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Abstract P2028: Air Pollution Induces Atrial Fibrosis via CARD9-Mediated Immune Response
Background: Exposure to ambient fine particulate matter (PM) triggers systemic inflammation and is associated with atrial fibrosis (AF) and cardiac arrhythmia. The cytosolic adaptor caspase recruitment domain 9 (CARD9) is crucial for macrophage function and innate immune response. This study aimed to investigate the role of CARD9-dependent immune response in PM-induced macrophage-mediated inflammation and the detrimental effects of PM on the heart atrium, exploring the underlying mechanisms. Methods: Male C57BL/6 wild type (WT) mice (4-6 months old, n=8-12) and age- and sex-matched CARD9 knockout (CARD9 -/- ) mice (n=8-12) were intranasally exposed to PM for 1, 2, 7, 14, and 28 days. Serum levels of TNF-α, IL-1β, IL-6, and IL-10 were measured using ELISA. Total macrophage populations and M1/M2 subpopulations in bone marrow (BM) and blood were analyzed in mice with and without PM exposure. BM macrophages were cultured for 48 hours in M0, M1, or M2 medium to analyze their populations and cytokine production with or without PM exposure. Phosphorylated Akt (p-Akt), p-Erk, and Ankyrin-B levels were determined in atrial cardiomyocytes using immunoblotting. AF area was measured with Masson’s trichrome staining. Results: PM exposure significantly elevated serum levels of TNF-α, IL-1β, and IL-6 in WT mice within 24 hours, but not in CARD9-/- mice （Fig. 1). In CARD9-/- mice, PM exposure increased the M2 macrophage population and IL-10 levels compared to WT mice (Fig. 2), with similar findings observed in vitro using BM cells cultured in M0, M1, and M2 media. PM-induced AF was linked to reduced atrial p-Akt and Ankyrin-B levels, effects that were mitigated in CARD9-/- mice compared to WT mice (Fig.3). Conclusion: PM exposure-induced AF may be linked to an enhanced macrophage inflammatory response through CARD9-mediated reduction in IL-10 secretion, resulting in a decreased M2 macrophage polarization from M0 macrophage. This study outlines the underlying mechanism of air pollution-induced atrial arrhythmia and explores potential prevention strategies and treatments.
Abstract P3077: Pro-Enkephalin A and Risk of Incident Hypertension: The REasons for Geographic and Racial Differences in Stroke (REGARDS) Study
Introduction: Hypertension, a risk factor for cardiovascular disease and chronic kidney disease, poses a significant burden in the U.S, especially among Black U.S. adults. Higher pro-enkephalin A (PENK-A), a byproduct of endogenous opioid peptide processing and a novel marker for estimation of glomerular filtration rate, is associated with antihypertensive use and greater risk of stroke, heart failure, and renal dysfunction. Whether low PENK-A is a risk factor for incident hypertension is unknown. Hypotheses: We hypothesized that lower PENK-A will be associated with greater risk of incident hypertension. Methods: REGARDS cohort study enrolled 30,239 Black and White U.S adults aged ≥45 years, with an initial visit between 2003-2007 and a follow-up visit in 2013-2016. A race-sex stratified sample of 4,400 participants were randomly selected. Hypertension was defined with a blood pressure (BP) threshold of 140/90 mm Hg or use of antihypertensive medications. We excluded those with prevalent hypertension, missing model covariates, or missing PENK-A, resulting in an analytical population of 1,859 participants. Proportion of incident hypertension events were calculated by tertile of PENK-A. Modified Poisson regression estimated unadjusted and adjusted risk ratios (RR) of incident hypertension per 1-SD higher of log-transformed PENK-A. Results: Among 1,859 participants (mean [SD] age 62 [8] years, 51% female, and 36% Black race), median (IQR) follow up was 9.5 (8.7 to 10.0) years. Median (IQR) PENK-A was 59.7 (49.6-72.4) pmol/L. Hypertension developed in 35.4% of participants overall, (37.7% of tertile 1, 34.9% of tertile 2, and 33.7% of tertile 3 of PENK-A). However, there was no difference in RR of incident hypertension per 1-SD higher of log PENK-A in unadjusted (RR 0.96; 95% CI 0.90-1.02) or fully-adjusted models (RR 1.01; 95% CI 0.94-1.08). Restricted cubic splines depict no difference in RR of incident hypertension across the means of PENK-A levels relative to the median value ( Figure ). Conclusions: PENK-A was not associated with greater risk of incident hypertension in a contemporary cohort study. PENK-A does not appear to influence risk for stroke and heart failure through hypertension, but whether PENK-A modifies cardiovascular disease risk among persons with hypertension is unclear given its bidirectional role in the cardiorenal pathway.
