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Introduction: Cigarette smoking leads to altered DNA methylation at the aryl-hydrocarbon receptor repressor (AHRR) gene. However, it remains unknown whether pipe or cigar smoking is associated with AHRR methylation. We evaluated associations of non-cigarette tobacco use with AHRR methylation and determined if AHRR methylation was associated with smoking-related health outcomes., Methods: Data were pooled across four population-based cohorts that enrolled participants from 1985 to 2002. Tobacco exposures were evaluated using smoking questionnaires. AHRR cg05575921 methylation was measured in peripheral blood leucocyte DNA. Spirometry and respiratory symptoms were evaluated at the time of methylation measurements and in subsequent visits. Vital status was monitored using the National Death Index., Results: Among 8252 adults (mean age 56.7±10.3 years, 58.1% women, 40.6% black), 4857 (58.9%) participants used cigarettes and 634 (7.7%) used non-cigarette tobacco products. Exclusive use of non-cigarette tobacco products was independently associated with lower AHRR methylation (-2.44 units, 95% CI -4.42 to -0.45), though to a lesser extent than exclusive use of cigarettes (-6.01 units, 95% CI -6.01 to -4.10). Among participants who exclusively used non-cigarette tobacco products, reduced AHRR methylation was associated with increased respiratory symptom burden (OR 1.60, 95% CI 1.03 to 2.68) and higher all-cause mortality (log-rank p=0.02)., Conclusion: Pipe and cigar smoking were independently associated with lower AHRR methylation in a multiethnic cohort of US adults. Among users of non-cigarette tobacco products, lower AHRR methylation was associated with poor respiratory health outcomes and increased mortality. AHRR methylation may identify non-cigarette tobacco users with an increased risk of adverse smoking-related health outcomes., Competing Interests: Competing interests: SPB has had consultancy agreements with Boehringer Ingelheim, Sanofi/Regeneron and IntegrityCE. He has participated in research with Nuvaira Sanofi for which his institution has been remunerated. RK has had consultancy agreements with CVS Caremark, AstraZeneca, GlaxoSmithKline and Boehringer Ingelheim. He has participated in research with AstraZeneca, PneumRx/BTG and Spiration, for which his institution has been remunerated., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Importance: Plasma biomarkers show promise for identifying Alzheimer disease (AD) neuropathology and neurodegeneration, but additional examination among diverse populations and throughout the life course is needed., Objective: To assess temporal plasma biomarker changes and their association with all-cause dementia, overall and among subgroups of community-dwelling adults., Design, Setting, and Participants: In 1525 participants from the US-based Atherosclerosis Risk in Communities (ARIC) study, plasma biomarkers were measured using stored specimens collected in midlife (1993-1995, mean age 58.3 years) and late life (2011-2013, mean age 76.0 years; followed up to 2016-2019, mean age 80.7 years). Midlife risk factors (hypertension, diabetes, lipids, coronary heart disease, cigarette use, and physical activity) were assessed for their associations with change in plasma biomarkers over time. The associations of biomarkers with incident all-cause dementia were evaluated in a subpopulation (n = 1339) who were dementia-free in 2011-2013 and had biomarker measurements in 1993-1995 and 2011-2013., Exposure: Plasma biomarkers of amyloid-β 42 to amyloid-β 40 (Aβ42:Aβ40) ratio, phosphorylated tau at threonine 181 (p-tau181), neurofilament light (NfL), and glial fibrillary acidic protein (GFAP) were measured using the Quanterix Simoa platform., Main Outcomes and Measures: Incident all-cause dementia was ascertained from January 1, 2012, through December 31, 2019, from neuropsychological assessments, semiannual participant or informant contact, and medical record surveillance., Results: Among 1525 participants (mean age, 58.3 [SD, 5.1] years), 914 participants (59.9%) were women, and 394 participants (25.8%) were Black. A total of 252 participants (16.5%) developed dementia. Decreasing Aβ42:Aβ40 ratio and increasing p-tau181, NfL, and GFAP were observed from midlife to late life, with more rapid biomarker changes among participants carrying the apolipoprotein E epsilon 4 (APOEε4) allele. Midlife hypertension was associated with a 0.15-SD faster NfL increase and a 0.08-SD faster GFAP increase per decade; estimates for midlife diabetes were a 0.11-SD faster for NfL and 0.15-SD faster for GFAP. Only AD-specific biomarkers in midlife demonstrated long-term associations with late-life dementia (hazard ratio per SD lower Aβ42:Aβ40 ratio, 1.11; 95% CI, 1.02-1.21; per SD higher p-tau181, 1.15; 95% CI, 1.06-1.25). All plasma biomarkers in late life had statistically significant associations with late-life dementia, with NfL demonstrating the largest association (1.92; 95% CI, 1.72-2.14)., Conclusions and Relevance: Plasma biomarkers of AD neuropathology, neuronal injury, and astrogliosis increase with age and are associated with known dementia risk factors. AD-specific biomarkers' association with dementia starts in midlife whereas late-life measures of AD, neuronal injury, and astrogliosis biomarkers are all associated with dementia.

Cerebral small vessel disease (SVD), as defined by neuroimaging characteristics such as white matter hyperintensities (WMHs), cerebral microhemorrhages (CMHs), and lacunar infarcts, is highly prevalent and has been associated with dementia risk and other clinical sequelae. Although conditions such as hypertension are known to contribute to SVD, little is known about the diverse set of subclinical biological processes and molecular mediators that may also influence the development and progression of SVD. To better understand the mechanisms underlying SVD and to identify novel SVD biomarkers, we used a large-scale proteomic platform to relate 4,877 plasma proteins to MRI-defined SVD characteristics within 1,508 participants of the Atherosclerosis Risk in Communities (ARIC) Study cohort. Our proteome-wide analysis of older adults (mean age: 76) identified 13 WMH-associated plasma proteins involved in synaptic function, endothelial integrity, and angiogenesis, two of which remained associated with late-life WMH volume when measured nearly 20 years earlier, during midlife. We replicated the relationship between 9 candidate proteins and WMH volume in one or more external cohorts; we found that 11 of the 13 proteins were associated with risk for future dementia; and we leveraged publicly available proteomic data from brain tissue to demonstrate that a subset of WMH-associated proteins was differentially expressed in the context of cerebral atherosclerosis, pathologically-defined Alzheimer's disease, and cognitive decline. Bidirectional two-sample Mendelian randomization analyses examined the causal relationships between candidate proteins and WMH volume, while pathway and network analyses identified discrete biological processes (lipid/cholesterol metabolism, NF-kB signaling, hemostasis) associated with distinct forms of SVD. Finally, we synthesized these findings to identify two plasma proteins, oligodendrocyte myelin glycoprotein (OMG) and neuronal pentraxin receptor (NPTXR), as top candidate biomarkers for elevated WMH volume and its clinical manifestations.

Background: Associations between magnetic resonance imaging markers of cerebral small vessel disease (CSVD) and dementia risk in older adults have been established, but it remains unclear how lifestyle factors, including psychosocial health, may modify this association., Methods: Social support and social isolation were assessed among participants of the community-based ARIC (Atherosclerosis Risk in Communities) Study, via self-reported questionnaires (1990-1992). Following categorization of both factors, participants were classified as having strong or poor mid-life social relationships. At visit 5 (2011-2013), participants underwent 3T brain magnetic resonance imaging quantifying CSVD measures: white matter hyperintensity volume, microbleeds (subcortical), infarcts (lacunar), and white matter integrity (diffusion tensor imaging). Incident dementia cases were identified from the time of imaging through December 31, 2020 with ongoing surveillance. Associations between CSVD magnetic resonance imaging markers and incident dementia were evaluated using Cox proportional-hazard regressions adjusted for demographic and additional risk factors (from visit 2). Effect modification by mid-life social relationships was evaluated., Results: Of the 1977 participants with magnetic resonance imaging, 1617 participants (60.7% women; 26.5% Black participants; mean age at visit 2, 55.4 years) were examined. In this sample, mid-life social relationships significantly modified the association between white matter hyperintensity volume and dementia risk ( P interaction=0.001). Greater white matter hyperintensity volume was significantly associated with risk of dementia in all participants, yet, more substantially in those with poor (hazard ratio, 1.84 [95% CI, 1.49-2.27]) versus strong (hazard ratio, 1.26 [95% CI, 1.08-1.47]) mid-life social relationships. Although not statistically significant, subcortical microbleeds in participants with poor mid-life social relationships were associated with a greater risk of dementia, relative to those with strong social relationships, in whom subcortical microbleeds were no longer associated with elevated dementia risk., Conclusions: The elevated risk of dementia associated with CSVD may be reduced in participants with strong mid-life social relationships. Future studies evaluating psychosocial health through the life course and the mechanisms by which they modify the relationship between CSVD and dementia are needed., Competing Interests: Dr Knopman serves on a Data Safety Monitoring Board for the Dominantly Inherited Alzheimer Network Treatment Unit study. He is an investigator in clinical trials sponsored by Biogen, Lilly Pharmaceuticals, and the University of Southern California. He has served as a consultant for Roche, Samus Therapeutics, Magellan Health, Biovie, and Alzeca Biosciences but receives no personal compensation. He attended an Eisai advisory board meeting for lecanemab on December 2, 2022 but received no compensation directly or indirectly. He receives funding from the NIH and grants from Washington University School of Medicine in St. Louis. Dr Lutsey reports grants from the National Institutes of Health (NIH) to her institution. Dr Mosley is supported by NIH/National Heart, Lung, and Blood Institute (NHLBI) 75N92022D0004 and NIH/NHLBI: U01HL096812. Dr Palta is supported by NIH/NHLBI 75N92022D00005. Dr Walker is supported by the National Institute on Aging’s Intramural Research Program (AG000348-01, AG000349-01). Dr Gottesman served on the American Neurological Association as program chair from 2021 to 2023 and received no personal compensation. The other authors report no conflicts.

