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Abstract P3074: Metabolomic Insights into Meat Consumption and Blood Pressure: The INTERLIPID Study
Introduction: The westernization and modernization of diet have gradually increased among the Japanese people, resulting in greater consumption of meat. Metabolic profiling can be considered a useful tool to ensure more accurate assessment of meat consumption and to clarify its underlying mechanisms associated with cardiovascular health outcomes. Hypothesis: We hypothesized that greater meat consumption could potentially lead to an elevation in blood pressure (BP), which was elucidated through meat-related candidate serum metabolites. Methods: A total of 1,007 Japanese participants aged 40-59 years residing in Japan were selected from the INTERLIPID study. Data on systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP), dietary intakes, urinary, serum metabolites and lifestyle factors were collected. Serum metabolites were measured by nuclear magnetic resonance (NMR) spectroscopy and liquid-chromatography mass spectrometry (LC-MS). Associations between BP and serum metabolites were identified through partial Spearman correlation, and the effect of candidate serum metabolites of meat consumption on BP was explored by stepwise multiple linear regression considering age and sex. Results: The median of self-reported total meat intake was 28.98 g/1000kcal in men and 24.50 g/1000kcal in women. The multivariable linear regression results indicated that total meat and poultry intakes were significantly and positively related to BP. A total of 7 metabolites among 25 NMR and 29 metabolites among 51 LC-MS serum metabolites significantly correlated with meat consumption. Stepwise multiple linear regression indicated that the commonly related metabolites (p-value <0.05) for SBP, DBP and MAP were palmitoylcarnitine, carnitine and octanoylcarnitine. Additionally, the other associated metabolites included isovalerylcarnitine for SBP (β 1.24, CI 0.32-2.15), while for DBP, hexanoylcarnitine (β 1.61, CI 0.78-2.44), and niacinamide (β 0.73, CI 0.16-1.30). Conclusions: Higher meat consumption was significantly associated with elevated BP in Japanese. Some metabolites including palmitoylcarnitine, carnitine and octanoylcarnitine were suggested as important contributors to this association, offering novel insights into the metabolic mechanisms linking diet and BP.
Abstract P2085: Variation in Incident Atherosclerotic Cardiovascular Disease Across Asian American, Native Hawaiian and other Pacific Islander Subgroups: The PANACHE Study
Introduction: Atherosclerotic cardiovascular disease (ASCVD) risk varies substantially across racial and ethnic groups, yet few data exist among disaggregated Asian American, Native Hawaiian, and Pacific Islander (AANHPI) subgroups. Methods: We identified 2,653,007 members of Kaiser Permanente Northern California and Kaiser Permanente Hawaii integrated healthcare delivery systems from 2012-2022 who were aged ≥30 years with no evidence of prior cardiovascular disease. ASCVD events (acute myocardial infarction and stroke) were identified through December 2023 using validated discharge codes and death certificates. We calculated age- and sex-adjusted rates of incident ASCVD by racial/ethnic subgroup. We then examined the multivariable association between AANHPI subgroup with incident ASCVD compared to non-Hispanic White, after adjustment for age, sex, diabetes, hypertension, dyslipidemia, chronic kidney disease, body mass index, and tobacco use. Results: Between 2012-2022, we identified 182,776 Chinese, 193,327 Filipino, 64,488 Native Hawaiian/other Pacific Islander, 45,502 Japanese, 21,989 Korean, 92,738 South Asian, 50,141 Vietnamese, 26,602 other Southeast Asian, and 1,975,444 non-Hispanic White eligible adults. Mean (SD) age was 49 (15) years overall, ranging from 41 (12) years in South Asian to 55 (16) years in Japanese, with 53% women and higher proportions of women in AANHPI subgroups compared to non-Hispanic Whites. Age- and sex-adjusted rates (per 1000 person-years) of incident ASCVD vs. non-Hispanic Whites (3.61) from highest to lowest in AANHPI subgroups were: Native Hawaiian/other Pacific Islander (6.97), other Southeast Asian (5.37), South Asian (4.85), Filipino (4.23), Vietnamese (3.28), Japanese (3.20), and Chinese (2.50). After adjustment for traditional mediators of cardiovascular risk, compared to non-Hispanic Whites, incident ASCVD was higher for Native Hawaiian/other Pacific Islanders, South Asians, and other Southeast Asians; lower for Chinese, Japanese and Korean; and not significantly different for Filipino and Vietnamese ( Figure ). Conclusions: In a large, contemporary population in California and Hawaii, notable variation existed in the risk of incident ASCVD across AANHPI subgroups that was only partially explained by differences in demographic characteristics and clinical ASCVD risk factors. Delineating AANHPI-specific factors will help to reduce disparities in ASCVD in these growing populations within the U.S.