Abstract P1120: Association Between Depression and Movement Behaviors with Risk of Mortality among people with Arthritis: The National Health and Nutrition Examination Survey (NHANES) 2007-2016
Arthritis is a chronic inflammatory disease characterized by joint pain, swelling and limited range of motion. Depression is prevalent among individuals with arthritis and is associated with increased risks of health conditions and mortality. P hysical activity (PA) is a strong predictor of lower mortality and can serve as a protective factor against both depression and arthritis. This study aimed to examine the associations between depression, moderate to vigorous PA (MVPA) and sedentary behavior (SB) with all-cause mortality among individuals with arthritis. Methods: We included 5129 participant aged ≥ 40 years from NHANES 2007-2016. The death records through 2019 were ascertained. Depression was assessed using Patient Health Questionnaire (PHQ9) and categorized into depressed and not depressed groups. MVPA and SB were measured using the Global Physical Activity Questionnaire (GPAQ). Individuals with no leisure time MVPA were classified as inactive and those with ≥ 8 hours of daily sitting were considered sedentary. To investigate joint associations, participants were grouped based on depression status and MVPA or sedentary status. Weighted multivariate Cox regression models adjusted for age (Model 1) and additional covariates (Model 2) were used to examine the associations of depression, MVPA and SB with mortality (Table). Results: Over 8 ± 3 years of follow-up,1247 (24%) participants died. Compared to active group without depression, inactive groups with and without depression had 1.98 (95% CI: 1.56-2.47) and 1.52 (95% CI: 1.25-1.84) times risk of mortality, respectively (Table). Compared to the non-sedentary group without depression, sedentary groups with and without depression had 1.92 (95% CI: 1.62-2.28) and 1.40 (95% CI: 1.16-1.70) times risk of mortality (Table). Conclusion: Depression, MVPA and SB, were independently and jointly associated with all-cause mortality among people with arthritis. Being more active and less sedentary may help lower the risk of mortality in this population.
Abstract P2107: Sex-Specific Associations of Plasma Proteins with HF Risk: The Atherosclerosis in Communities (ARIC) Study
Introduction: Heart failure (HF) epidemiology and pathophysiology differ by sex. Large scale plasma proteomics offers promise to provide insight into biologic mechanisms underlying sex-based differences, but limited data is available. Hypothesis: A subset of circulating proteins will differentially associate with incident HF in women compared to men. Methods: We examined 10983 participants in the community-based ARIC cohort study who attended study Visit 2 (1990-92), were free of HF, and had aptamer-based proteomic measurements (SomaLogic; 4955 aptamers corresponding to 4715 unique proteins). We used multivariable Cox regression to test the association of plasma proteins with HF. Models were adjusted for age, BMI, eGFR, Black race, smoking status, visit center, CHD, diabetes, and hypertension, and included sex interaction terms with protein measurement and all other model covariates except visit center. For proteins with a significant sex*protein interaction after FDR correction for multiple testing (FDR corrected p<0.05), we fit stratified models for men and women and fit interaction models to test for differential associations of protein measures with HF risk factors by sex. Results: Among 4935 men (mean age 57±6 years, 20% Black race) and 6048 women (57±6 years, 25% Black race), 369 and 298 incident HF events occurred over 10-year follow-up respectively. Effect modification of sex on the association of protein level with incident HF was observed for 9 proteins, all of which were significantly associated with HF in women, while 3 showed directionally opposite associations with HF in men in stratified models (Figure). In addition to known sex hormones (CGA/LHB), the proteins reflected processes related to inflammation, including immune regulation (RPS19) and TGF-beta signaling (SMAD3, WWP1); purine and cellular energy metabolism (ADSL, PPP1R2); and wound healing (MCF2L). ADSL was also more strongly associated with BMI among women than men. ADSL is expressed in adipose, cardiac, and skeletal muscle tissues, and has shared pQTLs with eQTLs in these tissues. Conclusions: High throughput proteomics identifies circulating proteins differentially related to HF risk in women versus men. These findings highlight potential differential roles for specific inflammatory pathways and alterations in cellular metabolism to HF development in women. Further studies of ADSL as potentially linking obesity, metabolic dysfunction, and HF in women are warranted.