Background: Biological age may be estimated by proteomic aging clocks (PACs). Previous published PACs were constructed either in smaller studies or mainly in white individuals, and they used proteomic measures from only one-time point. In this study, we created de novo PACs and compared their performance to published PACs at 2 different time points in the Atherosclerosis Risk in Communities (ARIC) study of white and black participants (around 75% white and 25% black)., Medthods and Findings: A total of 4,712 plasma proteins were measured using SomaScan in blood samples collected in 1990 to 1992 from 11,761 midlife participants (aged 46 to 70 years) and in 2011 to 2013 from 5,183 late-life participants (aged 66 to 90 years). The de novo ARIC PACs were constructed by training them against chronological age using elastic net regression in two-thirds of healthy participants in midlife and late life and validated in the remaining one-third of healthy participants at the corresponding time point. We also computed 3 published PACs. We estimated age acceleration for each PAC as residuals after regressing each PAC on chronological age. We also calculated the change in age acceleration from midlife to late life. We examined the associations of age acceleration and change in age acceleration with mortality through 2019 from all-cause, cardiovascular disease (CVD), cancer, and lower respiratory disease (LRD) using Cox proportional hazards regression in participants (irrespective of health) after excluding the training set. The model was adjusted for chronological age, smoking, body mass index (BMI), and other confounders. We externally validated the midlife PAC using the Multi-Ethnic Study of Atherosclerosis (MESA) Exam 1 data. The ARIC PACs had a slightly stronger correlation with chronological age than published PACs in healthy participants at each time point. Associations with mortality were similar for the ARIC PACs and published PACs. For late-life and midlife age acceleration for the ARIC PACs, respectively, hazard ratios (HRs) per 1 standard deviation were 1.65 and 1.38 (both p < 0.001) for all-cause mortality, 1.37 and 1.20 (both p < 0.001) for CVD mortality, 1.21 (p = 0.028) and 1.04 (p = 0.280) for cancer mortality, and 1.68 and 1.36 (both p < 0.001) for LRD mortality. For the change in age acceleration, HRs for all-cause, CVD, and LRD mortality were comparable to the HRs for late-life age acceleration. The association between the change in age acceleration and cancer mortality was not significant. The external validation of the midlife PAC in MESA showed significant associations with mortality, as observed for midlife participants in ARIC. The main limitation is that our PACs were constructed in midlife and late-life participants. It is unknown whether these PACs could be applied to young individuals., Conclusions: In this longitudinal study, we found that the ARIC PACs and published PACs were similarly associated with an increased risk of mortality. These findings suggested that PACs show promise as biomarkers of biological age. PACs may be serve as tools to predict mortality and evaluate the effect of anti-aging lifestyle and therapeutic interventions., Competing Interests: B.L. is a full-time employee of the biopharmaceutical company Alkahest, Inc. P.L.L’s institute receives grants from NIH., (Copyright: © 2024 Wang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Frailty is common in people with cardiovascular disease. Worse left atrial (LA) function is an independent risk factor for cardiovascular disease. However, whether worse LA function is associated with frailty is unclear., Methods: We included 3292 older adults from the Atherosclerosis Risk in Communities study who were non-frail at baseline (visit 5, 2011-2013) and had LA function (reservoir, conduit, and contractile strain) measured from two-dimensional speckle-tracking echocardiography. LA stiffness index was calculated as a ratio of E/e' to LA reservoir strain. Frailty was defined using the validated Fried frailty phenotype. Incident frailty was assessed between 2016 and 2019 during two follow-up visits. LA function was analyzed as quintiles. Multivariable logistic regression examined odds of incident frailty., Results: Median (interquartile range [IQR]) age was 74 (71-77) years, 58% were female, and 214 (7%) participants developed frailty during a median (IQR) follow-up of 6.3 (5.6-6.8) years. After adjusting for baseline confounders and incident cardiovascular events during follow-up, the odds of developing frailty was 2.42 (1.26-4.66) times greater among participants in the lowest (vs highest) quintile of LA reservoir strain and 2.41 (1.11-5.22) times greater among those in the highest (vs lowest) quintile of LA stiffness index. Worse LA function was significantly associated with the development of exhaustion, but not the other components of the Fried frailty phenotype., Conclusions: Worse LA function is associated with higher incidence of frailty and exhaustion component independent of LA size and left ventricular function. Future studies are needed to elucidate the underlying mechanisms that drive the observed association., (© 2024 The Author(s). Journal of the American Geriatrics Society published by Wiley Periodicals LLC on behalf of The American Geriatrics Society.)

Importance: The prevalence of absolute and functional iron deficiency among adults in the US is unknown., Objective: To estimate the prevalence of absolute and iron deficiency and iron supplement use in the US across age, sex, and comorbidity categories., Design, Setting, and Participants: This cross-sectional study analyzed data from the National Health and Nutritional Examination Survey (NHANES) 2017 to 2020 prepandemic cycle. Participants included noninstitutionalized, civilian women and men aged 18 years or older who had available serum ferritin, iron, and unsaturated iron binding capacity measurements. Data analysis was performed from March 21, 2023, to July 5, 2024., Exposure: Absolute iron deficiency and functional iron deficiency., Main Outcomes and Measures: Absolute iron deficiency was defined as serum ferritin less than 30 ng/mL regardless of transferrin saturation. Functional iron deficiency was defined as serum ferritin greater than or equal to 30 ng/mL with transferrin saturation less than 20%. The prevalence of absolute and functional iron deficiency was estimated among all adults in the US and separately among women and men according to age category (>18 years to <50 years, 50-65 years, and ≥65 years) using recommended sample weights and sampling design factors to provide estimates representative of the national, noninstitutionalized civilian population. The 95% CIs were calculated using the Korn-Graubard method., Results: A total of 8021 US adults (mean age, 48 years; 95% CI, 47-49 years; 52% [95% CI, 50%-53%] female) were included in this analysis. An estimated 14% (95% CI, 13%-15%) of adults in the US met the criteria for absolute iron deficiency, and an estimated 15% (95% CI, 14%-17%) met the criteria for functional iron deficiency. Among US adults without anemia, heart failure, chronic kidney disease, or current pregnancy, the estimated prevalence of absolute iron deficiency was 11% (95% CI, 10%-11%), and that of functional iron deficiency was 15% (95% CI, 14%-17%). The prevalence of functional iron deficiency exceeded that of absolute iron deficiency in all US adults except women younger than 50 years. Iron supplement use ranged from 22% (95% CI, 12%-37%) to 35% (95% CI, 29%-42%) of women with iron deficiency and 12% (95% CI, 5%-21%) to 18% (95% CI, 8%-32%) of men with iron deficiency depending on age., Conclusions and Relevance: These findings suggest that absolute and functional iron deficiency affect a large proportion of American adults even in the absence of anemia, heart failure, or chronic kidney disease. Further research on the role of functional iron deficiency in adverse health outcomes and on iron deficiency screening strategies is needed.

Background: Lower left atrial (LA) function is associated with increased risk for cardiovascular disease events; data on risk factors for impaired LA function are limited. We evaluated the effect of cumulative systolic blood pressure (cSBP) from midlife to older age on LA strain in adults with normal LA size., Methods: We included participants in the Atherosclerosis Risk in Communities study with LA strain measured on the visit 5 echocardiogram (2011-13), excluding those with atrial fibrillation and LA volume index >34 mL/m 2 . The cSBP was calculated from visit 1 (1987-89) through visit 5. Linear regression models were used to evaluate associations between cSBP and LA strain measures., Results: A total of 3,859 participants with a mean (SD) age of 75.2 (5.0) years were included in the analysis; 725 (18.8%) were Black and 2,342 (60.7%) were women. After adjusting for demographics, cardiovascular disease risk factors, heart failure, and coronary heart disease, each 10 mm Hg increase in cSBP was associated with 0.32% (95% CI, -0.52%, -0.13%) and 0.37% (95% CI, -0.51%, -0.22%) absolute reduction in LA reservoir and conduit strain, respectively. Associations were attenuated after adjustment for left ventricular (LV) systolic and diastolic function and mass (-0.12%: 95% CI, -0.31, 0.06 for reservoir strain; and -0.24%: 95% CI -0.38%, -0.10% for conduit strain). In subgroup analyses, the association of cSBP with conduit strain was statistically significant among those with normal LV systolic and diastolic function., Conclusions: Cumulative exposure to elevated blood pressure from midlife to late life was modestly associated with lower LA reservoir and conduit strain in older adults with normal LA size, mostly related to the effect of blood pressure on LV function and mass. However, the association of cSBP and LA conduit strain in subgroups with normal LV function suggests that LA remodeling in response to hypertension occurs before LV dysfunction is detected on echocardiography., Competing Interests: Disclosures A.A., A.M.S., P.L.L., and L.Y.C. have all received National Institutes of Health funding related to the subject matter of this manuscript. A.S. has received research support from Novartis through Brigham and Women’s Hospital and consulting fees from Philips Ultrasound and Janssen outside of the submitted work. S.S. has received grants or contracts from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, BMS, Celladon, Cytokinetics, Eidos, Gilead, GSK, Ionis, Lilly, Mesoblast, MyoKardia, National Institutes of Health/National Heart, Lung, and Blood Institute, Neurotronik, Novartis, NovoNordisk, Respicardia, Sanofi Pasteur, Theracos, and US2.AI outside the submitted work. K.M. received research support from Resolve to Save Lives outside of the submitted work. S.S. has received consulting feeds from Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boeringer-Ingelheim, BMS, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, GSK, Lilly, Merck, Myokardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, Sanofi-Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, Sarepta, Lexicon, Anacardio, Akros, and Puretech Health. The remaining authors have nothing to disclose., (Copyright © 2024 American Society of Echocardiography. Published by Elsevier Inc. All rights reserved.)

