BACKGROUND:Obesity increases risks for mobility limitations and disability in older adults. We examined the long-term effects of an intensive lifestyle intervention (ILI) versus diabetes support and education (DSE) and body mass index (BMI) on disability. METHODS:Disability was assessed using the Pepper Assessment Tool for Disability (PAT-D) over four post-trial visits in Look AHEAD participants with type 2 diabetes and overweight/obesity. Disability and severe disability were defined as self-reporting "a lot of difficulty" or "unable" to perform ≥1 and ≥3 activities, respectively, on PAT-D subscales for mobility, instrumental, and basic activities of daily living (IADLs and BADLs). Associations between intervention group and BMI with disability prevalence were analyzed with GEE regression models, adjusting for demographics, multimorbidity index, cognition, physical performance, and diabetes control. RESULTS:Among 1191 participants at the first post-trial visit, mean (±SD) age was 68.7 ± 5.7 years, BMI was 34.4 ± 6.1 kg/m2; 61% were female, 69% White, and 52% assigned to ILI. Over nine years of follow-up, odds of severe mobility disability were higher for ILI participants aged ≥70 years (OR [95% CI]: 1.50 [1.02-2.20]) but lower for those in ILI <70 years (0.69 [0.48-0.99]) compared to controls (interaction p = .0043). Participants with BMI ≥35 kg/m2 had higher odds of mobility disability (2.06 [1.57-2.70]), severe mobility disability (2.52 [1.79-3.56]), and IADL disability (OR [95% CI]: 2.15 [1.53-3.02]) compared to those with BMI <30 kg/m2. CONCLUSION:ILI was associated with greater severe mobility disability in participants ≥70. Regardless of age, those with higher BMI had increased late-life mobility and IADL disability.

Both short and long sleep duration have been associated with poor glycemic control and an increased risk of developing type 2 diabetes mellitus. Although sleep duration may differentially modify the effects of genetic risk factors for type 2 diabetes, this has not been systematically investigated. In the present study, we conducted genome-wide gene by sleep duration meta-analyses, separately assessing interactions of short and long sleep, for fasting glucose, fasting insulin, and hemoglobin A1c in up to 489,309 individuals without diabetes from seven different population groups. In total, 16 loci were identified to interact with sleep duration - six with short sleep and ten with long sleep. Of these, four loci were identified through cross-population meta-analysis. Mapped genes exhibit pathway connections to pericyte apoptosis, NMDA receptor activity, the GLUT1 receptor, neurological health, and sleep architecture. Eleven loci (VRK2, PCDH7, TFAP2A, CAP2, PAPPA, ZCCHC2, MYH9, SGIP1, JAKMIP3, RRAS2, MAPT) have not been reported in previous glycemic trait genome-wide association studies. Interaction loci identify divergent biological mechanisms for short and long sleep duration influencing glycemic control, suggesting specific pathways of intervention for precision medicine approaches to diabetes prevention and management.

The aim of this study was to assess the prevalence of potentially inappropriate medication (PIM) use among adults ≥ 65 years, overall and for population subgroups, and factors associated with prevalent PIM use. Participant and medications data from the Atherosclerosis Risk in Communities (ARIC), Multi-ethnic Study of Atherosclerosis (MESA), and Action for Health in Diabetes (Look AHEAD) were used. The total number of individuals contributing to analysis was 9439 for ARIC, 5223 for MESA, and 3771 for Look AHEAD. Participants’ medication data were collected at study exams with medication inventories. Prevalence of any PIM use (yes/no), total number of PIMs used, and the major drug classes of PIMs used within a cohort were identified using Beers Criteria closest to the time of study exam (1997 onward) for all participants aged 65 years or older. Multivariable adjusted logistic regression was used to assess demographic and clinical factors associated with prevalence of any Beers Criteria PIM at the first exam after turning 65 years of age, separately for each cohort. The prevalence of PIM use at the first exam at ≥ 65 years was 67