Abstract P3170: Identifying moderate to severe food insecurity among hypertensive patients in a low and middle-income Caribbean country
Introduction: The Caribbean is experiencing a high burden from food insecurity (FI) and cardiovascular disorders including hypertension. Hypertensive patients with FI need to be easily identified to address social and dietary factors that may worsen blood pressure control and result in adverse health outcomes. In this study we evaluated the ability of single questions from the Latin American and Caribbean Food Security Scale (ELCSA) to identify patients with moderate to severe FI. Hypothesis: We hypothesized that a single question from the ELCSA could be used to screen for moderate to severe FI in adults during a routine clinical encounter Methods: The Addressing Blood Pressure Control using Dietary Approaches (ABCD) study was a cross-sectional study of hypertensive outpatients from a semi-private hospital referral specialist clinic and a government-run primary care facility in Jamaica. The ELCSA scale (excluding questions about children/adolescents) was administered by trained interviewers to all participants. Those with a score of 0 were categorized as food secure, 1-3 mild FI, and ≥ 4 as moderate to severe FI. We calculated the sensitivity, specificity, and positive predictive value of each ELCSA question to evaluate its ability to identify patients with moderate to severe FI. Results: Of the 257 patients interviewed (28% male, 50% over 65 years), 35% had moderate to severe FI. The three questions that best identified these patients were asking whether (i) they or any adult in the home ate less food than what was needed because there was not enough food (sensitivity 79%, specificity 88%), (ii) if the home ran out of food at any time (sensitivity 80%, specificity 87%), and (iii) if they were worried about running out of food (sensitivity 75%, specificity – 88%). All three questions had a positive predictive value over 78%. Conclusion: The inclusion of a single item on food availability during clinical encounters could identify most patients with moderate to severe FI and provides a practical approach to FI screening for Jamaican clinicians. Caribbean clinicians should be encouraged to screen for FI to address this important social determinant of health.
Abstract P2032: Associations of Volatile Organic Compound Metabolites with Urinary Catecholamines: A Cross-Sectional Study with Green Heart Louisville
Volatile organic compounds (VOCs) are ubiquitous gaseous chemicals present in indoor and outdoor air. These compounds are emitted from several sources such as automobiles, paints, and household items. Human exposures are frequent and expected to increase with climate change. VOC exposures have been linked to negative cardiometabolic effects; however, the underlying mechanisms by which they impact cardiovascular function remain unknown. Exposure to VOCs may stimulate sympathetic nervous system activity. Thus, we aim to investigate the association of urinary VOC metabolites with levels of catecholamines as a biomarker of sympathetic activation. Participants (n=806, age 25-70) were recruited between 2018-2021 from low- to middle-income neighborhoods in Louisville, KY. Clean catch, spot urine samples were obtained during an in-person study visit. Urinary samples were used to quantify metabolites of VOCs and catecholamines using UPLC-MS/MS. The associations of log-transformed, creatinine standardized urinary constituents were examined using adjusted multivariable linear regression models for individual metabolites and quantile-based g computation for overall mixture models. Final models were adjusted for relevant demographic factors, stress, smoking status, medication use, and urine collection time. Detectable levels of acrylamide, acrolein, 1,3-butadiene, crotonaldehyde, N, N-dimethylformamide, propylene oxide, styrene, toluene, and xylene metabolites were present in >80% of urinary samples. In adjusted models, higher concentrations of most VOC metabolites, other than BMA (a metabolite of toluene), were associated with higher levels of urinary catecholamines (p<0.001). Specifically, a 10% increase in 11 individual VOC metabolites was associated with 1.2% to 2.4% higher epinephrine, 0.7% to 1.4% higher norepinephrine, and 0.7% to 1.5% higher dopamine levels. A quartile increase in the overall VOC metabolite mixture was associated with 57% higher epinephrine (95%CI = 41, 76%; p<0.001), 37% higher norepinephrine (95%CI=28, 48%; p<0.001), and 40% dopamine levels (95%CI=31, 48%; p<0.001). Our results suggest that exposure to these ubiquitous volatile compounds is associated with an increase in sympathetic stimulation. Mixture analysis further demonstrated potential additive effects of VOC exposures on autonomic modulation. Hence, an elevated sympathetic tone may in part be responsible for the negative cardiometabolic outcomes related to increased VOC exposure.