Objective: The impact of age of diabetes diagnosis on dementia risk across the life course is poorly characterized. We estimated the lifetime risk of dementia by age of diabetes diagnosis., Research Design and Methods: We included 13,087 participants from the Atherosclerosis Risk in Communities Study who were free from dementia at age 60 years. We categorized participants as having middle age-onset diabetes (diagnosis <60 years), older-onset diabetes (diagnosis 60-69 years), or no diabetes. Incident dementia was ascertained via adjudication and active surveillance. We used the cumulative incidence function estimator to characterize the lifetime risk of dementia by age of diabetes diagnosis while accounting for the competing risk of mortality. We used restricted mean survival time to calculate years lived without and with dementia., Results: Among 13,087 participants, there were 2,982 individuals with dementia and 4,662 deaths without dementia during a median follow-up of 24.1 (percentile 25-percentile 75, 17.4-28.3) years. Individuals with middle age-onset diabetes had a significantly higher lifetime risk of dementia than those with older-onset diabetes (36.0% vs. 31.0%). Compared with those with no diabetes, participants with middle age-onset diabetes also had a higher cumulative incidence of dementia by age 80 years (16.1% vs. 9.4%) but a lower lifetime risk (36.0% vs. 45.6%) due to shorter survival. Individuals with middle age-onset diabetes developed dementia 4 and 1 years earlier than those without diabetes and those with older-onset diabetes, respectively., Conclusions: Preventing or delaying diabetes may be an important approach for reducing dementia risk throughout the life course., (© 2024 by the American Diabetes Association.)

Direct oral anticoagulants (DOACs; rivaroxaban, apixaban) and warfarin are approved for venous thromboembolism (VTE) treatment. Few direct comparisons of DOACs on risk of mortality among VTE patients exist, and for patients with concomitant conditions (e.g., kidney and liver disease) clinical guidelines are unclear. We evaluated 6-month all-cause mortality by anticoagulant prescribed for primary treatment of VTE. Using Medicare 20% sample data, we created a propensity score matched analytic dataset of 47,860 beneficiaries with non-cancer incident VTE. We used Cox regression to estimate adjusted hazard ratios (HRs) of OACs with 6-month mortality, and tested interactions by liver/kidney disease. There were 3,422 deaths over 6 months of follow-up. In adjusted models, patients prescribed rivaroxaban [HR: 0.82 (95% CI: 0.76-0.90)] had lower rates of mortality versus warfarin. There was no association comparing apixaban to warfarin [HR: 0.96 (95% CI: 0.87-1.07)]. In head-to-head comparisons of apixaban versus rivaroxaban the HR was 1.14 (95% CI: 1.01-1.28)]. Findings were similar among patients with liver and kidney disease. Overall, risk of death was similar by OAC prescribed. Though it is possible residual confounding remained, there was some suggestion of lower risk with rivaroxaban than warfarin. DOACs appear safe among VTE patients with concomitant kidney or liver disease., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Numerous studies have shown inverse associations between serum magnesium (Mg) and risk of cardiovascular disease (CVD), but studies of dietary Mg have not been consistent., Aim: To examine the association of a Mg-rich diet score with risks of CVD, coronary heart disease (CHD), and ischemic stroke in the Atherosclerosis Risk in Communities (ARIC) study., Methods: There were 15,022 Black and White adults without prevalent CVD at baseline (1987-89) included in this analysis. Diet was assessed at two visits 6 years apart using an interviewer-administered 66-item food frequency questionnaire. A Mg-rich diet score was created that included servings of whole grain products, nuts, vegetables, fruit, legumes, coffee, and tea. Cox proportional hazard regression evaluated associations of incident CVD, CHD and stroke across quintiles of Mg-rich diet score, adjusting for demographics, lifestyle factors, and clinical characteristics., Results: Over >30 years of follow-up, there were 3,531 incident CVD events (2,562 CHD, 1,332 ischemic stroke). Participants who consumed more Mg-rich foods were older, female, White, had lower blood pressure, fewer were not current smokers, and more reported being physically active. A Mg-rich diet was inversely associated with incident CVD (HRQ5 vs Q1=0.87, 95%CI: 0.77-0.98, ptrend=0.02) CHD (HRQ5 vs Q1=0.82, 95%CI: 0.71-0.95, ptrend=0.01); however, the diet-stroke association was null (HRQ5 vs Q1=1.00, 95%CI: 0.82-1.22, ptrend=0.97)., Conclusions: Consuming a diet including Mg-rich foods, such as whole grains, nuts, vegetables, fruits, legumes, coffee and tea, is associated with lower risk of CVD and CHD, but not ischemic stroke., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

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

Background: Self-rated health is a simple measure that may identify individuals who are at a higher risk for hospitalization or death., Objective: To quantify the association between a single measure of self-rated health and future risk of recurrent hospitalizations or death., Participants: 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., Main Measures: 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., Key Results: 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 27.7 years, 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., Conclusions: 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., (© 2024. The Author(s).)

Aims: Few studies investigate whether psychosocial factors (social isolation, social support, trait anger, and depressive symptoms) are associated with cardiovascular health, and none with the American Heart Association's new definition of cardiovascular health, Life's Essential 8 (LE8). Therefore, we assessed the cross-sectional associations of psychosocial factors with Life's Essential 8 and individual components of Life's Essential 8., Methods: We included 11,311 Atherosclerosis Risk in Communities cohort participants (58% females; 23% Black; mean age 57 (standard deviation: 6) years) who attended Visit 2 (1990-1992) in this secondary data analysis using cross-sectional data from the ARIC cohort study. Life's Essential 8 components included diet, physical activity, nicotine exposure, sleep quality, body mass index, blood lipids, blood glucose, and blood pressure. Life's Essential 8 was scored per the American Heart Association definition (0-100 range); higher scores indicate better cardiovascular health. Associations of categories (high, moderate, and low) of each psychosocial factor with continuous Life's Essential 8 score and individual Life's Essential 8 components were assessed using multivariable linear regressions., Results: 11% of participants had high Life's Essential 8 scores (80-100), while 67% and 22% had moderate (50-79) and low Life's Essential 8 scores (0-49) respectively. Poor scores on psychosocial factor assessments were associated with lower Life's Essential 8 scores, with the largest magnitude of association for categories of depressive symptoms (low β = Ref.; moderate β = -3.1, (95% confidence interval: -3.7, -2.5; high β = -8.2 (95% confidence interval: -8.8, -7.5)). Most psychosocial factors were associated with Life's Essential 8 scores for diet, physical activity, nicotine, and sleep, but psychosocial factors were not associated with body mass index, blood lipids, blood glucose, or blood pressure., Conclusion: Less favorable measures of psychosocial health were associated with lower Life's Essential 8 scores compared better measures of psychosocial health among middle-aged males and females., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Peter-Marske et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: We sought to evaluate the associations of chest pain and dyspnea with the long-term risk of cardiovascular disease including coronary disease, heart failure, atrial fibrillation, and stroke., Methods: In 13,200 participants without cardiovascular disease in the Atherosclerosis Risk in Communities study (1987-1989), chest pain was categorized into definite angina, possible angina, non-anginal chest pain, and no chest pain using the Rose questionnaire. Dyspnea was categorized into grades 3-4, 2, 1, and 0 by the modified Medical Research Council scale. The associations of chest pain and dyspnea with incident myocardial infarction, heart failure, atrial fibrillation, and stroke over a median follow-up of ∼27 years were quantified with multivariable Cox models., Results: Definite angina and possible angina were associated with myocardial infarction (adjusted hazard ratios [HR] 1.80 [95%CI 1.45-2.13] and 1.65 [1.27-2.15]). Although lesser magnitude than myocardial infarction, both definite and possible angina were associated with heart failure. For atrial fibrillation, possible angina showed higher HR than definite angina. Dyspnea showed similar HRs for myocardial infarction and heart failure in grades 3-4 (2.00 [1.61-2.49] and 1.94 [1.62-2.32]). Stroke was least associated with chest symptoms. Chest pain and dyspnea significantly improved the discrimination of cardiovascular disease except stroke, beyond traditional risk factors., Conclusions: In individuals without cardiovascular disease, chest pain and dyspnea were independently associated with incident cardiovascular disease for about three decades, suggesting the need for evaluating chest pain from a broader perspective of cardiovascular disease beyond coronary disease and the importance of dyspnea for cardiovascular risk assessment including myocardial infarction., Competing Interests: Declaration of competing interest Dr Rosamond received grants from National Heart, Lung, and Blood Institute. Dr Shah received consulting fees from Phillips Ultrasound and Jansen. Dr Blaha received grants from Amgen, American Heart Association, Bayer, Food and Drug Administration, National Institute of Health, and Novo Nordisk; consulting fees from Agepha, Astra Zeneca, Bayer, Boehringer Ingelheim, Eli Lily, Merck, Novartis, and Novo Nordisk; honoraria for lectures from Novo Nordisk; payment for expert testimony from Novo Nordisk and US FTC. Dr Mathews received grants from National Heart, Lung, and Blood Institute. Dr Matsushita received grants from Resolve to Save Lives; consulting fees from AMGA, Kowa Company, and Rhythm X AI; honoraria for lectures fee from Fukuda Denshi. The other authors have nothing to declare., (Copyright © 2024. Published by Elsevier Inc.)