ABSTRACT Objective We explore associations that four weight-sensitive and neuroactive cytokines – adiponectin, leptin, interleukin-6 (IL-6), and vascular endothelial growth factor (VEGF) – have with cross-sectional brain volumes among adults with obesity or overweight and with type 2 diabetes (T2D). Methods Cytokine concentrations were assayed at baseline and proximal to the end of two 10-year lifestyle interventions among 233 Look AHEAD trial participants. Magnetic resonance imaging measured total, white, and gray matter brain volumes. Associations that cytokine concentrations and changes in concentrations had with brain volumes and weight changes were assessed. Results Higher IL-6 and VEGF concentrations were associated with smaller total brain volumes (β=-3.00 [95% CI -14.82,-3.07] and β=-2.79 [-10.08,-1.74] log-units/cc respectively). Higher leptin concentrations were associated with higher white matter volumes (β=2.00 [-0.06,6.92] log-units/cc). Increases in adiponectin were associated with greater total brain volumes (β=2.14 [0.50,11.94] log-units/cc). Higher leptin and IL-6 concentrations were associated cross-sectionally with greater body mass index (BMI) and increases in leptin, IL-6, and VEGF concentrations were associated with increases in BMI. Neither lifestyle intervention nor changes in BMI materially affected associations between cytokines and brain volumes. Conclusions Weight-sensitive neuroactive cytokine concentrations are related to brain volumes. Weight changes and lifestyle interventions targeting weight loss may not materially influence these associations in adults with T2D.

BACKGROUND:Home blood pressure (BP) monitoring (HBPM) is increasingly used as an alternative to office BP. However, factors influencing agreement between office and home BP among very old adults remain unclear. METHODS:During ARIC (Atherosclerosis Risk in Communities) visit 10, participants underwent 3 automated office BP (AOBP) measurements using an Omron HEM-907XL and performed HBPM twice daily for 8 days using an Omron BP7450. Discordance was defined as a systolic BP difference of ±10 mm Hg between mean AOBP and HBPM. Multivariable regression models evaluated demographic, anthropometric, and clinical factors associated with discordance. RESULTS:Among 792 participants (58% female; mean age, 84±3.7 years), mean systolic BP was 130.6 mm Hg (AOBP) and 129.6 mm Hg (HBPM). Despite a minimal average difference (1.0±15.7 mm Hg), 49% had ≥10 mm Hg systolic BP discordance. Higher AOBP was associated with greater discordance. Compared with females, males had lower AOBP relative to HBPM (-4.69 mm Hg [95% CI, -6.86 to -2.51]). Smaller arm circumference was associated with higher discordance (β=14.4 mm Hg [95% CI, 4.78-24.04]). Frail adults had lower AOBP relative to HBPM (β, -5.1 mm Hg [95% CI, -11.0 to 0.9]). Baseline AOBP systolic BP ≥140 mm Hg strongly predicted discordance ≥+10 mm Hg (odds ratio, 8.27 [95% CI, 5.52-12.40]). Participants aged 91 to 100 years had lower AOBP than those aged 78 to 80 years (β, -5.0 mm Hg [95% CI, -10.06 to 0.001]). CONCLUSIONS:Among very old adults, substantial BP discordance between AOBP and HBPM was common and influenced by higher BP, age, male sex, arm circumference, and frailty.

The Atherosclerosis Risk in Communities (ARIC) study started in 1987-1989 (visit 1), when participants from four U.S. communities were 45-64yo. Participants have been seen at up to 10 additional in-person visits with annual/semi-annual telephone calls to ascertain clinical events, hospitalizations, and other health outcomes. In 2011-2013, at ARIC visit 5, the ARIC Neurocognitive Study (ARIC-NCS) was initiated for surviving participants, incorporating neuropsychological assessments at multiple in-person visits and informant interviews to support cognitive adjudication. A subset of participants have undergone brain MRI with measurement of brain volumes, cortical thickness, arterial disease and vascular lesions, with a smaller subset having brain florbetapir PET. Blood-based Alzheimer's disease (AD) biomarkers are available at multiple visits along with extensive measurement of vascular risk factors, vascular markers, and -omic (e.g.genomic and proteomic) data. This presentation will focus on the available data in ARIC, the methods underlying its collection and subsequent analysis, and some of the primary contributions of this study to the field. With 37 years of follow-up, a great strength of ARIC is the ability to evaluate risk factors in midlife; ARIC studies have supported an association of midlife hypertension, diabetes, physical inactivity, and other vascular risk factors with reduced dementia risk, even among those with increased genetic risk for dementia. ARIC studies have demonstrated associations between stroke and dementia, and have linked vascular risk factors with blood-based and imaging biomarkers of AD-related dementias. ARIC has demonstrated the importance of hearing loss in dementia risk, and a subset of ARIC participants were recruited into (and were those who most benefited from the intervention of) the ACHIEVE study of hearing aid use for reduction of dementia. Proteomic studies have identified markers of dementia risk when evaluated in midlife. Recently, ARIC data informed updated estimates on lifetime risk of dementia, where it was estimated that among individuals surviving beyond age 55, 42% would develop dementia over their lifetime through age 95. ARIC studies continue to focus on risk factors for dementia, particularly now in the oldest old, and on contributors to cognitive reserve and resilience. ARIC follows a model of data sharing and broad collaboration.