Abstract 019: Association Of Sleep Irregularity And Variability With Leptin And Adiponectin Levels In Adolescents
Introduction: Hormone fluctuations and circadian rhythms, including the sleep-wake cycle, are reciprocally associated. Lipid and glucose metabolism pace depend on leptin and adiponectin levels. Alignment of the sleep-wake cycle is associated with optimal sleep duration and metabolic regulation. Therefore, deviations in sleep timing and duration resulting from circadian misalignment, which is highly prevalent in adolescents, are potentially impacting this association. Hypothesis: Objective metrics of sleep timing and duration are associated with adiponectin and leptin levels in adolescents. Methods: We assessed 344 adolescents from the Penn State Child Cohort [16.2 (2.2) years; 44.4% female; 21.5% racial/ethnic minority], of whom 215 were evaluated while in school and 129 while on break. All subjects had a minimum of 3-nights of at-home actigraphy and 9-hour in-lab polysomnography. Sleep midpoint (SM) was calculated as the central point of the sleep period, while sleep irregularity (SI) and sleep variability (SV) as the intra-individual standard deviation of the SM and total sleep time, respectively. Adiponectin and leptin levels were assayed via ELISA from blood samples. Linear regression models adjusted for sex, race/ethnicity, age, apnea/hypopnea index, BMI percentile, and SES. Results: Greater SI and SV while attending school were associated with lower log-adiponectin levels (B=-0.155, SD=0.057, p=0.007 and B=-0.127, SD=0.054, p=0.021, respectively). SM was not significantly associated with either log-leptin or log-adiponectin levels. Conclusions: Increased irregularity and variability in the timing and duration of sleep during the academic year affect glucose and fatty acid control mechanisms in adolescents. Our findings further support targeting sleep from a multidimensional standpoint to better prevent its impact on cardiometabolic health. Support: National Institutes of Health (R01HL136587, UL1TR000127)
Allosteric inhibition of the IZUMO1–JUNO fertilization complex by the naturally occurring antisperm antibody OBF13
Sperm IZUMO1 binds to egg JUNO, and this interaction is essential for mammalian fertilization. Isolated from a female mouse immunized with syngeneic sperm, the antisperm antibody OBF13 recognizes IZUMO1 and inhibits murine fertilization. How OBF13 interferes with sperm–egg interactions was unknown. Here, we present the X-ray crystal structure of IZUMO1 in complex with OBF13. OBF13 binds to the apex of the four-helix domain of IZUMO1, distant from the JUNO-binding site. Our crystal structure of OBF13-bound IZUMO1 resembles apo-IZUMO1 and differs from the structure of IZUMO1 in complex with JUNO. We identify that OBF13 carries a low level of somatic hypermutation, and through deep mutational scanning, we engineer an affinity-enhanced OBF13 variant. This OBF13 variant single-chain fragment variable decreases the apparent affinity of IZUMO1 for membrane-bound murine JUNO and blocks the binding of acrosome-reacted sperm to eggs, thereby preventing fertilization. We propose allostery between the OBF13 epitope and the JUNO-binding site. OBF13 inhibits a conformational change in IZUMO1, preventing fusion-competent sperm from adhering to murine eggs during fertilization. Surprisingly, murine IZUMO1 binds to hamster JUNO with an affinity ~20-fold higher than to murine JUNO. The decreased affinity caused by OBF13 of murine IZUMO1 for hamster JUNO is sufficient for murine sperm to bind to and fuse with hamster eggs. Our studies provide a structural and mechanistic framework for species-specific, allosteric inhibition of IZUMO1 by a naturally occurring antisperm antibody and offer insights into the development of immunocontraceptives.