Stroke is a leading cause of death in the United States across all race/ethnicity and sex groups, though disparities exist. We investigated the potential for primary prevention of total first stroke for Americans aged 20 and older, stratified by sex and race/ethnicity. Specifically, we calculated population attributable fractions (PAF) of first stroke for 7 potentially modifiable risk factors: smoking, physical inactivity, poor diet, obesity, hypertension, diabetes, and atrial fibrillation. PAFs are a function of (1) the relative risk of first stroke for people with the exposure and (2) the prevalence of the risk factor in the population. Relative risks came from recent meta-analyses and sex-race/ethnicity-specific prevalence estimates came from the 2015-2018 NHANES or Multi-Ethnic Study of Atherosclerosis (for atrial fibrillation only). Approximately 1/3 (35.7% [CI: 21.6%-49.0%]) for women, 32.7% [CI: 19.2%-45.1%] for men) of strokes were attributable to the 7 risk factors we considered. A 20% proportional reduction in stroke risk factors would result in approximately 37,000 fewer strokes annually in the United States. The estimated PAF was highest for non-Hispanic Black women (39.3% [CI: 24.8%-52.3%]) and lowest for non-Hispanic Asian men (25.5% [CI: 14.6%-36.2%]). For most groups, obesity and hypertension were the largest contributors to stroke rates., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Study Objective: 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., Methods: 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., Results: 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)., Conclusions: 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., (© The Author(s) 2023. Published by Oxford University Press on behalf of Sleep Research Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Objective: To examine the association of left atrial (LA) function with incident chronic kidney disease (CKD) and assess the clinical utility of adding LA function to a CKD risk prediction equation., Patients and Methods: We included 4002 Atherosclerosis Risk in Communities study participants without prevalent CKD (mean ± SD age, 75±5 years; 58% female, 18% Black). Left atrial function (reservoir, conduit, and contractile strain) was evaluated by 2D-echocardiograms on 2011 to 2013. Chronic kidney disease was defined as greater than 25% decline in estimated glomerular filtration rate of less than 60 mL/min/1.73 m 2 , end-stage kidney disease, or hospital records. Cox proportional hazards models were used. Risk prediction and decision curve analyses evaluated 5-year CKD risk by diabetes status., Results: Median follow-up was 7.2 years, and 598 participants developed incident CKD. Incidence rate for CKD was 2.29 per 100 person-years. After multivariable adjustments, the lowest quintile of LA reservoir, conduit, and contractile strain (vs highest quintile) had a higher risk of CKD (hazard ratios [95% CIs]: 1.94 [1.42-2.64], 1.62 [1.19-2.20], and 1.49 [1.12-1.99]). Adding LA reservoir strain to the CKD risk prediction equation variables increased the C-index by 0.026 (95% CI: 0.005-0.051) and 0.031 (95% CI: 0.006-0.058) in participants without and with diabetes, respectively. Decision curve analysis found the model with LA reservoir strain had a higher net benefit than the model with CKD risk prediction equation variables alone., Conclusion: Lower LA function is independently associated with incident CKD. Adding LA function to the CKD risk prediction enhances prediction and yields a higher clinical net benefit. These findings suggest that impaired LA function may be a novel risk factor for CKD., Competing Interests: Dr Eaton reported grant support from the National Institutes of Health to the institution. Dr Herzog reported grant support from the National Heart, Lung, and Blood Institute, National Institutes of Health to the institution, consulting fees from Astra-Zeneca, personal fees from Merck (DSMB) for participation on a Data Safety Monitoring, and stock ownership in Merck, Pfizer and Boston Scientific. Dr Matsushita reported grant supports from the National Institutes of Health and Resolve to Save Lives, consulting fees from Fukuda Denshi and RhythmX AI. Dr Coresh reported grant supports from the National Institutes of Health and National Kidney Foundation, consulting fees from Healthy.IO, and stock ownership in Healthy.IO. Dr Shah reported funding from Novartis and Philips Ultrasound, and consulting fees from Philips Ultrasound and Janssen outside the submitted work. Dr Solomon reported funding from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, BMS, Celladon, Cytokinetics, Eidos, Gilead, GSK, Ionis, Lilly, Mesoblast, MyoKardia, NIH/NHLBI, Neurotronik, Novartis, NovoNordisk, Respicardia, Sanofi Pasteur, Theracos, US2.AI grant to institution, outside the submitted work and personal fees from Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boeringer-Ingelheim, BMS, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi- Sankyo, GSK, Lilly, Merck, Myokardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, SanofiPasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, Sarepta, Lexicon, Anacardio, Akros, PureHealth consulting outside the submitted work. The other authors declare no competing interests., (© 2024 The Authors.)

Background: Multiple myeloma (MM) is associated with high risk of venous thromboembolism (VTE). Anticoagulant prophylaxis is frequently recommended but underutilized partly due to the absence of studies assessing bleeding risk., Objectives: To determine the rate of severe (hospitalized) bleeding from thromboprophylaxis in patients treated for MM and identify clinical risk factors for bleeding in this population., Methods: Using the MarketScan database, we analyzed 6656 patients treated for MM between 2013 and 2021. Concomitant thromboprophylaxis was defined using prescription claims. Hospitalized bleeding was identified through the Cunningham algorithm. Bleeding rates were compared by thromboprophylaxis status, and Cox regression identified risk factors for bleeding., Results: Anticoagulant thromboprophylaxis was used in 6.6% (436) patients treated for MM. Patients on thromboprophylaxis had a higher rate of immunomodulatory-based therapy (63.8% vs 46.7%; P  < .01) and lower rate of antiplatelet use (2.1% vs 4.7%; P  < .01). Bleeding occurred in 1.4% of them during median follow-up of 1.3 years. Rate of severe bleeding was not different between those on prophylaxis (7.8 per 1000 person-years) and those not on prophylaxis (10.1 per 1000 person-years). No association was identified between thromboprophylaxis and bleeding. Factors associated with increased bleeding included age (hazard ratio [HR], 1.38 per 10 years increase in age), comorbidity index (HR, 1.18 per SD increase), history of bleeding (HR, 1.54), hypertension (HR, 1.87), and renal disease (HR, 1.56)., Conclusion: Risk of serious bleeding from thromboprophylaxis in patients treated for MM was low, and concomitant anticoagulant therapy did not result in increased bleeding risk. Clinical risk factors for bleeding included age, comorbidity index, bleeding history, hypertension, and renal disease., (© 2024 The Author(s).)

