated using machine learning provided predictive value for asthma (AUC = 0.77, 95% CI = 0.75-0.79 in training set; AUC = 0.72, 95% CI = 0.69-0.75 in validation set). Twenty proteins are targeted by approved or investigational drugs for asthma or other conditions, suggesting potential drug repurposing. The combined asthma-atopy phenotype showed significant associations with 20 proteins, including five not identified in the overall asthma analysis. This first large-scale proteomics study identified over 100 plasma proteins associated with current asthma in adults. In addition to validating previous associations, we identified many novel proteins that could inform development of diagnostic biomarkers and therapeutic targets in asthma management.

A polygenic risk score of atrial fibrillation improves prediction of lifetime risk for heart failure.

Heart failure (HF) has shared genetic architecture with its risk factors: atrial fibrillation (AF), body mass index (BMI), coronary heart disease (CHD), systolic blood pressure (SBP), and type 2 diabetes (T2D). We aim to assess the association and risk prediction performance of risk-factor polygenic risk scores (PRSs) for incident HF and its subtypes in bi-racial populations. Five PRSs were constructed for AF, BMI, CHD, SBP, and T2D in White participants of the Atherosclerosis Risk in Communities (ARIC) study. The associations between PRSs and incident HF and its subtypes were assessed using Cox models, and the risk prediction performance of PRSs was assessed using C statistics. Replication was performed in the ARIC study Black and Cardiovascular Health Study (CHS) White participants. In 8624 ARIC study Whites, 1922 (31% cumulative incidence) HF cases developed over 30years of follow-up. PRSs of AF, BMI, and CHD were associated with incident HF (P<0.001), where PRSAF showed the strongest association [hazard ratio (HR): 1.47, 95% confidence interval (CI): 1.41-1.53]. Only the addition of PRSAF to the ARIC study HF risk equation improved C statistics for 10year risk prediction from 0.812 to 0.829 (∆C: 0.017, 95% CI: 0.009-0.026). The PRSAF was associated with both incident HF with reduced ejection fraction (HR: 1.43, 95% CI: 1.27-1.60) and incident HF with preserved ejection fraction (HR: 1.46, 95% CI: 1.33-1.62). The associations between PRSAF and incident HF and its subtypes, as well as the improved risk prediction, were replicated in the ARIC study Blacks and the CHS Whites (P<0.050). Protein analyses revealed that N-terminal pro-brain natriuretic peptide and other 98 proteins were associated with PRSAF. The PRSAF was associated with incident HF and its subtypes and had significant incremental value over an established HF risk prediction equation.

Identification of Fatigue Subtypes and Their Correlates in Prevalent Heart Failure: A Secondary Analysis of the Atherosclerosis Risk in Communities Study.

Among patients with heart failure (HF), fatigue is common and linked to quality of life and functional status. Fatigue is hypothesized to manifest as multiple types, with general and exertional components. Unique subtypes of fatigue in HF may require differential assessment and treatment to improve outcomes. We conducted this study to identify fatigue subtypes in persons with prevalent HF in the ARIC study (Atherosclerosis Risk in Communities) and describe the distribution of characteristics across subtypes. We performed a cross-sectional analysis of 1065 participants with prevalent HF at ARIC visit 5 (2011-2013). We measured exertional fatigue using the Modified Medical Research Council Breathlessness scale and general fatigue using the Patient Reported Outcomes Measurement Information System fatigue scale. We used latent class analysis to identify subtypes of fatigue. Number of classes was determined using model fit statistics, and classes were interpreted and assigned fatigue severity rating based on the conditional probability of endorsing survey items given class. We compared characteristics across classes using multinomial regression. Overall, participants were 54% female and 38% Black with a mean age of 77. We identified 4 latent classes (fatigue subtypes): (1) high general/high exertional fatigue (18%), (2) high general/low exertional fatigue (27%), (3) moderate general/moderate exertional fatigue (20%), and (4) low/no general and exertional fatigue (35%). Female sex, Black race, lower education level, higher body mass index, increased depressive symptoms, and higher prevalence of diabetes were associated with higher levels of general and exertional fatigue. We identified unique subtypes of fatigue in patients with HF who have not been previously described. Within subtype, general and exertional fatigue were mostly concordant in severity, and exertional fatigue only occurred in conjunction with general fatigue, not alone. Further understanding these fatigue types and their relationships to outcomes may enhance our understanding of the symptom experience and inform prognostication and secondary prevention efforts for persons with HF.