Abstract 015: Sleep Health and Cardiometabolic Risk in Health Care Workers: The role of heart rate and heart rate variability
Purpose: Despite strong evidence linking poor sleep with cardiometabolic risk, underlying mechanisms are poorly understood, limiting interventions to improve sleep&cardiometabolic health. Higher heart rate (HR) and lower HR variability (HRV) are associated with worse cardiometabolic health and may be affected by sleep. We determined associations between multidimensional sleep health, HR, and HRV among healthcare workers (HCW) from federally qualified health centers (FQHCs) in Louisiana. Methods: Eighty HCW wore wrist-worn sensors capturing sleep onset, wake, HR, and HRV for 6 weeks. Four dimensions of sleep health were measured: regularity was assessed as the standard deviation (SD) of midpoints of all nighttime sleep periods for a participant; “irregular”=SD >60 minutes. Timing was assessed using participants’ mean sleep midpoint; “poor timing”=midpoint not between 1am&3am. Efficiency was calculated as % of time in bed spent asleep; “inefficient”=mean efficiency across nights <85%. Duration was calculated as time between first sleep onset after 8pm&last wake, minus time spent awake during the night; “insufficient”=mean duration <7 hours. Dichotomized regularity, timing, efficiency&duration were summed; multidimensional “poor sleep”=score ≥2. HR (beats/minute) and HRV (root mean square of successive differences between beats) were measured every 5 minutes. Multivariable linear regression estimated differences in HR and HRV across each sleep metric, adjusting for age and mental health/sleep medications. Results: 74 participants recorded sleep data: 90% women, 41% Black, mean age 45.6 (SD 11.5) years; 36% were taking mental health/sleep medications. Sixty-eight had ≥7 nights of sleep data&complete medication data. Among those, inefficient sleep and insufficient sleep duration were associated with 6.6 (95% CI 0.6, 12.7) and 4.0 (95% CI 0.0, 7.9) higher HR in the 2 hours before wake, respectively. “Poor sleep” was associated with 4.6 (95% CI 0.8, 8.5) higher HR. Irregular sleep and poor timing were not associated with HR. No sleep metrics were associated with HRV in the period spanning the hour before&hour after wake. Conclusion: Louisiana FQHC HCWs with inefficient sleep and insufficient sleep duration had higher mean HR in the 2 hours before wake. Sleep was not associated with HRV, which may be less sensitive to short term change. Further research is needed in larger samples to determine mechanisms linking poor sleep to cardiometabolic risk.
Abstract P1035: The Association between PREVENT 10-Year Overall Cardiovascular Disease Risk and Incident Fractures in Postmenopausal Women
Background: This study aimed to estimate the association between cardiovascular disease (CVD) risk and incident fracture in postmenopausal women. Methods: The study included data from women without a history of CVD enrolled in the Women’s Health Initiative, who had available CVD biomarker information at baseline necessary to compute a 10-year overall CVD risk using the PREVENT equation. Outcomes included self-reported any clinical, major osteoporotic (MOF-hip, spine, wrist, shoulder), and hip fractures. Women reporting anti-osteoporosis medications at baseline and pathologic fractures during follow-up were excluded. Hierarchical multivariable Cox proportional hazard models assessed the association of CVD risk with fracture and if the association was modified by race and ethnicity or body mass index (BMI). Results: Our study comprised 21,300 women (age: 63.7±7.3 years; non-Hispanic (NH) White: 48%; NH-Black: 33%). The mean 10-year overall CVD risk score was 9.3 ± 5.7, with 5,370 (25.2%), 4,169 (19.6%), 10,661 (50.0%), and 1,100 (5.2%) participants in the low (<5.0%), borderline (5.0-7.4%), intermediate (7.5-19.9%, and high ≥20.0%) categories, respectively. A total of 9,399, 5,104, and 1,769 clinical, MOF, and hip fracture cases were reported over a mean follow-up of 17.1 ± 6.7 years. After full covariate adjustment (Model 4) and adjustment for factors significantly associated with fracture from stepwise modeling (Model 5), women with intermediate- and high- overall CVD risk scores had significantly higher risk for all fracture types, particularly hip fracture [Model 5 HR (95% CI) - intermediate: 2.43 (1.53, 3.87); high: 3.56 (2.01, 6.15)] (Table). Neither race and ethnicity nor BMI modified the association between overall CVD risk and fracture. Conclusion: In postmenopausal women, higher CVD risk scores significantly associated with a higher risk of incident fractures. Future studies assessing if management of CVD aids in fracture prevention in high-risk CVD populations based on PREVENT score is warranted.