Introduction: This study aimed to assess whether social relationships in mid-life reduce the risk of dementia related to amyloid burden., Methods: Participants in the Atherosclerosis Risk in Communities (ARIC) study were assessed for social support and isolation (visit 2; 1990-1992). A composite measure, "social relationships," was generated. Brain amyloid was evaluated with florbetapir positron emission tomography (PET); (visit 5; 2012-2014). Incident dementia cases were identified following visit 5 through 2019 using ongoing surveillance. Relative contributions of mid-life social relationships and elevated brain amyloid to incident dementia were evaluated with Cox regression models., Results: Among 310 participants without dementia, strong mid-life social relationships were associated independently with lower dementia risk. Elevated late-life brain amyloid was associated with greater dementia risk., Discussion: Although mid-life social relationships did not moderate the relationship between amyloid burden and dementia, these findings affirm the importance of strong social relationships as a potentially protective factor against dementia., Competing Interests: Renée C. Groechel, Albert C. Liu, Chelsea Liu, Silvia Koton, Anna M. Kucharska‐Newton, Pamela L. Lutsey, Thomas H. Mosley Jr., Priya Palta, A. Richey Sharrett, Keenan A. Walker, Dean F. Wong, Rebecca F. Gottesman: no conflicts to report. David S. Knopman: serves on a data safety monitoring board for the Dominantly Inherited Alzheimer Network Treatment Unit study. He served on a data safety monitoring board for a tau therapeutic for Biogen (until 2021) but received no personal compensation. He is an investigator in clinical trials sponsored by Biogen, Lilly Pharmaceuticals, and the University of Southern California. He has served as a consultant for Roche, Samus Therapeutics, Magellan Health, Biovie, and Alzeca Biosciences but receives no personal compensation. He attended an Eisai advisory board meeting for lecanemab in December 2, 2022, but received no compensation directly or indirectly. He receives funding from the NIH. Author disclosures are available in the Supporting Information., (© 2024 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals LLC on behalf of Alzheimer's Association. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Purpose: Among patients with atrial fibrillation (AF), a nonpharmacologic option (e.g., percutaneous left atrial appendage occlusion [LAAO]) is needed for patients with oral anticoagulant (OAC) contraindications. Among beneficiaries in the Medicare fee-for-service coverage 20% sample databases (2015-18) who had AF and an elevated CHA 2 DS 2 -VASc score, we assessed the association between percutaneous LAAO versus OAC use and risk of stroke, hospitalized bleeding, and death., Methods: Patients undergoing percutaneous LAAO were matched to up to five OAC users by sex, age, date of enrollment, index date, CHA 2 DS 2 -VASc score, and HAS-BLED score. Overall, 17 156 patients with AF (2905 with percutaneous LAAO) were matched (average ± SD 78 ± 6 years, 44% female). Cox proportional hazards model were used., Results: Median follow-up was 10.3 months. After multivariable adjustments, no significant difference for risk of stroke or death was noted when patients with percutaneous LAAO were compared with OAC users (HRs [95% CIs]: 1.14 [0.86-1.52], 0.98 [0.86-1.10]). There was a 2.94-fold (95% CI: 2.50-3.45) increased risk for hospitalized bleeding for percutaneous LAAO compared with OAC use. Among patients 65 to <78 years old, those undergoing percutaneous LAAO had higher risk of stroke compared with OAC users. No association was present in those ≥78 years., Conclusion: In this analysis of real-world AF patients, percutaneous LAAO versus OAC use was associated with similar risk of death, nonsignificantly elevated risk of stroke, and an elevated risk of bleeding in the post-procedural period. Overall, these results support results of randomized trials that percutaneous LAAO may be an alternative to OAC use for patients with contraindications., (© 2024 The Authors. Pharmacoepidemiology and Drug Safety published by John Wiley & Sons Ltd.)

Background and Aims: Although glycemic status is associated with impaired cardiac structure and function, less is known on left atrial (LA) function across the glycemic spectrum. We evaluated the association of diabetes and glycemic control with LA function in a community-based cohort of older adults., Methods and Results: This cross-sectional analysis included 5075 participants from the Atherosclerosis Risk in Communities Study (mean age 75.5 years, 58 % women, and 20 % Black adults) with echocardiographic strain data for LA reservoir, conduit, and contractile function. Multivariable linear regression was used to assess associations of diabetes status and glycemic control with LA function. In participants without diabetes, we used ordinal linear regression to evaluate associations of fasting glucose and HbA1c with LA function. Compared to individuals with a normal fasting glucose, prevalent diabetes was associated with 0.68 % lower LA conduit function (95 % confidence interval (CI): 1.11 to -0.25) and prediabetes a 0.47 % reduction (95 % CI: 0.85 to -0.09) in fully adjusted analyses. Persons with diabetes and high HbA1c (HgbA1c ≥ 7 % vs <7 %) had 1.05 % lower LA conduit function (95 % CI: 1.63, -0.48). Among individuals without diagnosed diabetes, higher fasting glucose, but not HbA1c, was significantly associated with worse LA conduit function. No significant associations were observed for LA reservoir and contractile function., Conclusions: A history of diabetes, prediabetes, and higher fasting glucose levels in persons without diabetes were associated with worse LA conduit function. Corroborative research is needed in prospective cohorts as well as studies that explore underlying mechanisms., Competing Interests: Declaration of competing interest The authors declare that they have conflicts of interest., (Copyright © 2023. Published by Elsevier B.V.)

Background: Contemporary use of sodium-glucose cotransporter-2 inhibitors (SGLT2i) and angiotensin receptor-neprilysin inhibitors (ARNi) in patients with atrial fibrillation (AF) and heart failure (HF) has not been described., Methods and Results: We analyzed the MarketScan databases for the period January 1, 2021 to July 30, 2022. Validated algorithms were used to identify patients with AF and HF, and to classify patients into HF with reduced ejection fraction (HFrEF) or HF with preserved ejection fraction (HFpEF). We assessed the prevalence of SGLT2i and ARNi use overall and by HF type. Additionally, we explored correlates of lower use, including demographics and comorbidities. The study population included 60 927 patients (mean age, 75 years; 43% women) diagnosed with AF and HF (85% with HFpEF, 15% with HFrEF). Prevalence of ARNi use was 11% overall (30% in HFrEF, 8% in HFpEF), whereas the corresponding figure was 6% for SGLT2i (13% in HFrEF, 5% in HFpEF). Use of both medications increased over the study period: ARNi from 9% to 12% (22%-29% in HFrEF, 6%-8% in HFpEF), and SGLT2i from 3% to 9% (6%-16% in HFrEF, 2%-7% in HFpEF). Female sex, older age, and specific comorbidities were associated with lower use of these 2 medication types overall and by HF type., Conclusions: Use of ARNi and SGLT2i in patients with AF and HF is suboptimal, particularly among women and older individuals, though use is increasing. These results underscore the need for understanding reasons for these disparities and developing interventions to improve adoption of evidence-based therapies among patients with comorbid AF and HF.

Importance: 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., Objective: 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., Design, Setting, and Participants: 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., Exposures: LDL-C, cumulative past LDL-C, FH variant status., Main Outcomes and Measures: 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., Results: 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., Conclusions and Relevance: 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.

Accumulating evidence supports a link between sleep disorders, disturbed sleep, and adverse brain health, ranging from stroke to subclinical cerebrovascular disease to cognitive outcomes, including the development of Alzheimer disease and Alzheimer disease-related dementias. Sleep disorders such as sleep-disordered breathing (eg, obstructive sleep apnea), and other sleep disturbances, as well, some of which are also considered sleep disorders (eg, insomnia, sleep fragmentation, circadian rhythm disorders, and extreme sleep duration), have been associated with adverse brain health. Understanding the causal role of sleep disorders and disturbances in the development of adverse brain health is complicated by the common development of sleep disorders among individuals with neurodegenerative disease. In addition to the role of sleep disorders in stroke and cerebrovascular injury, mechanistic hypotheses linking sleep with brain health and biomarker data (blood-based, cerebrospinal fluid-based, and imaging) suggest direct links to Alzheimer disease-specific pathology. These potential mechanisms and the increasing understanding of the "glymphatic system," and the recognition of the importance of sleep in poststroke recovery, as well, support a biological basis for the indirect (through the worsening of vascular disease) and direct (through specific effects on neuropathology) connections between sleep disorders and brain health. Given promising evidence for the benefits of treatment and prevention, sleep disorders and disturbances represent potential targets for early treatment that may improve brain health more broadly. In this scientific statement, we discuss the evidence supporting an association between sleep disorders and disturbances and poor brain health ranging from stroke to dementia and opportunities for prevention and early treatment.

Background: Whether 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., Objectives: The 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., Methods: Participants 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., Results: The 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., Conclusions: Among 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., Competing Interests: Funding Support and Author Disclosures The ARIC study has been funded in whole or in part with federal funds from the National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health, U.S. Department of Health and Human Services, (contracts 75N92022D00001, 75N92022D00002, 75N92022D00003, 75N92022D00004, and 75N92022D00005). This work was supported in part by NHLBI grant R01 HL134320. Dr Buckley was supported by NHLBI grant K23HL150311, the BWH Khoury Innovation Fund, and an American Society of Nephrology/KidneyCure Carl W. Gottschalk Research Scholar Grant. Dr Shah was supported by NHLBI grants R01HL135008, R01HL143224, R01HL150342, R01HL148218, R01HL160025, and K24HL152008. Dr Lutsey was supported by NHLBI grant K24HL159246. Dr Shah has received research support (not related to this study) from Novartis and Philips Ultrasound; and has received consulting fees from Philips Ultrasound. Dr Farag is an employee of Bayer U.S. (not related to this study). Dr Lennep has received consulting fees from Pfizer (not related to this study). Dr Matsushita has received personal fee from Kyowa Kirin and Akebia (outside the submitted work). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Cancer survivors may have elevated atherosclerotic cardiovascular disease (ASCVD) risk. Therefore, we tested how accurately the American College of Cardiology/American Heart Association 2013 pooled cohort equations (PCEs) predict 10-year ASCVD risk in cancer survivors., Objectives: To estimate the calibration and discrimination of the PCEs in cancer survivors compared to non-cancer participants in the Atherosclerosis Risk in Communities (ARIC) study., Methods: We evaluated the PCEs' performance among 1244 cancer survivors and 3849 cancer-free participants who were free of ASCVD at the start of follow-up. Each cancer survivor was incidence-density matched with up to five controls by age, race, sex, and study center. Follow-up began at the first study visit at least 1 year after the diagnosis date of the cancer survivor and finished at the ASCVD event, death, or end of follow-up. Calibration and discrimination were assessed and compared between cancer survivors and cancer-free participants., Results: Cancer survivors had higher PCE-predicted risk, at 26.1%, compared with 23.1% for cancer-free participants. There were 110 ASCVD events in cancer survivors and 332 ASCVD events in cancer-free participants. The PCEs overestimated ASCVD risk in cancer survivors and cancer-free participants by 45.6% and 47.4%, respectively, with poor discrimination in both groups (C-statistic for cancer survivors = 0.623; for cancer-free participants, C = 0.671)., Conclusions: The PCEs overestimated ASCVD risk in all participants. The performance of the PCEs was similar in cancer survivors and cancer-free participants., Implications for Cancer Survivors: Our findings suggest that ASCVD risk prediction tools tailored to survivors of adult cancers may not be needed., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Habitual physical activity (PA) impacts the plasma proteome and reduces the risk of developing type 2 diabetes (T2D). Using a large-scale proteome-wide approach in Atherosclerosis Risk in Communities study participants, we aimed to identify plasma proteins associated with PA and determine which of these may be causally related to lower T2D risk. PA was associated with 92 plasma proteins in discovery (P < 1.01 × 10-5), and 40 remained significant in replication (P < 5.43 × 10-4). Eighteen of these proteins were independently associated with incident T2D (P < 1.25 × 10-3), including neuronal growth regulator 1 (NeGR1; hazard ratio per SD 0.85; P = 7.5 × 10-11). Two-sample Mendelian randomization (MR) inverse variance weighted analysis indicated that higher NeGR1 reduces T2D risk (odds ratio [OR] per SD 0.92; P = 0.03) and was consistent with MR-Egger, weighted median, and weighted mode sensitivity analyses. A stronger association was observed for the single cis-acting NeGR1 genetic variant (OR per SD 0.80; P = 6.3 × 10-5). Coupled with previous evidence that low circulating NeGR1 levels promote adiposity, its association with PA and potential causal role in T2D shown here suggest that NeGR1 may link PA exposure with metabolic outcomes. Further research is warranted to confirm our findings and examine the interplay of PA, NeGR1, adiposity, and metabolic health., (© 2024 by the American Diabetes Association.)