Abstract P3025: Evaluating the Correlation Between Urinary Microalbumin (ACR), Serum C-Reactive Protein (CRP), and Cardiovascular Risk Markers in Type 2 Diabetes Mellitus
Introduction: Diabetes mellitus (DM) is a common endocrine disorder characterized by hyperglycemia due to insulin deficiency. Over the past 35 years, the incidence of DM has nearly quadrupled, contributing to around 1 million deaths in 2019, with cardiovascular complications as a leading cause. Current management strategies in type 2 DM patients focus on early detection of cardiovascular risk markers, such as urinary microalbumin and serum C-reactive protein (CRP), both of which are cost-effective and minimally invasive. Objectives: To determine the correlation between urinary microalbumin, serum CRP, and albumin-to-creatinine ratio (ACR) with traditional cardiovascular risk markers in patients with type 2 diabetes mellitus. Methods: The study included 87 clinically diagnosed type 2 diabetes mellitus patients on oral antidiabetic medication, aged 35 to 60 years, and with normal serum creatinine levels. After obtaining informed consent, blood and urine samples were collected to assess blood glucose, serum CRP, renal profile, lipid profile, liver function tests, and urinary microalbumin. Albumin creatinine ratio (ACR) and atherogenic index of plasma (AIP) were calculated. Results: Comparison of profiles in the study revealed a significant decrease in serum HDL levels, a higher TG: HDL ratio, elevated glycated hemoglobin (HbA1c), and a raised atherogenic index of plasma (AIP) in cases with CRP ≥ 0.3 mg/dL compared to those with CRP < 0.3 mg/dL. Conversely, serum albumin (p<0.01), ALT, and A:G ratio were decreased in cases with CRP ≥ 0.3 mg/dL. MAU and blood urea nitrogen (BUN) were elevated in cases with ACR ≥ 30 mg/g (p<0.01) compared to those with ACR < 30 mg/g. Pearson’s correlation with CRP showed a negative correlation with total protein, albumin (p=0.01), A:G ratio, and hemoglobin, while BUN and serum ALP showed a positive correlation with CRP. ACR correlated positively with MAU (p=0.01) and negatively with albumin (p=0.05), with both correlations being statistically significant. These results demonstrate an association between urinary microalbumin (ACR), serum CRP, atherogenic index of plasma, and cardiovascular risk markers in type 2 DM. Conclusion: The study suggests that spot microalbuminuria and serum CRP are correlate well with traditional cardiovascular risk markers and can be used as screening tools for cardiovascular disease in DM patients. These markers are inexpensive, minimally invasive and can warrant for timely intervention's.
Characterization of microRNA candidates at the primary site of infectious bronchitis virus infection: A comparative study of in vitro and in vivo avian models
Infectious bronchitis virus (IBV) is an important avian pathogen with a positive-sense single-stranded RNA genome. IBV is the causative agent of infectious bronchitis (IB), a primarily respiratory disease affecting chickens, with the ability to disseminate to other organ systems, such as the gastrointestinal, renal, lymphoid, and reproductive systems. Tracheal epithelial cells are the primary target of IBV, and these cells play a vital role in the effective induction of the antiviral response and eventual clearance of IBV. The host immune system is regulated by a number of different molecular players, including micro-ribonucleic acids (microRNAs), which are small, conserved, non-coding RNA molecules that regulate gene expression of complementary messenger RNA (mRNA) sequences, resulting in gene silencing through translational repression or target degradation. The goal of this study was to characterize and compare the microRNA expression profiles in chicken tracheal epithelial cells (cTECs) in vitro and the trachea in vivo upon IBV Delmarva/1639 (DMV/1639) or IBV Massachusetts 41 (Mass41) infections. We hypothesized that IBV infection influences the expression of the host microRNA expression profiles. cTECs and young specific pathogen-free (SPF) chickens were infected with IBV DMV/1639 or IBV Mass41 and the microRNA expression at 3 and 18 hours post-infection (hpi) in the cTECs and at 4 and 11 days post-infection (dpi) in the trachea were determined using small RNA-sequencing (RNA-seq). We found that the profile of differentially expressed (DE) microRNAs is largely dependent on the IBV strain and time point of sample collection. Furthermore, we predicted the interaction between host microRNA and IBV viral RNA using microRNA-RNA interaction prediction platforms. We identified several candidate microRNAs suitable for future functional studies, such as gga-miR-155, gga-miR-1388a, gga-miR-7/7b and gga-miR-21-5p. Characterizing the interaction between IBV and the host cells at the level of microRNA regulation provides further insight into the regulatory mechanisms involved in viral infection and host defense in chickens following IBV infection.
Genetic ablation of the TET family in retinal progenitor cells impairs photoreceptor development and leads to blindness
The retina is responsible for converting light into electrical signals that, when transmitted to the brain, create the sensation of vision. The mammalian retina is epigenetically unique since the differentiation of retinal progenitor cells (RPCs) into retinal cells is accompanied by a decrease in DNA methylation in the promoters of many genes important for retinal development and function. However, the pathway responsible for DNA demethylation and its role in retinal development and function were unknown. We hypothesized that the Ten-Eleven Translocation (TET) family of dioxygenases plays a key role in this pathway. To this end, we knocked out the TET family in RPCs and characterized the TET-deficient and control retinas using various approaches including electron microscopy, electroretinogram tests, TUNEL, RNA-seq, WGBS, and 5hmC-Seal. We found that while the TET-dependent DNA demethylation pathway contributes to the development of many retinal cell types, it is the most significant contributor to rod and cone photoreceptor development and function. We found that genetic ablation of TET enzymes in RPCs prevents demethylation and the activity of genes essential for rod specification and for rod and cone maturation. Reduced activity of genes responsible for rod specification results in the TET-deficient retina being depleted of these neurons. Meanwhile, reduced activity of genes responsible for rod and cone maturation leads to the underdevelopment or complete absence of outer segments and synaptic termini in the TET-deficient photoreceptors, which results in loss of their function and leads to blindness. These function-deprived, underdeveloped photoreceptors die over time, leading to retinal dystrophy.