Abstract P1136: Fetal C-Reactive Protein rs1205 Genotype Associated with Maternal Pre-eclampsia
Introduction: Maternal variants including C-Reactive Protein, CRP rs1205 have previously been associated with risk of pre-eclampsia (PE). These findings were replicated in two non-American Indian populations. The rs1205 T allele is associated with reduced serum levels of CRP. Our objective was to determine if the fetal rs1205 genotype contributed to maternal risk of PE independent of maternal rs1205 genotype. Methods: Only offspring of both case and control mothers heterozygous for rs1205 were enrolled, thus controlling for maternal genetic influence at this locus. Offspring were then genotyped for rs1205 by TaqMan assay. Association was assessed by chi-square and multivariate logistic regression. Results: Offspring of 35 of 45 normal pregnancies and 12 of 23 PE pregnancies exhibited the rs1205 T allele dominant genotype (Pearson chi square p=0.031). Multivariate logistic regression analysis adjusted for maternal age, nulliparity and BMI demonstrates an odds ratio of 0.255, p=0.032, 95% CI 0.073-0.891 for the fetal, T-dominant genotype. Discussion: Among 68 women, heterozygous for the rs1205 allele, both chi-square and multivariate adjusted logistic analysis show reduced risk of PE among pregnancies with fetal T allele dominant genotypes. This is consistent with previous findings of reduced risk associated with this maternal genotype, and with a pathophysiologic model wherein less placental CRP expression reduces risk of PE.
A WRKY transcription factor confers broad-spectrum resistance to biotic stresses and yield stability in rice
Plants are subject to attack by diverse pests and pathogens. Few genes conferring broad-spectrum resistance to both insects and pathogens have been identified. Because of the growth–defense tradeoff, it is often challenging to balance biotic stress resistance and yield for crops. Here, we report that OsWRKY36 suppresses the resistance to insects and pathogens via transcriptional repression of Phenylalanine Ammonia Lyases ( PALs ), a key enzyme in phenylpropanoid pathway in rice. Knocking out OsWRKY36 causes elevated lignin biosynthesis and increased sclerenchyma thickness of leaf sheath, leading to enhanced resistance to multiple pests and pathogens. Additionally, loss of OsWRKY36 also derepresses the transcription of Ideal Plant Architecture 1 ( IPA1 ) and MONOCULM2 ( MOC2 ), resulting in increased spikelet number per panicle and tiller number. These findings provide mechanistic insights into biotic stress tolerance in rice and offer a promising strategy to breed rice cultivars with broad-spectrum resistance to insects and pathogens while maintaining stable yield.
Abstract MP64: PREVENT 30-Year CVD Risk During Pregnancy Is Associated With Inflammatory and Vascular Placental Pathology
Introduction: Many adverse pregnancy outcomes (APOs) associated with long-term CVD risk, such as preeclampsia, are mediated by placental function. Notably, the vascular and inflammatory placental pathology underlying APOs are also found in 20-35% of healthy pregnancies. Thus, we aimed to investigate the link between 30-year CVD risk and placental pathology. Hypothesis: We hypothesized that higher 30-year CVD risk, as estimated based on the PREVENT equation calculated in mid-pregnancy, would be associated with greater likelihood of placental pathology, including chronic inflammation (CI), maternal vascular malperfusion (MVM), and fetal vascular malperfusion (FVM). Methods: Data are from the Stress, Pregnancy, and Health (SPAH) study, a prospective pregnancy cohort conducted from 2018-2023 in Evanston, IL. The PREVENT 30-year CVD risk estimate was calculated based on the 2 nd trimester study visit. At the study visit, blood pressure was assessed, and a blood sample was collected and used to measure cholesterol and estimate eGFR from creatinine. Participants self-reported smoking status. Age, pre-gestational diabetes diagnosis, and use of anti-hypertensive or lipid-lowering medications were abstracted from medical records. Following delivery, placentas were collected and reviewed by a perinatal pathologist and patterns of placental injury (CI, MVM, FVM) were identified based on Amsterdam consensus criteria. Logistic models were used to test associations between CVD risk in pregnancy and placental pathology, adjusted for race/ethnicity, socioeconomic position, and gestational age at the study visit. Results: The SPAH study included 605 participants, 505 of whom had placental pathology exams and complete data to estimate 30-year CVD risk during pregnancy. The mean gestational age at the study visit was 23.7 weeks (SD: 1.7) and the mean age of study participants was 33.3 years (SD: 5.6). The mean 30-year CVD risk was 7.6% (SD: 6.7) and 54% had CI, 29% had MVM, and 34% had FVM. In the adjusted model, a 1 SD increase in CVD risk was associated with 24% greater odds of having CI (95% CI: 1.01, 1.52) and 25% greater odds of having MVM (95% CI: 1.04, 1.50; Figure 1) at delivery. CVD risk was not associated with FVM. Conclusions: Results demonstrate that PREVENT 30-year CVD risk estimated in the second trimester is associated with CI and MVM in the placenta at delivery, which may provide insight into the mechanisms linking CVD risk and APOs.