Study Objectives: 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., Methods: 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., Results: 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 ( P trend = 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% ( p trend < 0.0001)., Conclusions: 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., (© The Author(s) 2024. Published by Oxford University Press on behalf of Sleep Research Society.)

Introduction: Anemia is a risk factor for all-cause mortality in older adults. Iron deficiency may also be associated with adverse outcomes, independent of its role in causing anemia. This study tested the hypotheses that anemia, and low ferritin among non-anemic participants, were associated with all-cause and cause-specific mortality in a community-based cohort of older adults., Methods: Fasting blood was obtained from 5,070 ARIC participants (median age: 75 years) in 2011-2013. Anemia was defined by hemoglobin concentrations &lt;12 g/dL in women and &lt;13 g/dL in men. We classified 4,020 non-anemic participants by quartiles of plasma ferritin, measured by the SomaScan proteomics platform. Cox proportional hazards regression was used. Mortality was ascertained via phone calls with proxies as part of twice-yearly cohort follow-up, surveillance of local hospital discharge indexes, state death records, and linkage to the National Death Index., Results: Of the total participants, 21% had anemia at baseline. Over a median of 7.5 years, there were 1,147 deaths, including 357 due to cardiovascular disease (CVD), 302 to cancer, and 132 to respiratory disease. Compared to those with normal hemoglobin, participants with anemia had a higher risk of all-cause mortality (hazard ratio 1.81 [95% CI: 1.60-2.06]), and mortality due to CVD (1.77 [1.41-2.22]), cancer (1.81 [1.41-2.33]), and respiratory disease (1.72 [1.18-2.52]) in demographics-adjusted models. In fully adjusted models, associations with all-cause mortality (1.37 [1.19-1.58]) and cause-specific mortality were attenuated. In non-anemic participants, lower ferritin levels were not associated with all-cause or cause-specific mortality, though associations were observed among participants with lesser evidence of inflammation (CRP below the median level of 1.9 mg/L) and for cancer mortality in men only., Conclusion: Anemia is common among older adults and is associated with all-cause mortality, as well as mortality due to CVD, cancer, and respiratory disease. Our results do not provide evidence that iron deficiency, independent of anemia, is associated with mortality in this population., (© 2024 S. Karger AG, Basel.)

Background: Brain imaging studies may provide etiologic insight into observed links between lung function and dementia and stroke., Objective: We evaluated associations of lung function measures with brain MRI markers of vascular and neurodegenerative disease in the ARIC Neurocognitive Study, as few studies have examined the associations., Methods: Lung function was measured at participants' midlife in 1990-1992 (mean age = 56±5 years) and later-life in 2011-2013 (mean age = 76±5 years), and brain MRI was performed in 2011-2013. Linear regression models were used to examine the associations of lung function with brain and white matter hyperintensity (WMH) volumes, and logistic regression models were used for cerebral infarcts and microbleeds, adjusting for potential confounders., Results: In cross-sectional analysis (i.e., examining later-life lung function and MRI markers, n = 1,223), higher forced-expiratory volume in one second (FEV1) and forced vital capacity (FVC) were associated with larger brain and lower WMH volumes [e.g., 8.62 (95% CI:2.54-14.71) cm3 greater total brain volume per one-liter higher FEV1]. No association was seen with microbleeds in the overall sample, but higher FVC was associated with lower odds of microbleeds in never-smokers and higher odds in ever-smokers. In the cross-temporal analysis (i.e., associations with midlife lung function, n = 1,787), higher FVC levels were significantly associated with lower later-life brain volumes., Conclusions: Our results support modest associations of better lung function with less neurodegenerative and cerebrovascular pathology, although findings for microbleeds were unexpected in ever-smokers.

Background: 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., Objective: 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)., Methods: 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)., Results: 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., Conclusions: 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.

Background: Management of orthostatic hypotension (OH) prioritizes prevention of standing hypotension, sometimes at the expense of supine hypertension. It is unclear whether supine hypertension is associated with adverse outcomes relative to standing hypotension., Objectives: To compare the long-term clinical consequences of supine hypertension and standing hypotension among middle-aged adults with and without OH., Methods: The ARIC study (Atherosclerosis Risk in Communities) measured supine and standing blood pressure (BP) in adults aged 45 to 64 years, without neurogenic OH, between 1987 and 1989. We defined OH as a positional drop in systolic BP ≥20 mm Hg or diastolic BP ≥10 mm Hg, supine hypertension as supine BP≥140/≥90 mm Hg, and standing hypotension as standing BP≤105/≤65 mm Hg. Participants were followed for >30 years. We used Cox regression models to examine associations with cardiovascular disease events, all-cause mortality, falls, and syncope., Results: Of 12 489 participants (55% female, 26% Black, mean age 54 years, SD 6), 4.4% had OH. Among those without OH (N=11 943), 19% had supine hypertension and 21% had standing hypotension, while among those with OH (N=546), 58% had supine hypertension and 38% had standing hypotension. Associations with outcomes did not differ by OH status ( P -interactions >0.25). Supine hypertension was associated with heart failure (hazard ratio, 1.83 [95% CI, 1.68-1.99]), falls (hazard ratio, 1.12 [95% CI, 1.02-1.22]), and all-cause mortality (hazard ratio, 1.45 [95% CI, 1.37-1.54]), while standing hypotension was only significantly associated with mortality (hazard ratio, 1.06 [95% CI, 1.00-1.14])., Conclusions: Supine hypertension was associated with higher risk of adverse events than standing hypotension, regardless of OH status. This challenges conventional OH management, which prioritizes standing hypotension over supine hypertension., Competing Interests: Disclosures None.

Background and Objectives: Studies on the association between proton pump inhibitor (PPI) use and dementia report mixed results and do not examine the impact of cumulative PPI use. We evaluated the associations between current and cumulative PPI use and risk of incident dementia in the Atherosclerosis Risk in Communities (ARIC) Study., Methods: These analyses used participants from a community-based cohort (ARIC) from the time of enrollment (1987-1989) through 2017. PPI use was assessed through visual medication inventory at clinic visits 1 (1987-1989) to 5 (2011-2013) and reported annually in study phone calls (2006-2011). This study uses ARIC visit 5 as baseline because this was the first visit in which PPI use was common. PPI use was examined 2 ways: current use at visit 5 and duration of use before visit 5 (from visit 1 to 2011, exposure categories: 0 day, 1 day-2.8 years, 2.8-4.4 years, >4.4 years). The outcome was incident dementia after visit 5. Cox proportional hazard models were used, adjusted for demographics, comorbid conditions, and other medication use., Results: A total of 5,712 dementia-free participants at visit 5 (mean age 75.4 ± 5.1 years; 22% Black race; 58% female) were included in our analysis. The median follow-up was 5.5 years. The minimum cumulative PPI use was 112 days, and the maximum use was 20.3 years. There were 585 cases of incident dementia identified during follow-up. Participants using PPIs at visit 5 were not at a significantly higher risk of developing dementia during subsequent follow-up than those not using PPIs (hazard ratio (HR): 1.1 [95% confidence interval (CI) 0.9-1.3]). Those who used PPIs for >4.4 cumulative years before visit 5 were at 33% higher risk of developing dementia during follow-up (HR: 1.3 [95% CI 1.0-1.8]) than those reporting no use. Associations were not significant for lesser durations of PPI use., Discussion: Future studies are needed to understand possible pathways between cumulative PPI use and the development of dementia., Classification of Evidence: This study provides Class III evidence that the use of prescribed PPIs for >4.4 years by individuals aged 45 years and older is associated with a higher incidence of newly diagnosed dementia., (Written work prepared by employees of the Federal Government as part of their official duties is, under the U.S. Copyright Act, a “work of the United States Government” for which copyright protection under Title 17 of the United States Code is not available. As such, copyright does not extend to the contributions of employees of the Federal Government.)