Abstract P1128: Trajectories of Physical Activity Before and After Cardiovascular Disease Events in a Diverse Cohort
Background: Physical activity plays a critical role in cardiovascular health throughout the life course. However, data on its trajectories before and after cardiovascular disease (CVD) are limited. We analyzed a bi-racial U.S. cohort with 35 years of repeated assessments of moderate-to-vigorous-intensity physical activity (MVPA) to examine trends and potential variations by race. Methods: CARDIA participants (n=5,115) underwent up to 10 MVPA assessments from 1985-6 to 2020-2. MVPA was assessed via a Physical Activity History Questionnaire and scored in exercise units (EU), with 300 EU approximating 150 minutes/week. During follow-up, 332 participants experienced an incident non-fatal CVD event, and 236 (71%) had subsequent MVPA data, forming the case group. Nested controls were matched 1:1 to cases by age, sex, and race using risk set sampling. LOESS regression explored non-linear MVPA trends, while linear mixed-effects models assessed differences in MVPA slopes between groups. Generalized estimating equation (GEE) models evaluated the odds ratio (OR) of low MVPA (<300 EU) post-CVD. Results: The mean baseline age of the matched sample (n=472) was 26 years; 64% were Black, and 60% were men. The mean age at incident CVD was 49 years. The median (IQR) number of MVPA assessments in cases was 6 (5-8) before and 2 (1-3) after CVD. MVPA levels were consistently higher in controls than in cases, with the gap widening after CVD (Figure), supported by a significant time-by-CVD status interaction ( P = .002). The OR for low MVPA post-CVD in cases vs. controls was 2.45 (95% CI: 1.76-3.41) and was stronger in Black (OR = 3.67, 95% CI: 2.36-5.70) than in White (OR = 1.49, 95% CI: 0.90-2.48) participants ( P interaction = .017). No heterogeneity was detected across CVD types (CHD, stroke, heart failure; P = .90). Conclusions: MVPA levels were consistently lower in cases than controls, with a more pronounced decrease after CVD, perhaps due to physical limitations. The odds of lower-than-recommended MVPA post-CVD were notably higher among Black participants.
Abstract P2095: Demographics, Vascular Risk Factors, and History of Cardiovascular Disease in Relation to Prevalent Epilepsy in Older Adults: A Pooled Analysis of ARIC, CHS, MESA, NOMAS, and WHICAP Cohorts
Introduction: Epilepsy is the third most common neurological disorder in older adults after dementia and stroke. Previous research suggests that vascular risk factors (VRFs) and cardiovascular disease (CVD) are more common in people with epilepsy. Pooling multiple cohorts with detailed characterization of vascular risk factors, CVD, and harmonized epilepsy case ascertainment increases diversity of the sample to be more representative of the US population and increases the numbers of epilepsy cases for greater statistical power. Methods: We pooled individual participant data from five cohorts, including ARIC, CHS, MESA, NOMAS, and WHICAP. For this analysis, we included participants who were 65 years of age or above. In ARIC, CHS, MESA, and WHICAP, which were linked to Medicare Claims, we included participants who had a minimum 2-year continuous Medicare enrollment and ascertained prevalent epilepsy using an algorithm based on ICD codes and antiepileptic medication. In NOMAS, which was not Medicare-linked, prevalent epilepsy cases were ascertained by telephone interview, medical record review, and ICD codes in New York Statewide Planning and Research Cooperative System (SPARCS) data. Risk factors were assessed by self report, blood measures, ECG, physical exams, and medications at cohort baseline. We calculated unadjusted prevalence of epilepsy in each risk factor category and prevalence differences and prevalence ratios adjusted for age, sex, race/ethnicity, and cohort. Results: Among 26,476 participants, 264 had prevalent epilepsy (9.9 cases per 1,000). Unadjusted prevalence of epilepsy was higher in older age groups, women, non-Hispanic Black and Hispanic groups, those with less education, never or current smokers, heavier alcohol drinkers, those with hypertension, diabetes, high cholesterol, underweight, obesity, history of stroke or heart disease, or 2 APOE e4 alleles (Table). Adjusted prevalence of epilepsy was higher among participants in the non-Hispanic Black group (5.3 additional cases per 1,000 [95% CI: 2.1, 8.5]) and among participants who had a history of stroke (12.9 additional cases per 1,000 [95% CI: 3.5, 22.3]). Conclusions: In this pooled cohort analysis, adjusted for age, sex, race/ethnicity, and cohort, prevalence of epilepsy in those over the age of 65 was higher among non-Hispanic Black individuals and among those with a history of stroke.