ObjectiveThe objective of this study was to elucidate associations between adiposity reduction and changes in HbA1c and insulin use among adults with type 2 diabetes and overweight or obesity.MethodsChanges in BMI, waist circumference, and total percent fat mass were obtained over 8 years among 1316 individuals (aged 45-76 years) enrolled in the Look AHEAD (Action for Health in Diabetes) clinical trial of weight loss. Generalized linear models were used to assess relationships between 5% decreases in adiposity measures with glycated hemoglobin (HbA1c) and insulin use over time.ResultsA 5% reduction in total percent fat was associated with 0.15% (95% CI: 0.12%-0.18%) lower mean HbA1c. Similarly, 5% reductions in waist circumference and BMI were also associated with slightly lower mean HbA1c: 0.16% (95% CI: 0.13%-0.19%) and 0.13% (95% CI: 0.11%-0.16%), respectively. These reductions were associated with lower odds of insulin use over time, ranging from 21% lower odds for a 5% reduction in percent body fat to 32% lower odds for 5% reductions in waist circumference and BMI. Associations were evident across subgroups defined by sex, diabetes duration, obesity status, and intervention assignment.ConclusionsReductions in adiposity are associated with stabilized and slightly lower HbA1c and a marked reduction in the need for insulin therapy. These benefits generalize across clinical subgroups.

BACKGROUND:The Aging and Cognitive Health Evaluation in Elders (ACHIEVE) randomized trial (n = 977;ClinicalTrials.gov:NCT03243422) demonstrated that hearing intervention slowed 3-year cognitive decline by 48% among a subgroup of participants. To further investigate differences by treatment with respect to cognitive benefit, we tested the hypothesis that hearing intervention is associated with improved neurodegeneration blood biomarkers 3-years post-randomization and assessed whether combining biomarkers and cognitive results improved power in the trial design. METHOD:The ACHIEVE study is a multicenter, parallel-arm, randomized trial (hearing intervention vs health education control) on 3-year cognitive decline among adults 70-84years with untreated hearing loss and without substantial cognitive impairment. Participants were recruited from two populations: (1) a long-standing cardiovascular health observational study (Atherosclerosis Risk in Communities [ARIC]), and (2) de novo community volunteers. Plasma was collected in year 3 in a subsample (n = 540) while ARIC participants (n = 164) also had baseline plasma. Glial fibrillary acidic protein (GFAP) and neurofilament light (NfL) neurodegenerative biomarkers were derived using the Alamar CNS protein panel. Regression models estimated the association of treatment with 3-year biomarkers and global cognitive differences in the combined sample and by recruitment source and annualized change from baseline in the ARIC sample. We included a simple composite score of the standardized outcomes (Table 2). RESULT:Among the subsample, baseline characteristics were balanced by treatment. There were no significant differences on 3-year neurodegeneration biomarker levels by treatment in the combined (Table 1) or de novo groups (Table 2). Among ARIC participants, intervention resulted in lower 3-year GFAP (mean:-0.415;95%CI:-0.712,-0.118) and NfL (mean:-0.349;95%CI:-0.652,-0.046) (Table 2). Annualized change from baseline analyses among ARIC participants (Table 3) revealed intervention was associated with a slower rate of cognitive decline (difference-in-means:0.059;95%CI:0.018,0.100) and a slower rate of increase in GFAP (difference-in-means: -0.060;95%CI:-0.112,-0.009). Differences in estimates suggest combined score, relative to cognition alone, may increase power in clinical trials that show a positive effect (ARIC subgroup: p = 0.02vs. 0.08[Table 2] and p = 0.0009vs.0.048[Table 3]). CONCLUSION:Hearing intervention was associated with positive 3-year effects on neurodegeneration blood biomarkers in ARIC participants which parallels cognitive decline results. Results provides objective evidence of brain changes following hearing intervention and potential signal of a more powerful combined outcome approach for future brain health clinical trials.