Association of Segment-Specific Pulse Wave Velocity With Vascular Calcification: The ARIC (Atherosclerosis Risk in Communities) Study.

Pulse wave velocity (PWV) is a noninvasive measure of arterial stiffness and predictor of cardiovascular disease. However, the association between PWV and vascular calcification across different vascular beds has not been fully investigated. This study aimed to quantify the association between PWV and multiterritory calcification and to explore whether PWV can identify individuals with vascular calcification beyond traditional risk factors. Among 1351 older adults (mean age, 79.2 years [SD, 4.1]) from the ARIC (Atherosclerosis Risk in Communities) study, we measured segment-specific PWVs: heart-carotid, heart-femoral, carotid-femoral, heart-ankle, brachial-ankle, and femoral-ankle. Dependent variables were high calcium score (≥75th percentile of Agatston score) across different vascular beds: coronary arteries, aortic valve ring, aortic valve, mitral valve, ascending aorta, and descending aorta. Quartiles of carotid-femoral, heart-femoral, heart-ankle, and brachial-ankle PWV were significantly associated with coronary artery calcium (eg, adjusted odds ratio [OR] for the highest versus lowest quartile of carotid-femoral PWV, 1.84 [95% CI, 1.24-2.74]). Overall, PWVs were most strongly associated with descending aorta calcification, with significant results for carotid-femoral, heart-femoral, heart-ankle, and brachial-ankle PWV (eg, adjusted OR for the highest versus lowest quartile of carotid-femoral PWV, 3.99 [95% CI, 2.61-6.17]). In contrast, femoral-ankle PWV was inversely associated with descending aorta calcification. Some PWVs improved the discrimination of coronary artery calcium and descending aorta calcification beyond traditional risk factors. The associations of PWV with vascular calcification varied substantially across segments, with descending aorta calcification most closely linked to PWVs. Our study suggests that some PWVs, especially carotid-femoral PWV, are helpful to identify individuals with coronary artery calcium and descending aorta calcification.

Potential disease biomarkers for diabetic retinopathy identified through Mendelian randomization analysis.

Diabetic retinopathy (DR), a leading cause of vision loss, has limited options for effective prevention and treatment. This study aims to utilize genomics and proteomics data to identify potential drug targets for DR. We utilized plasma protein quantitative trait loci data from the Atherosclerosis Risk in Communities Study and the Icelandic Decoding Genetics Study for discovery and replication, respectively. Genetic associations with DR, including its subtypes, were derived from the FinnGen study. Mendelian Randomization (MR) analysis estimated associations between protein levels and DR risk, complemented by colocalization analysis to examine shared causal variants. Our MR analysis identified significant associations of specific plasma proteins with DR and proliferative DR (PDR). Elevated genetically predicted levels of WARS (OR = 1.16; 95% CI = 0.095-0.208, FDR = 1.31×10-4) and SIRPG (OR = 1.15; 95% CI = 0.071-0.201, FDR = 1.46×10-2) were associated with higher DR risk, while increased levels of ALDOC (OR = 1.56; 95% CI = 0.246-0.637, FDR = 5.48×10-3) and SIRPG (OR = 1.15; 95% CI = 0.068-0.208, FDR = 4.73×10-2) were associated with higher PDR risk. These findings were corroborated by strong colocalization evidence. Our study highlights WARS, SIRPG, and ALDOC as significant proteins associated with DR and PDR, providing a basis for further exploration in drug development. Additional studies are needed to validate these proteins as disease biomarkers across diverse populations.

Plasma Ferritin Levels, Incident Heart Failure, and Cardiac Structure and Function: The ARIC Study