Abstract P3078: Long-Term Sustainability of a Hypertension Control Initiative
Sustainability, the continuation of a new program, is an ongoing challenge and a barrier to “sustaining” success. The American Heart Association (AHA) has completed the National Hypertension Control Initiative (NHCI), a 3-year demonstration project jointly funded by the United States Department of Health and Human Services’ Office of Minority Health and the Health Resources Services Administration (HRSA) to improve blood pressure (BP) control in 350 low-performing HRSA-funded community health centers (CHCs) with about 1.5 million persons with hypertension (HTN). Implementation strategies to improve BP control included accurate BP measurement, team-based care, standardized treatment protocols, culturally and linguistically appropriate services, and use of self-measured BP (SMBP) monitoring. Sustainability strategies for NHCI include the standardization and protocolization of care processes; adoption of data-informed performance improvement; and continuation and reinforcement of BP control efforts through Target: BP™, a BP control initiative jointly developed and delivered by AHA and the American Medical Association, serving about 9 million persons with HTN. Eligibility for NHCI included BP control < 60%. In 2023, year 3, 55.5% of NHCI CHCs reported BP control ≥60%. They experienced a 9.6% improvement (18.8% relative change) in BP control from 2020-2023, compared to a 7.7% improvement (13.2% relative change) for all HRSA CHCs. In 2023, 89% of NHCI CHCs reported using a BP measurement protocol, 93% reported an SMBP protocol, and 77% reported a BP treatment algorithm. Implementation of protocols and BP improvement will be sustained by pursuing participation in Target: BP. In the 1st and 2nd years of NHCI, 33% and 35%, respectively, of 346 NHCI CHCs concurrently participated in Target: BP. Of those submitting data in 2023, 25% reported control rates ≥70% and 67% reported adoption of evidence-based practices. In 2024, 55% of all CHCs participated in Target: BP. AHA’s NHCI work can be sustained by 1) enrollment of all NHCI CHCs in Target: BP through efforts of AHA staff that supported NHCI activities, 2) leveraging Target: BP tools, resources, and quality improvement support, and 3) seeking extramural funding to support AHA BP control efforts. Sustainability of NHCI through Target: BP could be extended from 346 NHCI CHCs to all 1487 CHCs with over 31 million patients. AHA can ensure sustainability of NHCI efforts beyond the 3-year NHCI period through Target: BP.
Atomic ionization: sd energy imbalance and Perdew–Zunger self-interaction correction energy penalty in 3d atoms
To accurately describe the energetics of transition metal systems, density functional approximations (DFAs) must provide a balanced description of s- and d- electrons. One measure of this is the sd transfer error, which has previously been defined as E ( 3 d n − 1 4 s 1 ) − E ( 3 d n − 2 4 s 2 ) . Theoretical concerns have been raised about this definition due to its evaluation of excited-state energies using ground-state DFAs. A more serious concern appears to be strong correlation in the 4s 2 configuration. Here, we define a ground-state measure of the sd energy imbalance, based on the errors of s- and d-electron second ionization energies of the 3d atoms, that effectively circumvents the aforementioned problems. We find an improved performance as we move from the local spin density approximation (LSDA) to the Perdew-Burke-Ernzerhof (PBE) generalized gradient approximation (GGA) to the regularized and restored Strongly Constrained and Appropriately Normed (r 2 SCAN) meta-GGA for first-row transition metal atoms. However, we find large (∼2 eV) ground-state sd energy imbalances when applying a Perdew–Zunger 1981 self-interaction correction. This is attributed to an “energy penalty” associated with the noded 3d orbitals. A local scaling of the self-interaction correction to LSDA results in a balance of s- and d-errors.
Abstract P1100: Risk of Incident Heart Failure by Gender Identity among US Veterans
Background: Disparities in heart failure (HF) are driven in part by social and structural determinants of health. Rates of HF among transgender and gender diverse (TGD) individuals relative to cisgender (cis) peers are not well described. Methods: We used EHR data from the Veterans Healthcare Administration (VHA) to identify veterans with >2 outpatient encounters from 2010-2019. Gender identity was ascertained using natural language processing in combination with gender-affirming hormone therapy (GAHT) and a validated algorithm utilizing ICD codes and VHA data. Among 1,103,923 veterans, 42,157 were classified as TGD. We examined sample characteristics by gender identity and used Cox regression to assess the association of gender identity with incident HF. Results: TGD veterans’ mean age was 46 years (cis females=40; cis males=53). Median follow-up was 9.41 years. There were 107,766 incident HF events (3,078 among TGD veterans). The HF rate among TGD veterans was 8.19 [95% CI: 7.90-8.48] per 1,000 person-years compared to 13.05 [12.97-13.13] and 3.87 [3.76-3.98] among cis male and cis female veterans, respectively. Adjusting for age, race, Hispanic ethnicity, and sexual minority identity, TGD veterans had 1.51 [1.44-1.58] and 0.89 [0.86-0.92] times the risk of HF compared to cis females and cis males, respectively. Results remained statistically significant with adjustment for additional social, clinical, and structural factors ( Table ). When stratified by gender identity, trans feminine veterans (HR [95% CI]: 1.19 [1.07-1.33]) were at higher HF risk than cis females; trans masculine (HR [95% CI]: 0.79 [0.72-0.86]) and trans feminine veterans (HR [95% CI]: 0.80 [0.72-0.89]) were at lower HF risk than cis males. Conclusion: Trans feminine veterans experienced greater HF risk than cis females, while trans feminine and trans masculine veterans’ HF risk was less than cis males. Future studies should consider the underlying mechanisms of these associations, HF subtypes (HFrEF and HFpEF), and the role of GAHT on HF risk.