Background: Postural drops in systolic blood pressure (SBP) are associated with cardiovascular and hypotension-related adverse events (falls, syncope). These associations are traditionally thought to be secondary to low standing blood pressure; however, the role of both high and low SBP in supine and standing positions has not been thoroughly characterized. Objectives: To compare traditional and alternative derivations of supine and standing SBP with adverse cardiovascular and hypotension-related outcomes. Methods: The Atherosclerosis Risk in Communities (ARIC) study measured supine and standing SBP in adult participants aged 45-64 between 1987–1989 and followed them for over 30 years. We examined low and high values (see Table) of supine SBP, standing SBP, absolute and relative differences in SBP after standing, and mean SBP between both positions in relation to adjudicated coronary heart disease (CHD) or all-cause mortality events as well as medical claims-based falls and syncope. We used Cox regression with adjustment for CVD risk factors. Cutpoints were chosen to match a population percentile approximating a 20 mm Hg difference between supine and standing SBP (the traditional definition for orthostatic hypotension). Results: Among 11,399 participants (mean age 54 yr [SD, 5.7]; 56% female; 25% Black adults), relative or absolute drops in SBP were associated with CHD and mortality. Higher mean supine and standing BP was also associated with CHD (HR 1.72; 1.41, 2.09) and all-cause mortality (HR 1.74; 1.54, 1.96). An absolute decrease (HR 1.24; 1.02, 1.50) or increase (HR 1.27; 1.01, 1.60) in SBP was associated with falls. An absolute or relative decrease (both HRs 1.48) and higher supine SBP (HR 1.30; 1.07, 1.58) were associated with syncope. Lower supine SBP was inversely associated with CHD (HR 0.62) and all-cause mortality (HR 0.82). Lower standing SBP was also inversely associated with CHD (HR 0.78; 0.64, 0.94) but not with falls or syncope. Conclusion: While both cardiovascular and hypotension-related outcomes were associated with postural drops in SBP, these outcomes were not consistently associated with low standing SBP. Rather, high supine SBP was associated with a greater risk of CHD, syncope, and death. Moreover, a rise in SBP with standing was associated with falls. These findings call attention to high SBP as a risk factor for both cardiovascular and hypotension-related outcomes and may have implications for treatment strategies if replicated.

BACKGROUND:Our understanding of traditional atherosclerotic risk factors is based predominantly on one-time measurements and associations with adverse cardiovascular outcomes. OBJECTIVES:The aim of this study was to evaluate the contribution of mid- to late-life cumulative risk factor exposure to healthy arterial aging, represented by a persistent coronary artery calcium (CAC) score of zero. METHODS:Among 2,044 community-dwelling, participants free of coronary heart disease from the ARIC (Atherosclerosis Risk in Communities) study, the associations of ∼30-year time-weighted average mid- to late-life (starting at a median age of 49 years in 1987-1989) traditional atherosclerotic risk factors (cholesterol, systolic blood pressure, fasting glucose, and smoking) with late-life (median age 80 years in 2018-2019) CAC 0 were evaluated. RESULTS:A total of 204 participants (10.0%) had CAC 0, and they tended to have more favorable mid- to late-life average risk factor profiles than those with CAC: lower total cholesterol, especially <160 mg/dL; lower systolic blood pressure, especially <125 mm Hg; and higher high-density lipoprotein cholesterol, especially >45 mg/dL. The association was less evident for fasting glucose, with no increased probability of CAC 0 at <95 mg/dL. Never smoking was associated with a 5.7 (95% CI: 2.3-16.7) times greater odds of CAC 0 vs smoking throughout mid- to late-life. Within sex-race groups, average modifiable risk factors predicted substantial differences in CAC 0 probability (eg, for a Black woman, 53% vs 0.4% for a low vs high risk factor profile, respectively). CONCLUSIONS:Favorable average risk factor profiles at mid- to late-life were associated with a greater probability of CAC 0 at older age. These results highlight the importance of maintaining a healthy risk factor profile from mid- to late-life, with implications for public health promotion and policy.