BackgroundWhether iron deficiency contributes to incident heart failure (HF) and cardiac dysfunction has important implications given the prevalence of iron deficiency and the availability of several therapeutics for iron repletion. ObjectivesThe aim of this study was to estimate the associations of plasma ferritin level with incident HF overall, HF phenotypes, and cardiac structure and function measures in older adults. MethodsParticipants in the ongoing, longitudinal ARIC (Atherosclerosis Risk In Communities) study who were free of prevalent HF and anemia were studied. The associations of plasma ferritin levels with incident HF overall and heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF) were estimated using Cox proportional hazards regression models. Linear regression models estimated the cross-sectional associations of plasma ferritin with echocardiographic measures of cardiac structure and function. ResultsThe cohort included 3,472 individuals with a mean age of 75 ± 5 years (56% women, 14% Black individuals). In fully adjusted models, lower ferritin was associated with higher risk for incident HF overall (HR: 1.20 [95% CI: 1.08-1.34] per 50% lower ferritin level) and higher risk for incident HFpEF (HR: 1.28 [95% CI: 1.09-1.50]). Associations with incident HFrEF were not statistically significant. Lower ferritin levels were associated with higher E/e′ ratio and higher pulmonary artery systolic pressure after adjustment for demographics and HF risk factors but not with measures of left ventricular structure or systolic function. ConclusionsAmong older adults without prevalent HF or anemia, lower plasma ferritin level is associated with a higher risk for incident HF, HFpEF, and higher measures of left ventricular filling pressure.

Obstructive sleep apnea, nocturnal hypoxemia, and retinal microvasculature: The Atherosclerosis Risk in Communities Study.

Retinal microvascular pathology (RMP) and obstructive sleep apnea (OSA) are both cardiovascular disease risk factors. Limited data exists on their interrelationship. We tested the hypotheses that OSA and nocturnal hypoxemia would be associated with RMP and vessel calibers. We conducted a quasi-cross-sectional analysis of 1625 participants in the Atherosclerosis Risk in Communities Sleep Heart Health Study. Participants completed in-home polysomnography monitoring (1996-1998) and were categorized by OSA severity (apnea-hypopnea index: <5, 5-14.9, and ≥15) and proportion of total sleep time with oxygen saturation < 90% (T90). Retinal photography (1993-1995) was used to assess RMP and measure vascular diameters (central retinal arteriolar equivalent [CRAE] and central retinal venular equivalent [CRVE]). Logistic and linear models were adjusted for demographics, behaviors, and BMI. Of the participants, 19% had OSA (AHI > 15) and 4% had RMP. Severe OSA was not associated with RMP [OR (95% CI): 1.08 (0.49 to 2.38)] or CRAE in adjusted models. OSA severity showed a positive linear relationship with CRVE; adjusted mean CRVE for those with OSA was 195.8 μm compared to 193.2 μm for those without OSA (Ptrend = 0.03). T90 was strongly associated with CRVE, but not with RMP or CRAE. Adjusted mean CRVE for T90 ≥ 5% was 199.0 and 192.9 for T90 < 1% (ptrend < 0.0001). OSA and T90 were not associated with RMP or CRAE. However, both OSA and T90 ≥ 5% were associated with wider venules, which may be early and indicative changes of increased inflammation and future risk of stroke and CHD.

Association between structural brain MRI abnormalities and epilepsy in older adults.

To determine the association between brain MRI abnormalities and incident epilepsy in older adults. Men and women (ages 45-64 years) from the Atherosclerosis Risk in Communities study were followed up from 1987 to 2018 with brain MRI performed between 2011 and 2013. We identified cases of incident late-onset epilepsy (LOE) with onset of seizures occurring after the acquisition of brain MRI. We evaluated the relative pattern of cortical thickness, subcortical volume, and white matter integrity among participants with incident LOE after MRI in comparison with participants without seizures. We examined the association between MRI abnormalities and incident LOE using Cox proportional hazards regression. Models were adjusted for demographics, hypertension, diabetes, smoking, stroke, and dementia status. Among 1251 participants with brain MRI data, 27 (2.2%) developed LOE after MRI over a median of 6.4 years (25-75 percentile 5.8-6.9) of follow-up. Participants with incident LOE after MRI had higher levels of cortical thinning and white matter microstructural abnormalities before seizure onset compared to those without seizures. In longitudinal analyses, greater number of abnormalities was associated with incident LOE after controlling for demographic factors, risk factors for cardiovascular disease, stroke, and dementia (gray matter: hazard ratio [HR]: 2.3, 95% confidence interval [CI]: 1.0-4.9; white matter diffusivity: HR: 3.0, 95% CI: 1.2-7.3). This study demonstrates considerable gray and white matter pathology among individuals with LOE, which is present prior to the onset of seizures and provides important insights into the role of neurodegeneration, both of gray and white matter, and the risk of LOE.