Abstract P2104: Prevalence of Hypertrophic Cardiomyopathy Core Gene Variants in Hispanics/Latinos: A Study from The Hispanic Community Health Study / Study of Latinos (HCHS-SOL)
Introduction: Hypertrophic cardiomyopathy (HCM) is an inherited disease associated with genetic variants in sarcomeric genes, mostly studied in White populations. There is a paucity of literature, especially Hispanics/Latinos (H/L) populations where HCM sarcomeric variant prevalence is unknown. Methods: We analyzed whole-genome sequencing data from the Hispanic Community Health Study to assess sarcomeric variants in a diverse H/L sample. We identified HCM variant carriers based on eight sarcomeric genes (MYBPC3, MYH7, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1). Carriers were defined according to predictions from the HumDiv model of PolyPhen-2, by having at least one nonsynonymous deleterious (category D) variant. The prevalence of HCM genetic carrier was estimated accounting for complex survey design. Sociodemographic and clinical variables were analyzed across HCM variant carrier/non-carrier carrier status, with sampling weights used to calculate weighted means, frequencies, and population estimates. Results: Among 7,724 individuals self-identified as H/L, the overall prevalence of HCM variant carrier was 6.08%. The most commonly detected variants were on MYBPC3 and MYH7 while ACTC1 was not observed. (Figure 1. A) HCM variant carriers had a mean age of 41.20 ± 1.00 years, 50.32% were female, and the mean BMI was 30.13 ± 0.36 kg/m^2. There was no difference in burden of comorbidities among carriers and non-carriers. HCM variant carrier status was more likely among the H/L of Dominican descent than any other H/L background group (p<0.001). (Figure 1. B) Conclusions: The prevalence of HCM sarcomeric variants among H/L individuals was higher than previously reported in non-Hispanic populations. Among H/L, MYH7 and MYBPC3 were the most common, consistent with previous reports in non-Hispanic populations. HCM variant carrier prevalence varied across Hispanic background groups, likely due to different makeup of genetic ancestries. Our results identify the H/L population at possible elevated risk for developing clinical HCM, underscoring the need for inclusion of H/L in ongoing studies of HCM evaluation and management strategies. Authors: Jorge Silva Enciso and Reniell Iñiguez are co-first authors.
Abstract P3056: A Metabolomic Study of Cardiac Dysfunction in Hyperglycemia
Objective: Hyperglycemia (pre-diabetes and diabetes, DM) is associated with heart failure (HF). We aimed to identify distinct metabolites for subclinical cardiac dysfunction (CD), a precursor of HF, in hyperglycemic vs. euglycemic groups. Method: We used data from the ARIC study (Atherosclerosis Risk in Communities). In HF-free 2492 participants at baseline (2011-2013), 1297 were hyperglycemic (HbA1c>5.7%, fasting glucose>100 mg/dL, DM medication, or a DM diagnosis) and 1195 were euglycemic. We performed logistic regression for the association of 790 metabolites and CD, defined by echocardiographic abnormalities (LV hypertrophy, systolic or diastolic dysfunction) or elevated biomarkers (NTproBNP>125 pg/mL or HS troponin T>14 ng/L in women, >22 ng/L in men) at baseline in two glycemic groups separately. We used Cox regression to evaluate the association between CD-related metabolites (i.e., significant metabolites in the cross-sectional analyses) with HF risk. Analyses were adjusted for clinical risk factors and multiple comparisons (FDR< 5%) and replicated in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). Results: 34 out of 790 and 16 out of 790 metabolites were associated with CD in the hyperglycemic (15% Black, 33% men) and euglycemic (22% Black, 47% men) groups, respectively. Metabolites previously identified as microvascular disease-related markers (e.g., pseudouridine, N6-carbamoylthreonyladenosine, N6-acetyllysine, N2, N5-diacetylornithine) were associated with CD in the hyperglycemic group (Fig1). Carbohydrate and cofactor-derived metabolites (e.g., gulonate, erythrocyte) were associated with CD in the euglycemic group (Fig1). 10 and 12 distinct CD-related metabolites in hyperglycemic and euglycemic groups, respectively, were also prospectively associated with HF risk (Hazard Ratios 1.2-1.9)(Fig2). 24 out of 34 and 11 out of 16 CD-related metabolites in the hyperglycemic and euglycemic groups, respectively, were available for validation in HCHS/SOL (n 1202, 34% men). The results were consistent with ARIC, where 10 and 12 distinct CD-related metabolites showed nominal significant association with incident HF in two glycemic groups, respectively. Conclusion: Metabolites known for microvascular complications (retinopathy, kidney disease) were associated with CD among hyperglycemic participants, supporting the premise that microvascular dysfunction contributes to HF pathogenesis in people with hyperglycemia.
Scaling language model size yields diminishing returns for single-message political persuasion
Large language models can now generate political messages as persuasive as those written by humans, raising concerns about how far this persuasiveness may continue to increase with model size. Here, we generate 720 persuasive messages on 10 US political issues from 24 language models spanning several orders of magnitude in size. We then deploy these messages in a large-scale randomized survey experiment ( N = 25,982) to estimate the persuasive capability of each model. Our findings are twofold. First, we find evidence that model persuasiveness is characterized by sharply diminishing returns, such that current frontier models are only slightly more persuasive than models smaller in size by an order of magnitude or more. Second, we find that the association between language model size and persuasiveness shrinks toward zero and is no longer statistically significant once we adjust for mere task completion (coherence, staying on topic), a pattern that highlights task completion as a potential mediator of larger models’ persuasive advantage. Given that current frontier models are already at ceiling on this task completion metric in our setting, taken together, our results suggest that further scaling model size may not much increase the persuasiveness of static LLM-generated political messages.