Background: ACC/AHA guidelines caution against the use of antihypertensive therapy in the setting of low standing systolic BP (SBP) < 110 mm Hg due to unclear benefits., Methods: The Atherosclerosis Risk in Communities (ARIC) Study measured supine and standing SBP in adults aged 45-64 years between 1987 and 1989. We used Cox regression to evaluate the associations of low standing SBP (<110 mm Hg) with risk of falls, syncope, coronary heart disease (CHD), and mortality through December 31, 2019. Falls and syncope were ascertained by hospitalization and outpatient claims; CHD events were adjudicated. Associations were examined overall and in strata of hypertension stage, 10-year atherosclerotic cardiovascular disease (ASCVD) risk, age, and sex., Results: Among 12,467 adults followed a median of 24 years (mean age at enrollment 54.1 ± 5.8 years, 55% women, 26% Black adults), 3,000 (24%) had a standing SBP < 110 mm Hg. A standing SBP < 110 mm Hg compared to standing SBP ≥ 110 mm Hg was not significantly associated with falls or syncope, and was associated with a lower risk of CHD events and mortality with HRs of 1.02 (95% CI 0.94, 1.11), 1.02 (0.93, 1.11), 0.88 (0.80, 0.97), and 0.91 (0.86, 0.97), respectively. There were no clinically meaningful differences when stratified by hypertension stage, 10-year ASCVD risk, age, and sex., Conclusions: In this community-based population, low standing SBP was common and not significantly associated with falls or syncope, but was associated with a lower risk of CHD and mortality. These findings do not support screening for low standing BP as a risk factor for adverse events., (© The Author(s) 2023. Published by Oxford University Press on behalf of American Journal of Hypertension, Ltd. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

We examined the associations between lung function and incident dementia and cognitive decline in 12,688 participants in the ARIC Study who provided lung function measurements in 1990-1992. Cognitive tests were administered up to 7 times, and dementia was ascertained through 2019. We used shared parameter models to jointly fit proportional hazard models and linear mixed-effect models to estimate lung-function-associated dementia rate and cognitive change, respectively. Higher forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) were associated with reduced dementia (n = 2,452 persons developed dementia); hazard ratios per 1-L increase in FEV1 and FVC were 0.79 (95% confidence interval (CI): 0.71, 0.89) and 0.81 (95% CI: 0.74, 0.89), respectively. Each 1-L increase in FEV1 and FVC was associated with a 0.08-standard deviation (SD) (95% CI: 0.05, 0.12) and a 0.05-SD (95% CI: 0.02, 0.07) attenuation of 30-year cognitive decline, respectively. A 1% increase in FEV1/FVC ratio was associated with 0.008-SD (95% CI: 0.004, 0.012) less cognitive decline. We observed statistical interaction between FEV1 and FVC, suggesting that cognitive declines depended on values of specific FEV1 and FVC (as compared with FEV1, FVC, or FEV1/FVC ratio models that suggested linear incremental associations). Our findings may have important implications for reducing the burden of cognitive decline that is attributable to environmental exposures and associated lung function impairment., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Rationale: The autonomic nervous system extensively innervates the lungs, but its role in chronic obstructive pulmonary disease (COPD) outcomes has not been well studied. Objective: We assessed relationships between cardiovascular autonomic nervous system measures (heart rate variability [HRV] and orthostatic hypotension [OH]) and incident COPD hospitalization in the multicenter ARIC (Atherosclerosis Risk In Communities) study. Methods: We used Cox proportional hazards regression models to estimate hazard ratios and 95% confidence intervals between baseline (1987-1989) autonomic function measures (HRV measures from 2-minute electrocardiograms and OH variables) and incident COPD hospitalizations through 2019. Adjusted analyses included demographic data, smoking status, lung function, comorbidities, and physical activity. We also performed analyses stratified by baseline airflow obstruction. Results: Of the 11,625 participants, (mean age, 53.8 yr), 56.5% were female and 26.3% identified as Black. Baseline mean percentage predicted forced expiratory volume in 1 second was 94 ± 17% (standard deviation), and 2,599 participants (22.4%) had airflow obstruction. During a median follow-up time of 26.9 years, there were 2,406 incident COPD hospitalizations. Higher HRV (i.e., better autonomic function) was associated with a lower risk of incident COPD hospitalization. Markers of worse autonomic function (OH and greater orthostatic changes in systolic and diastolic blood pressure) were associated with a higher risk of incident COPD hospitalization (hazard ratio for the presence of OH, 1.5; 95% confidence interval, 1.25-1.92). In stratified analyses, results were more robust in participants without airflow obstruction at baseline. Conclusions: In this large multicenter prospective community cohort, better cardiovascular autonomic function at baseline was associated with a lower risk of subsequent hospitalization for COPD, particularly among participants without evidence of lung disease at baseline.

Objective: Reproductive factors, including parity, may contribute to dementia risk, due to hormonal, physiological, social, and demographic factors. We hypothesized that higher parity would be associated with increased dementia risk. Materials and Methods: We utilized data from the Atherosclerosis Risk in Communities (ARIC) community-based cohort study. Participants were recruited in 1987-1989 and followed through 2017. Participants, all born between 1921 and 1945, were from four U.S. communities in Forsyth County, NC; Jackson, MS; Minneapolis, MN; and Washington County, MD. We included all female participants seen at ARIC visit three or five for whom parity and dementia outcomes were available ( N  = 7,921). The primary exposure was self-reported number of live births. Our primary outcome was dementia, diagnosed via neurocognitive assessments, informant interviews, and expert adjudication. We created Cox proportional hazards models to evaluate the association between parity and incident dementia, adjusting for demographic factors, education level, apolipoprotein E allele status, and vascular risk factors. We tested for interactions by race and birth cohort. Results: The adjusted hazard ratio was 0.82 (95% confidence intervals [CI] 0.69-0.99) for dementia in women with 0-1 births and 0.85 (95% CI 0.72-0.99) for women with 5+ births, compared to women with 2 births (reference group). This association was present in women born from 1924 to 1934, but not in women born in 1935 or later ( p -interaction <0.001). Conclusion: We found an inverted U-shaped association of parity with dementia risk. This effect was modified by birth cohort, suggesting that the association may depend on demographic and sociocultural factors.

Objectives: This study investigated associations of late midlife sleep characteristics with late-life hearing, which adds to the existing cross-sectional evidence and is novel in examining polysomnographic sleep measures and central auditory processing., Methods: A subset of Atherosclerosis Risk in Communities Study participants underwent sleep assessment in the Sleep Heart Health Study in 1996-1998 and hearing assessment in 2016-2017. Peripheral hearing thresholds (0.5-4kHz) assessed by pure-tone audiometry were averaged to calculate speech-frequency pure-tone average in better-hearing ear (higher pure-tone average=worse hearing). Central auditory processing was measured by the Quick Speech-in-Noise Test (lower score=worse performance). Sleep was measured using polysomnography (time spent in stage 1, stage 2, stage 3/4, rapid eye movement sleep; sleep-disordered breathing [apnea-hypopnea index ≥5]) and self-report (habitual sleep duration; excessive daytime sleepiness [Epworth Sleepiness Scale 10]). Linear regression models adjusted for demographic and lifestyle factors with additional adjustment for cardiovascular factors., Results: Among 719 Atherosclerosis Risk in Communities-Sleep Heart Health Study participants (61 ± 5years, 54% female, 100% White), worse speech-frequency pure-tone average was found with sleep-disordered breathing (2.51dB, 95% confidence interval: 0.27, 4.75) and excessive daytime sleepiness (3.35 dB, 95% confidence interval: 0.81, 5.90). Every additional hour of sleep when sleeping >8 hours was associated with worse Quick Speech-in-Noise score (1.61 points, 95% confidence interval: 0.03, 3.19). Every 10-minute increase in rapid eye movement sleep was associated with 0.14-point better Quick Speech-in-Noise score (95% confidence interval: 0.02, 0.25)., Conclusions: Sleep abnormalities might be risk factors for late-life hearing loss. Future longitudinal studies are needed to confirm these novel findings and clarify the mechanisms., Competing Interests: Declaration of conflicts of interest Dr. Spira received payment for serving as a consultant for Merck, received honoraria from Springer Nature Switzerland AG for guest editing special issues of Current Sleep Medicine Reports, and is a paid consultant to Sequoia Neurovitality. Dr. Lin reported being a consultant to Frequency Therapeutics, receiving speaker honoraria from Caption Call, and being the director of a public health research center funded in part by a philanthropic donation from Cochlear Ltd to the Johns Hopkins Bloomberg School of Public Health. Dr. Reed reported membership on the advisory board of Neosensory. No other disclosures were reported., (Copyright © 2023 National Sleep Foundation. Published by Elsevier Inc. All rights reserved.)