Abstract P2049: Race and Ethnicity and Oral Anticoagulation Adherence in Older Adults with Atrial Fibrillation: A Nationwide Study
Background: Atrial fibrillation (AF) is the most common arrhythmia and is associated with morbidity from ischemic stroke. Oral anticoagulant (OAC) therapy reduces stroke risk. Prior work has shown lower OAC initiation in minoritized racial/ethnic groups. Less is known about how OAC adherence differs by race/ethnicity, which may contribute to higher stroke rates in minoritized groups. Hypothesis: Minoritized racial/ethnic groups will have poorer adherence to OAC therapy than White individuals. Goal/Aim: To examine the association of race/ethnicity and OAC adherence in AF. Methods: Using VA Corporate Data Warehouse data, we identified patients enrolled in VA from 1/1/2014-12/31/2020 with an AF diagnosis. We excluded those who received OAC before their index AF diagnosis, were on multiple OAC drugs within 1 year of treatment or died within 1 year of treatment. The independent variable was race/ethnicity (i.e., non-Hispanic Black, Other, White, and Hispanic). The primary outcome was adherence to OAC therapy (warfarin or direct oral anticoagulant, DOAC) defined as ≥80% proportion of days covered within the first year of index treatment. Multivariable logistic regression was used to estimate racial/ethnic differences in OAC adherence, adjusting for age, OAC type, stroke risk score, area deprivation index, and year of first OAC prescription. Results: We identified 99,461 OAC initiators: 3.4% Hispanic, 8.8% Non-Hispanic Black, 85.7% Non-Hispanic White, 2.1% Non-Hispanic Other, mean age 72.8 years. Overall, 1-year OAC adherence was 70%. Adherence varied by race/ethnicity with DOAC adherence greater than warfarin for all groups except Black patients ( Figure ). In adjusted models, Black (aOR 0.63, 95% CI 0.57-0.62), Hispanic (aOR 0.78, 95% CI 0.65-0.77), and Other patients (aOR 0.79, 95% CI 0.71-0.86) had significantly lower odds of adherence vs. White patients. Cumulatively, 1.4% of patients had a newly diagnosed stroke during their first year of treatment, with stroke rates lower in adherent (1.4%) vs. non-adherent (1.6%) patients. Adherent Black (2.9%) and Hispanic (1.7%) patients had significantly higher rates of strokes than White (1.3%) patients (P<0.001). Conclusion: In a national cohort of VA patients with AF, we found significant racial/ethnic disparities in OAC adherence and incident stroke. Identifying drivers of these disparities is essential to improve outcomes in patients with AF including those managed in the largest, low-drug cost, US health care system.