Abstract 053: Menopausal Status and Race/Ethnicity on the Association of Lipoprotein(a) with CAD
Overview: Lipoprotein(a) (Lp(a)) is a risk factor for atherosclerotic coronary artery disease (CAD). Little is known about menopausal status and hormone therapy in racial/ethnic-specific associations of elevated Lp(a) with CAD. We investigated this in an age- and racially-diverse cohort of women from the U.S.’s largest integrated healthcare system. Methods: We extracted structured cross-sectional electronic health record data for 2831 women with a laboratory result for Lp(a) between 1999-2023 in the Veterans Health Administration. We designated menopausal status (pre, surgical, natural), use of hormone contraception or menopausal hormone therapy (HT), and history of CAD as of the Lp(a) test date. Elevated Lp(a) was Lp(a) >125 nmol/L. Using multivariate logistic regression with correction for multiple comparisons, we estimated association of elevated Lp(a) with prevalent CAD adjusted for age, race/ethnicity, menopausal status, and HT. Within menopausal subgroups, we conducted analogous multivariate logistic regressions. We tested for interaction between Lp(a) and menopausal status and between HT and race/ethnicity. Results: Elevated Lp(a) was associated with prevalent CAD among all women (OR=1.5, 95% CI [1.2, 1.9], p<0.002). In subgroup analysis by menopause status, elevated Lp(a) was associated with prevalent CAD only for women over 60 with natural menopause (OR=2.1, 95% CI [1.5, 3.0], p<0.001). An interaction model between elevated Lp(a) and menopause status on prevalent CAD was assessed with premenopausal women under 60 without elevated Lp(a) as the reference group. Premenopausal women under 60 with elevated Lp(a) had an OR of 1.4 (95% CI [0.8, 2.5] p=0.274). Women over 60 with natural menopause and without elevated Lp(a) had an OR of 4.9 (95% CI [3.4, 7.3], p<0.001). Women over 60 with natural menopause and elevated Lp(a) had the highest OR of 10.4 (95% CI [6.7, 16.0], p<0.001). Relative excess risk due to interaction (RERI) of 5.1 (95% CI [2.2, 9.7]) supports an additive interaction of menopausal status over/under age 60 with Lp(a) on risk of prevalent CAD. The p-value for multiplicative interaction was 0.22. In smaller-sized menopausal subgroups, no observations were observed between race/ethnicity and HT on risk of elevated Lp(a) or on prevalent CAD. Conclusions: Menopausal status over age 60 and elevated Lp(a) (>125 nmol/L) interacted to modify the risk of prevalent CAD. HT use as a possible effect modifier, by race/ethnicity, warrants further exploration.
Abstract MP01: Butter and Plant-Based Oils Intakes and Mortality in Three Large Prospective Cohorts of US Women and Men
Objective: To investigate associations of butter and plant-based oil intakes with risk of total and cause-specific mortality. Participants: 221,054 women and men from the Nurses’ Health Study (1990-2018), Nurses’ Health Study II (1991-2018), and Health Professionals Follow-up Study (1990-2018) were included, all of whom were free of cancer, cardiovascular disease (CVD), diabetes, or neurodegenerative disease at baseline. Exposure: We assessed dietary intake repeatedly using validated semiquantitative food frequency questionnaires every 4 years. Primary exposures included total butter (butter added at the table and from baking and frying) and plant-based oil intake (safflower, soybean, corn, canola, and olive oil). Main Outcome: We identified deaths through the National Death Index and other sources. A physician classified the cause of death based on all available records. Total mortality was the primary outcome, and mortality due to cancer and CVD were secondary outcomes. Results: During up to 28 years of follow-up, we documented 41,618 deaths, including 11,380 from cancer and 9,114 from CVD. After adjusting for confounding factors, the highest butter intake was associated with an 18% higher risk of total mortality compared to the lowest intake (HR: 1.18; 95% CI: 1.10-1.25; P trend <0.001). Conversely, the highest plant-based oil intake was linked to an 18% lower risk of total mortality (HR: 0.82; 95% CI: 0.76-0.89; P trend <0.001). Higher olive, soybean, and canola oil intakes were also significantly associated with lower total mortality (all P trend <0.001). For every 10 g/day increase in plant-based oil intake, cancer mortality risk decreased by 11% (HR: 0.89; 95% CI: 0.85-0.94; P trend <0.001), and CVD mortality risk by 6% (HR: 0.94; 95% CI: 0.89-0.99; P trend = 0.03). Higher butter intake was associated with increased cancer mortality (HRper10g/day: 1.12; 95% CI: 1.04-1.20; P trend <0.001), but not with CVD mortality ( P trend =0.61). Replacing 10 g/day of butter with plant-based oils was associated with a 19% reduction in total mortality (HR: 0.81; 95% CI: 0.77-0.85; P trend <0.001) and a 20% reduction in cancer mortality (HR: 0.80; 95% CI: 0.74-0.88; P trend <0.001). Conclusion: A higher intake of butter is associated with higher mortality, while a higher intake of plant-based oil is associated with lower mortality. Substituting butter with plant-based oils may confer substantial benefits for preventing premature deaths.