BACKGROUND AND AIMS:Deviations from the population mean in sleep duration have been associated with increased risk for developing dyslipidemia and atherosclerotic cardiovascular disease, but the mechanism of effect is poorly characterized. We performed large-scale genome-wide gene-sleep interaction analyses of lipid levels to identify genetic variants underpinning the biomolecular pathways of sleep-associated lipid disturbances and to suggest possible druggable targets. METHODS:We collected data from 55 cohorts with a combined sample size of 732,564 participants (87 % European ancestry) with data on lipid traits (high-density lipoprotein [HDL-c] and low-density lipoprotein [LDL-c] cholesterol and triglycerides [TG]). Short (STST) and long (LTST) total sleep time were defined by the extreme 20 % of the age- and sex-standardized values within each cohort. Based on cohort-level summary statistics data, we performed meta-analyses for one-degree of freedom tests of interaction and two-degree of freedom joint tests of the SNP-main and -interaction effect on lipid levels. RESULTS:The one-degree of freedom variant-sleep interaction test identified 10 novel loci (Pint<5.0e-9), and we additionally identify 7 loci within the two-degree of freedom analyses (Pjoint<5.0e-9 in combination with Pint<6.6e-6). Multiple loci, including those mapped to APSH (target for aspartic and succinic acid) and SLC8A1 showed biological plausibility and druggability potential based on literature. CONCLUSIONS:Collectively, the 17 (9 with short and 8 with long sleep) loci provided evidence into the biomolecular mechanisms underlying sleep-associated lipid changes, including potential involvement of the vitamin D receptor pathway. Collectively, these findings may contribute developing novel interventions for treating dyslipidemia in people with sleep disturbances.

Introduction and Objective: Look AHEAD, a randomized trial initiated in 2001 comparing intensive lifestyle intervention (ILI) and diabetes support and education (DSE) in 5145 individuals with overweight/obesity and type 2 diabetes, found no significant differences in all-cause mortality during 10 yrs of intervention nor at 17 yrs of follow-up. The cohort has been followed continuously since the close of the trial in an observational study. Throughout this period, cumulative weight loss has been significantly greater in ILI than in DSE. Since effects of ILI may take many years to emerge, we pursued an intense mortality search, yielding 500 new deaths, and conducted an intent-to-treat analysis comparing mortality in ILI to DSE for a maximum of 23 yrs. Methods: The cohort of 5145 initially included adults aged 45-76 yrs, 59% female, 37% from underrepresented groups, and 14% with prior cardiovascular disease. Primary outcome for the current analysis was all-cause mortality from randomization to 23 yrs. Other outcomes included interactions by pre-specified subgroups. Analyses used proportional hazards regression and likelihood ratio tests. Results: A total of 1661 deaths were recorded (800 in ILI and 861 in DSE) across 80,725 person-yrs. The incidence of all-cause mortality was reduced in ILI relative to DSE (hazard ratio [HR] 0.89 [95% CI 0.81, 0.98]). There were no significant interactions between treatment and prespecified subgroups of age, sex, and cardiovascular disease history. However, race/ethnicity interacted with treatment (p = 0.01) yielding HRs for participants identifying as Hispanic 0.54 (CI 0.39, 0.74), Caucasian 0.94 (CI 0.84, 1.05), and African American 0.96 (CI 0.75, 1.23). Conclusion: ILI focused on weight loss modestly reduced long-term mortality risk in persons with diabetes and obesity/overweight, which appears to be driven by a strong reduction in mortality among participants of Hispanic ethnicity. L.E. Wagenknecht: None. J.K. Evans: None. H. Chen: None. D.K. Houston: None. C. Semelka: None. T.D. Beckner: None. P.J. Huckfeldt: None. M.E. Salive: None. S.B. Kritchevsky: None. H.P. Hazuda: None. D.M. Reboussin: None. R.R. Wing: None. M. Espeland: Consultant; Nestlé Health Science. Other Relationship; AnnovisBio, Acumen. National Institute of Aging (U01AG073697)