P2Y12 inhibitors (i.e., clopidogrel, prasugrel, or ticagrelor) are effective at reducing adverse cardiovascular outcomes post-revascularization in coronary artery disease (CAD). However, the choice of a specific P2Y12 inhibitor may vary according to the patient's characteristics, and trends in the use of different P2Y12 inhibitors are not well studied in real-world settings. The objective of this study is to determine trends in the prescription patterns of P2Y12 inhibitors in patients with CAD. We studied 137,073 patients with CAD cross-sectionally using the IBM MarketScan database (2013-2018). Patients with CAD prescribed P2Y12 inhibitors within 14 days of index revascularization were included to compare the utilization of P2Y12 inhibitors based on age and clinical characteristics. There were differences in prescription patterns by age. Among patients aged less than or equal to 65 years (N = 92,734), a continuously increased utilization of ticagrelor was observed from 13.7% to 45.6% replacing clopidogrel as the most prescribed medication by 2018. Similarly, ticagrelor was the choice of drug among patients undergoing percutaneous coronary intervention. Among the patients at high bleeding risk, clopidogrel remained the most prescribed medication with use in 50.6% of patients in 2018 in patients aged less than or equal to 65 years. Contrarily, among the older adults with age 65 or above (N = 44,339), although ticagrelor use increased with time, clopidogrel remained the most utilized drug and was used by 66.2% of patients in 2018. Additionally, clopidogrel was the preferred medication among patients with stroke history. With the increasing use of ticagrelor in real-world practice, further research is needed to observe its impact on cardiovascular outcomes., (© 2023 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Objectives: We investigated the relationship between the cognitive status of participants' spouses and participants' own cognitive outcomes, controlling for mid-life factors. Methods: Participants ( n = 1845; baseline age 66-90 years) from the prospective Atherosclerosis Risk in Communities Study were followed from 2011 to 2019. We used linear regression and Cox proportional hazard models to estimate whether spouses of people with MCI/dementia had lower cognitive functioning and elevated risk of incident dementia. Results: Having a spouse with MCI/dementia was associated with a deficit in cognitive function (b = -0.09 standard deviations; 95% CI = -0.18, 0.00). Adjustment for mid-life risk factors attenuated this association (b = -0.02 standard deviations; 95% CI = -0.10, 0.06). We observed no significant relationship between spousal MCI/dementia status and incident dementia (hazard ratio = 0.97; 95% CI = 0.69, 1.38). Discussion: Spousal cognitive status is not associated with poor cognitive outcomes independent of mid-life factors.

Study Objectives: Multiple sleep characteristics are informative of health, sleep characteristics cluster, and sleep health can be described as a composite of positive sleep attributes. We assessed the association between a sleep score reflecting multiple sleep dimensions, and mortality. We tested the hypothesis that more favorable sleep (higher sleep scores) is associated with lower mortality., Methods: The Multi-Ethnic Study of Atherosclerosis (MESA) is a racially and ethnically-diverse multi-site, prospective cohort study of US adults. Sleep was measured using unattended polysomnography, 7-day wrist actigraphy, and validated questionnaires (2010-2013). 1726 participants were followed for a median of 6.9 years (Q1-Q3, 6.4-7.4 years) until death (171 deaths) or last contact. Survival models were used to estimate the association between the exposure of sleep scores and the outcome of all-cause mortality, adjusting for socio-demographics, lifestyle, and medical comorbidities; follow-up analyses examined associations between individual metrics and mortality. The exposure, a sleep score, was constructed by an empirically-based Principal Components Analysis on 13 sleep metrics, selected a priori., Results: After adjusting for multiple confounders, a 1 standard deviation (sd) higher sleep score was associated with 25% lower hazard of mortality (Hazard Ratio [HR]: 0.75; 95% Confidence interval: [0.65, 0.87]). The largest drivers of this association were: night-to-night sleep regularity, total sleep time, and the Apnea-Hypopnea Index., Conclusion: More favorable sleep across multiple characteristics, operationalized by a sleep score, is associated with lower risk of death in a diverse US cohort of adults. Results suggest that interventions that address multiple dimensions may provide novel approaches for improving health., (© The Author(s) 2023. Published by Oxford University Press on behalf of Sleep Research Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Venous thromboembolism (VTE) affects 1.2 million people per year in the United States. With several clinical changes in diagnosis and treatment approaches in the past decade, we evaluated contemporary post-VTE mortality risk profiles and trends. Incident VTE cases were identified from the 2011-2019 Medicare 20% Sample, which is representative of nearly all Americans aged 65 and older. The social deprivation index was linked from public data; race/ethnicity and sex were self-reported. The all-cause mortality risk 30 days and 1 year after incident VTE was calculated in demographic subgroups and by prevalent cancer diagnosis status using model-based standardization. Risks for major cancer types, risk differences by age, sex, race/ethnicity, and socio-economic status (SES), and trends over time are also reported. The all-cause mortality risk among older US adults following incident VTE was 3.1% (95% CI 3.0-3.2) at 30 days and 19.6% (95% CI 19.2-20.1) at 1 year. For cancer-related VTE events, the age-sex-race-standardized risk was 6.0% at 30 days and 34.7% at 1 year. The standardized 30-day and 1-year risks were higher among non-White beneficiaries and among those with low SES. One-year mortality risk decreased 0.28 percentage points per year (95% CI 0.16-0.40) on average across the study period, with no trend observed for 30-day mortality risk. In sum, all-cause mortality risk following incident VTE has decreased slightly in the last decade, but racial and socio-economic disparities persist. Understanding patterns of mortality among demographic subgroups and in cancer-associated events is important for targeting efforts to improve VTE management., (© 2023 Wiley Periodicals LLC.)

Introduction: The fraction of dementia attributable to hypertension might vary depending on the age of the population considered and the age through which dementia occurs., Methods: In the Atherosclerosis Risk in Communities study, we quantified population attributable fractions (PAF) of dementia by age 80 and 90 from hypertension assessed at ages of 45-54 (n = 7572), 55-64 (n = 12,033), 65-74 (n = 6561), and 75-84 (n = 2086)., Results: The PAF for dementia by age 80 from all non-normal blood pressure at ages 45-54 was 15.3% (95% confidence interval [CI] = 6.9%-22.3%), 19.1% (95% CI = 9.9%-26.9%) at ages 55-64, and 19.9% (95% CI = -4.4%-38.5%) at ages 65-74. The strongest PAFs were from stage 2 hypertension (11.9%-21.3%). For dementia by age 90, PAFs from non-normal blood pressure up through age 75 were smaller (10.9%-13.8%), and non-significant by age 75-84., Discussion: Interventions targeting hypertension even in early late life might reduce a sizeable proportion of dementia., Highlights: We estimated prospective population attributable risks of dementia for hypertension. 15%-20% of dementia cases by age 80 are from non-normal blood pressure (BP). Associations between hypertension and dementia persisted through age 75. Midlife to early late-life BP control might reduce a large proportion of dementia., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Aims/hypothesis: The aim of this work was to evaluate whether the association of prediabetes with dementia is explained by the intervening onset of diabetes., Methods: Among participants of the Atherosclerosis Risk in Communities (ARIC) study we defined baseline prediabetes as HbA 1c 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., Results: 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., Conclusions/interpretation: 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., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Recent evidence indicates that abnormal P-wave parameters (PWPs)-ECG markers of atrial myopathy-are associated with incident dementia, independent of atrial fibrillation (AF) and clinical ischemic stroke. However, the mechanisms remain unclear and may include subclinical vascular brain injury. Hence, we evaluated the association of abnormal PWPs with brain MRI correlates of vascular brain injury in the Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS)., Methods: ARIC-NCS participants who underwent 3T brain MRI scans in 2011-2013 were included. PWPs were measured from standard 12-lead ECGs. Brain MRI outcomes included cortical infarcts, lacunar infarcts, cerebral microhemorrhages, brain volumes, and white matter disease (WMD) volume. We used weighted multivariable logistic and linear regression to evaluate the associations of abnormal PWPs with brain MRI outcomes., Results: Among 1715 participants (mean age, 76.1 years; 61% women; 29% Black), 797 (46%) had ≥1 abnormal PWP. After multivariable adjustment, including adjusting for prevalent AF, abnormal P-wave terminal force in lead V1 (aPTFV1) and prolonged P-wave duration (PPWD) were associated with increased odds of both cortical (OR 1.41; 95% CI, 1.14 to 1.74 and OR 1.30; 95% CI, 1.04 to 1.63, respectively) and lacunar infarcts (OR 1.36; 95% CI, 1.15 to 1.63 and OR 1.37; 95% CI, 1.15 to 1.65, respectively). Advanced interatrial block (aIAB) was associated with higher odds of subcortical microhemorrhage (OR 2.04; 95% CI, 1.36 to 3.06). Other than a significant association between aPTFV1 with lower parietal lobe volume, there were no other significant associations with brain or WMD volume., Conclusion: In this exploratory analysis of a US community-based cohort, ECG surrogates of atrial myopathy are associated with a higher prevalence of brain infarcts and microhemorrhage, suggesting subclinical vascular brain injury as a possible mechanism underlying the association of atrial myopathy with dementia., (© 2023 The Authors. Pacing and Clinical Electrophysiology published by Wiley Periodicals LLC.)