Abstract P3120: Obesity and the Risk of Advanced Stages of Cardiovascular-Kidney-Metabolic Syndrome among Obstructive Sleep Apnea Patients
Background: The cardiorenal metabolic (CKM) syndrome is a condition characterized by the interrelationship between the risk factors and relevant comorbidities. Obstructive sleep apnea (OSA) is associated with an increased risk of the advanced stages of CKM, cardiovascular disease (CVD) and chronic kidney disease (CKD). Obesity has been recognized as a significant risk factor for both the onset and worsening of OSA. However, it remains unclear whether the severity of obesity correlates with varying degrees of risk for CVD and CKD among patients with OSA. Methods: Using the most recent dataset from the All of Us Research Program, we included 29,570 participants with a BMI of ≥18.5 kg/m 2 , accessible electronic health records (EHR), and no prior history of OSA. BMI was assessed during physical examinations, and participants were categorized into normal weight, overweight, Class I, Class II, and Class III obesity based on World Health Organization criteria. We utilized the Systematized Nomenclature of Medicine to ascertain outcomes from the EHR, with CVD defined as a composite of heart failure, myocardial infarction, stroke, and atrial fibrillation. Cox regression models, adjusted for age, sex, race, and education, were employed to calculate hazard ratios (HRs) for CVD and CKD across the BMI categories in individuals with OSA. Results: The mean age of participants was 59.8 years (SD: 13.1), with females comprising 51.9% of the total sample. 70.7% were classified as with obesity. In general, compared to those with normal weight, participants with classes of obesity exhibited an increased risk of CVD and CKD; however, no association was observed between class I obesity and CVD. The risk increased with obesity severity. Class III obesity posed the highest risk, with a 2.34-fold increased risk of CVD (HR: 2.34, 95% CI: 1.87–2.93), a 2.38-fold increased risk of CKD (HR: 2.38, 95% CI: 1.82–3.10). Participants with overweight showed no statistically significant associations with incident CVD or CKD compared to those of normal weight. Conclusions: In patients with OSA, the risk of advanced stages of cardiorenal metabolic (CKM) syndrome, specifically CVD and CKD, progressively increases with more severe obesity. Our findings highlight the focused and effective weight management strategies, in addition to the regular treatment of OSA, to mitigate long-term CKM complications, ultimately aiding in the reduction of the complex and detrimental interplay of CKM.
Visualizing agonist-induced M2 receptor activation regulated by aromatic ring dynamics
Despite the growing number of G protein–coupled receptor (GPCR) structures being resolved, the dynamic process of how GPCRs transit from the inactive toward the active state remains unclear. In this study, comprehensive molecular dynamics simulations were performed to explore how ligand binding modulates the conformational dynamics of the M2 muscarinic acetylcholine receptor (M2R). We observed a sequential occurrence of structural changes in the inactive-to-active transition of M2R induced by a superagonist iperoxo, which includes the orthosteric binding site contraction, the TM6 opening into an intermediate conformation, and a further structural change toward full activation upon binding to G protein or a G protein mimetic nanobody. Two activation intermediates were identified, which show structural features different from those reported for apo-GPCRs. Moreover, our results suggest that stabilization of a specific W400 6.48 conformation and enhanced F396 6.44 dynamics are crucial for activation, whereas distinct side-chain rotamer equilibriums of Y206 5.58 in the cytoplasmic cavity are correlated with agonist efficacies. Our work provides atomic-level structural insights into the agonist-induced M2R activation pathway and highlights a mechanism by which ligand efficacy can be encoded and transduced in the form of aromatic ring dynamics.
Abstract 068: Associations Between Fish Oil Supplement Use or Plasma Omega-3 Levels with Risk for Atrial Fibrillation: The United Kingdom Biobank
Background: Recent observational studies in the UK Biobank (UKBB) concluded that self-reported fish oil supplement (FOS) use is associated with an increased risk for incident atrial fibrillation (AF). This lies in contradiction with a globally representative meta-analysis, which found an inverse relationship between blood levels of omega-3 fatty acids (n-3 FAs) and risk of AF. The extent to which plasma levels of n-3 FAs are related to risk of AF in UKBB has yet to be reported. Objectives: We have leveraged data from the UKBB to 1) determine the relationship between plasma levels of n-3 FAs and incident AF and 2) to further explore the previously reported association between FOS use and incident AF. Methods: Within the UKBB, we identified 266,477 individuals with data on blood plasma n-3 FAs and relevant covariates, and 433,607 individuals with data on self-reported FOS use. The primary outcome was incident AF during the follow-up period (median 12.7y). Multivariable-adjusted hazard ratios (95% CIs) for FAs were computed continuously (per inter-quintile range [IQ 5 R]) and by quintile (Q). HRs were computed for dichotomous FOS use. Covariates included: age, sex, ethnicity, education, physical exercise, smoking, alcohol use, BMI, use of beta-blocker, drugs for hypertension or cholesterol, prevalent diabetes, CVD or heart failure, and plasma linoleic acid levels. Notably, in our analyses we adjusted for age as a continuous variable to more completely account for age-related risk of AF, compared to previous analyses which adjusted for age as a dichotomous variable (i.e., 65+ vs <65) in their assessment of FOS and risk of AF. Results: Total n-3 levels in blood plasma were inversely associated with incident AF (HR per IQ 5 R = 0.90 [95% CI 0.86, 0.93]), and HR=0.87 (0.83, 0.91) in Q5 (vs Q1). FOS use was reported by 31% of the cohort, with higher use reported in older individuals. After adjusting for age continuously, there was no association between FOS use and risk of AF risk (HR=1.00 [097, 1.02]). Conclusion: In agreement with recent biomarker-based meta-analyses, higher circulating blood levels of n-3 FA were associated with reduced risk for AF in the UKBB. Secondly, this study reassessed the relationship between FOS use and risk of AF in the UKBB, and if age is adjusted for in a continuous fashion, the association between FOS and AF disappears. These findings indicate previous analyses may have insufficiently adjusted for the age-related risk of AF.