Cigarette smoking influences blood pressure (BP) levels. Studying and accounting for potential gene-smoking interactions can help discover novel loci and provide insights into biological pathways for smoking-associated BP regulation. We conducted a genome-wide association meta-analysis involving 1,188,241 individuals from 66 studies in five ancestry groups, analyzing systolic BP, diastolic BP, and pulse pressure while considering interactions between genetic variants and three smoking exposures: smoking status, cigarettes per day, and pack years. These analyses identified twelve novel loci for BP at genome-wide significance ( P < 5 × 10 - 9 ), and highlighted biological processes including tight junction integrity, mitochondrial health, vascular relaxation, and endothelial function. In smoking status-stratified analyses, smoking modifies the genetic effect of six variants on BP. To prioritize likely causal, we developed and applied SuSiEgxe, a fine-mapping method based on a two-degree-of-freedom joint test using gene-environment interaction summary statistics. Fine-mapped loci uncovered immune-related pathway for smoking-associated BP regulation.

The Atherosclerosis Risk in Communities (ARIC) study started in 1987-1989 (visit 1), when participants from four U.S. communities were 45-64yo. Participants have been seen at up to 10 additional in-person visits with annual/semi-annual telephone calls to ascertain clinical events, hospitalizations, and other health outcomes. In 2011-2013, at ARIC visit 5, the ARIC Neurocognitive Study (ARIC-NCS) was initiated for surviving participants, incorporating neuropsychological assessments at multiple in-person visits and informant interviews to support cognitive adjudication. A subset of participants have undergone brain MRI with measurement of brain volumes, cortical thickness, arterial disease and vascular lesions, with a smaller subset having brain florbetapir PET. Blood-based Alzheimer's disease (AD) biomarkers are available at multiple visits along with extensive measurement of vascular risk factors, vascular markers, and -omic (e.g.genomic and proteomic) data. This presentation will focus on the available data in ARIC, the methods underlying its collection and subsequent analysis, and some of the primary contributions of this study to the field. With 37 years of follow-up, a great strength of ARIC is the ability to evaluate risk factors in midlife; ARIC studies have supported an association of midlife hypertension, diabetes, physical inactivity, and other vascular risk factors with reduced dementia risk, even among those with increased genetic risk for dementia. ARIC studies have demonstrated associations between stroke and dementia, and have linked vascular risk factors with blood-based and imaging biomarkers of AD-related dementias. ARIC has demonstrated the importance of hearing loss in dementia risk, and a subset of ARIC participants were recruited into (and were those who most benefited from the intervention of) the ACHIEVE study of hearing aid use for reduction of dementia. Proteomic studies have identified markers of dementia risk when evaluated in midlife. Recently, ARIC data informed updated estimates on lifetime risk of dementia, where it was estimated that among individuals surviving beyond age 55, 42% would develop dementia over their lifetime through age 95. ARIC studies continue to focus on risk factors for dementia, particularly now in the oldest old, and on contributors to cognitive reserve and resilience. ARIC follows a model of data sharing and broad collaboration.

Importance Nocturnal hypertension while asleep is associated with substantial increases in risk of cardiovascular disease (CVD) and death. Whether hypertension while supine is a risk factor associated with CVD independent of seated hypertension remains unknown. Objective To investigate the association between supine hypertension and CVD outcomes and by hypertension treatment status. Design, Setting, and Participants This prospective cohort study used data from the Atherosclerosis Risk in Communities (ARIC) study, which was established in 1987 to examine cardiovascular risk factors among middle-aged adults from 4 communities in the US. Supine and seated blood pressure were measured in more than 13 000 middle-aged adults with longitudinal surveillance for CVD over 27 years. Participants with a history of coronary heart disease (CHD), heart failure, or stroke were excluded. Data were analyzed from May 2023 through December 2024. Exposures Supine hypertension (supine systolic blood pressure >= 130 or diastolic blood pressure >= 80 mm Hg) with and without seated hypertension (seated systolic blood pressure >= 130 or diastolic blood pressure >= 80 mm Hg). Main Outcomes and Measures Cox proportional hazard models with adjustment for CVD risk factors were performed to investigate the association of supine hypertension with and without seated hypertension with incident CHD, heart failure, stroke, fatal CHD, and all-cause mortality. Results Of 11 369 participants without known CVD (6332 female [55.7%] and 5037 male [44.3%]; 2858 Black [25.1%] and 8511 White [74.9%]; mean [SD] age 53.9 [5.7] years]), 16.4% (95% CI, 15.5%-17.2%) of those without seated hypertension had supine hypertension and 73.5% (95% CI, 72.2%-74.8%) of those with seated hypertension had supine hypertension. Supine hypertension was associated with incident CHD (hazard ratio [HR], 1.60; 95% CI, 1.45-1.76), heart failure (HR, 1.83; 95% CI, 1.68-2.01), stroke (HR, 1.86; 95% CI, 1.63-2.13), fatal CHD (HR, 2.18; 95% CI, 1.84-2.59), and all-cause mortality (HR, 1.43; 95% CI, 1.35-1.52) during a median (25th, 75th percentile) follow-up of 25.7 (15.4, 30.4) years, 26.9 (17.6, 30.5) years, 27.6 (18.5, 30.6 years), 28.3 (20.5, 30.7) years, and 28.3 (20.5 years, 30.7) years, respectively. There were no meaningful differences by seated hypertension status. Results were similar by hypertension medication use. Participants with supine hypertension alone had risk associations similar to those of participants with hypertension in both positions and significantly greater than those of participants with seated hypertension alone with the exception of fatal CHD; seated vs supine HRs were 0.72 (95% CI, 0.61-0.85) for CHD, 0.72 (95% CI, 0.60-0.85) for heart failure, 0.66 (95% CI, 0.51-0.86) for stroke, and 0.83 (95% CI, 0.74-0.92) for all-cause mortality. Conclusions and Relevance Supine hypertension regardless of seated hypertension had a higher HR for CVD risk than seated hypertension alone. Future research should evaluate supine hypertension in the setting of nocturnal hypertension and as an independent target of blood pressure treatment.

The Aging and Cognitive Health Evaluation in Elders (ACHIEVE) randomized trial ( n  = 977;ClinicalTrials.gov:NCT03243422) demonstrated that hearing intervention slowed 3-year cognitive decline by 48% among a subgroup of participants. To further investigate differences by treatment with respect to cognitive benefit, we tested the hypothesis that hearing intervention is associated with improved neurodegeneration blood biomarkers 3-years post-randomization and assessed whether combining biomarkers and cognitive results improved power in the trial design. The ACHIEVE study is a multicenter, parallel-arm, randomized trial (hearing intervention vs health education control) on 3-year cognitive decline among adults 70–84years with untreated hearing loss and without substantial cognitive impairment. Participants were recruited from two populations: (1) a long-standing cardiovascular health observational study (Atherosclerosis Risk in Communities [ARIC]), and (2) de novo community volunteers. Plasma was collected in year 3 in a subsample ( n  = 540) while ARIC participants ( n  = 164) also had baseline plasma. Glial fibrillary acidic protein (GFAP) and neurofilament light (NfL) neurodegenerative biomarkers were derived using the Alamar CNS protein panel. Regression models estimated the association of treatment with 3-year biomarkers and global cognitive differences in the combined sample and by recruitment source and annualized change from baseline in the ARIC sample. We included a simple composite score of the standardized outcomes (Table 2). Among the subsample, baseline characteristics were balanced by treatment. There were no significant differences on 3-year neurodegeneration biomarker levels by treatment in the combined (Table 1) or de novo groups (Table 2). Among ARIC participants, intervention resulted in lower 3-year GFAP (mean:-0.415;95%CI:-0.712,-0.118) and NfL (mean:-0.349;95%CI:-0.652,-0.046) (Table 2). Annualized change from baseline analyses among ARIC participants (Table 3) revealed intervention was associated with a slower rate of cognitive decline (difference-in-means:0.059;95%CI:0.018,0.100) and a slower rate of increase in GFAP (difference-in-means: -0.060;95%CI:-0.112,-0.009). Differences in estimates suggest combined score, relative to cognition alone, may increase power in clinical trials that show a positive effect (ARIC subgroup: p  = 0.02vs. 0.08[Table 2] and p  = 0.0009vs.0.048[Table 3]). Hearing intervention was associated with positive 3-year effects on neurodegeneration blood biomarkers in ARIC participants which parallels cognitive decline results. Results provides objective evidence of brain changes following hearing intervention and potential signal of a more powerful combined outcome approach for future brain health clinical trials.