Abstract MP22: A Measurement Model of Socioeconomic Status and its Association with Cardiovascular Disease in the Hispanic Community Health Study/Study of Latinos
Objectives: Low socioeconomic status (SES) is consistently associated with adverse cardiovascular health. Three key indicators are typically used as proxies for SES: income, education, and occupation. However, these indicators may not fully capture the unique sociodemographic features relevant to the SES of Hispanics/Latinos in the U.S. This study aims to expand the traditional SES model by identifying and incorporating additional features specific to Hispanic/Latino persons, providing a more comprehensive assessment of SES and its relationship with cardiovascular disease (CVD). Methods: The Hispanic Community Health Study/Study of Latinos (HCHS/SOL) is a community-based longitudinal cohort study of 16,415 adults self-identifying as Hispanic/Latino, enrolled from 2008-2011 from four U.S. urban communities. We utilized a multiple indicator multiple cause (MIMIC) model to identify formative and reflective indicators of a latent variable for SES. CVD was ascertained by self-report during the second in-person clinic examination from 2014-2017 (V2; N=11,623) and was defined as having had a heart attack, stroke, or angioplasty, stent, or bypass procedure. A survey logistic regression model was then used to examine the association of the latent SES with CVD at V2. Models were adjusted for age, sex, and study site. Results: Significant formative indicators of the SES latent variable included education level, whether the highest level of education was obtained in the US, employment status, and age at immigration (included in a second model with immigrants only; n=9,623). Significant reflective indicators of the SES latent variable included income, the MacArthur SES ladder, and affluence level. The measurement model demonstrated good fit to the data (RMSEA=0.016; CFI=0.984, SRMR=0.02). The SES latent variable was associated with CVD (OR=0.70, 95% CI 0.58, 0.84; for immigrants only OR=0.64, 95% CI 0.53-0.77). Conclusions: Incorporating indicators relevant to Hispanic/Latino populations provides a more comprehensive assessment of SES with potentially improved validity. The latent SES variable, including factors such as education location and age at immigration, was significantly associated with lower odds of cardiovascular disease. These findings highlight the importance of using a culturally-tailored SES framework when examining health outcomes in Hispanics/Latinos.
Abstract P3157: Traumatic Brain Injury and Risk of Early Onset Dementia: A Population-Based Cohort Study and Meta-analysis.
Introduction: Traumatic brain injury (TBI) is a recognized risk factor for late-onset dementia (LOD), though its specific association with early-onset dementia (EOD) (i.e., diagnosed before age 65) is less understood. This study examines the association between TBI, and the risk of developing EOD compared to LOD through a population-based cohort study. Additionally, a systematic review with meta-analysis examines the association between TBI and EOD. Hypothesis: TBI is a risk factor for developing EOD and this association between TBI and EOD is stronger than the association with LOD. Methods: We utilized data from 502,039 participants aged 40 - 69 years at recruitment from the UK Biobank and found that 16,959 people had TBI. Over a median follow-up of 13.6 years, 837 people were diagnosed with EOD, and 8948 with LOD. We estimated hazard ratios (HRs) for TBI's association with EOD and LOD using Cox proportional hazard models with TBI modeled as both a time-varying exposure and time-varying coefficient. Additionally, we conducted a systematic review of existing studies of TBI and EOD, with pooled effect estimates generated via a random-effects model. Results: TBI was significantly associated with an increased risk of both EOD (HR: 3.3, 95% CI: 2.5-4.5) and LOD (HR: 2.5, 95% CI: 2.3-2.7). The association was stronger for EOD compared to LOD (p-value: 0.05), especially in the case of moderate to severe TBI (p-value: 0.15) (Figure 1). A meta-analysis including 10 studies and the present study using UK Biobank, estimated a pooled effect estimate of 1.9 (95% CI: 1.2-3.0), with effect estimates ranging from 0.7 to 5.4, for EOD associated with TBI, albeit with high heterogeneity (I 2 = 96%). Conclusion: This study underscores that TBI is associated with an increased risk of EOD, more so than LOD. These findings emphasize the need for targeted preventive strategies and interventions for individuals with a history of TBI to mitigate or delay dementia onset.