Background and aims: The association of physical activity (PA) with coronary artery calcification (CAC), one of the strongest predictors of cardiovascular disease, is unclear. Moreover, different domains of PA (e.g., exercise/ sports vs. work) and extra-coronary calcification (ECC) have not been extensively studied. We comprehensively evaluated the association of PA with CAC and ECC. Methods: We investigated 2025 ARIC participants (age 73-95 years) without coronary heart disease at visit 7 (2018-19). Mid-life total and domain-specific (sport, leisure, and work) PA scores were estimated using a modified Baecke questionnaire. We modeled the averaged PA scores at visit 1 (1987-89; age 44-65 years) and visit 3 (1993-95; age 49-70 years). We explored continuous CAC and ECC (log-transformed [Agatston score+1]) or the presence of any CAC and ECC (Agatston score >0 vs. 0) as dependent variables using multivariable linear regression and logistic regression models, as appropriate. Results: Total PA scores showed a U-shaped association with both continuous and any vs. no CAC. Higher total PA scores were associated inversely with ECC and most pronounced for the descending aorta calcification. The associations were generally consistent across demographic subgroups. When specific PA domains were examined, higher sport and work PA scores were significantly associated with lower descending aorta calcification. Conclusions: Mid-life PA showed a U-shaped association with late-life CAC. Among ECC, the association of higher PA with lower calcification of the descending aorta was the most consistent. Our results further corroborate a complex interplay between PA and vascular health and unique pathological processes across different vascular beds.

Here, we present a multi-omics study of type 2 diabetes and quantitative blood lipid and lipoprotein traits conducted to date in Hispanic/Latino populations (nmax = 63,184). We conduct a meta-analysis of 16 type 2 diabetes and 19 lipid trait GWAS, identifying 20 genome-wide significant loci for type 2 diabetes, including one novel locus and novel signals at two known loci, based on fine-mapping. We also identify sixty-one genome-wide significant loci across the lipid/lipoprotein traits, including nine novel loci, and novel signals at 19 known loci through fine-mapping. Next, we analyze genetically regulated expression, perform Mendelian randomization, and analyze association with transcriptomic and proteomic measure using multi-omics data from a Hispanic/Latino population. Using this approach, we identify genes linked to type 2 diabetes and lipid/lipoprotein traits, including TMEM205 and NEDD9 for HDL cholesterol, TREH for triglycerides, and ANXA4 for type 2 diabetes.

Although both short and long sleep duration are associated with elevated hypertension risk, our understanding of their interplay with biological pathways governing blood pressure remains limited. To address this, we carried out genome-wide cross-population gene-by-short-sleep and long-sleep duration interaction analyses for three blood pressure traits (systolic, diastolic, and pulse pressure) in 811,405 individuals from diverse population groups. We discovered 22 novel gene-sleep duration interaction loci for blood pressure, mapped to 23 genes. Investigating these genes’ functional implications shed light on neurological, thyroidal, bone metabolism, and hematopoietic pathways that necessitate future investigation for blood pressure management that caters to sleep health lifestyle. Non-overlap between short sleep (12) and long sleep (10) interactions underscores the plausible nature of distinct influences of both sleep duration extremes in cardiovascular health. Several of our loci are specific towards a particular population background or sex, emphasizing the importance of addressing heterogeneity entangled in gene-environment interactions, when considering precision medicine design approaches for blood pressure management.