Abstract P1005: Associations between circulating reproductive hormones and cardiovascular-kidney-metabolic syndrome in older men
Introduction: The American Heart Association (AHA) recently introduced the cardiovascular-kidney-metabolic (CKM) syndrome as a systemic disorder with connections among heart disease, kidney disease, diabetes, and obesity. The relationship between cardiovascular-kidney-metabolic (CKM) syndrome and reproductive hormones in older men is unclear. Hypothesis: Testosterone and other major reproductive hormones in older men may be important biomarkers for CKM syndrome. Methods: Men ages 70 years and older from the Concord Health and Ageing in Men Project study (n = 1399) were assessed at baseline. Testosterone and dihydrotestosterone (DHT) were measured by liquid chromatography-tandem mass spectrometry, and luteinizing hormone (LH) and follicle-stimulating hormone (FSH) by immunoassay. CKM syndrome was defined based on the Presidential Advisory from the AHA. Logistic regression model (odds ratio, OR) was used for analyses. The model building for all analyses included relevant covariates notably age, marital status, alcohol consumption, smoking, and physical activity. Results: In this cross-sectional observational study of older men aged 76.8 ± 5.5 years, most participants had CKM stage 2 or higher. Approximately 46% in stage 2, 20% in stage 3, and 31% were in stage 4. In the multivariable-adjusted model, participants in the lowest testosterone quartile were more likely to have CKM stage 3 (OR:1.59, 95%CI:1.06-2.39) and stage 4 (OR: 1.59, 95%CI:1.14-2.21) when compared to those in the highest testosterone quartile. Similar observations were shown for DHT. In contrary, participants in the lowest LH quartile were less likely to have CKM stage 3 (OR:0.59, 95%CI:0.40-0.87) and stage 4 (OR:0.65, 95%CI:0.46-0.92) when compared to the highest LH quartile. Similar observations were shown for FSH. No significant associations were observed for the lower CKM stages across all the studied reproductive hormones. Conclusions Low testosterone and DHT, and high LH and FSH are associated with advanced stages of CKM syndrome in older men. Our follow-up longitudinal study will further explore whether observed associations between the reproductive hormones and CKM syndrome represents a causal relationship, or rather biomarkers of risk.
BIN1 reduction ameliorates <i>DNM2</i> -related Charcot–Marie–Tooth neuropathy
Charcot–Marie–Tooth (CMT) disease, the most common inherited neuromuscular disorder, manifests as progressive muscle weakness and peripheral nerve defects. Dominant mutations in DNM2 , encoding the large GTPase dynamin 2, result in CMT without any suggested therapeutic strategy. Different dominant mutations in DNM2 also cause centronuclear myopathy (CNM), and increasing BIN1 (amphiphysin 2), an endogenous modulator of DNM2, rescued CNM in mice. Here, we found that increasing BIN1 level exacerbated the phenotypes of the Dnm2 K562E/+ mouse carrying the most common DNM2 -CMT mutation. Conversely, whole-body reduction of Bin1 expression level, through the generation of Dnm2 K562E/+ mice with heterozygous loss of BIN1, restored motor performance and ameliorated muscle organization and structural defects of peripheral nerves. The rescue of motor defects was maintained at least up to 1 y of age. BIN1 inhibited the GTPase activity of DNM2, and the rescue was driven by an increased activity of the K562E DNM2 -CMT mutant, and a normalization of integrin localization in muscle. Overall, this study highlights BIN1 as a modifier of DNM2 -CMT, and its reduction as a potential therapeutic strategy. It also revealed an opposite pathological mechanism and inverse therapeutic concepts for DNM2 -CMT peripheral neuropathy versus DNM2 -CNM myopathy.
Abstract P1119: Model-based Replacement of Sedentary Time with Light Intensity Physical Activity is Associated with Improved Cardiometabolic Risk Score over 15 Years of Midlife in the CARDIA Study
Introduction: Current physical activity (PA) recommendations support replacing time spent sedentary with PA of any intensity. Replacing sedentary time with light intensity PA (LPA) may be a more accessible behavior change for many individuals compared with increasing moderate/vigorous intensity PA (MVPA). However, the longitudinal associations of replacing sedentary behavior with LPA and cardiometabolic health are not clear. Hypothesis: We hypothesized that replacing time spent sedentary with LPA is associated with improvement in cardiometabolic risk across midlife. Methods: Participants in the CARDIA study with accelerometer and cardiometabolic biomarker data at Year 20 (2005-06) and Year 35 (2020-22) study visits (n=996) were included in this analysis. Waist circumference, mean arterial pressure, fasting glucose, fasting insulin, triglycerides, and HDL cholesterol were standardized and averaged to create a z-score, where higher scores represent worse cardiometabolic health. We used compositional isotemporal substitution models to estimate changes in cardiometabolic risk score resulting from replacement of sedentary time with LPA and whether associations varied by initial sedentary time or MVPA level. Results: Across midlife (mean 45±SD 3.5 [Y20] to mean 60±SD 3.6 [Y35] years old), mean cardiometabolic risk score increased by 0.03 SD. In those with initially low sedentary time, replacing 1 hour of sedentary time with LPA from Y20 to Y35 was associated with a -0.03 SD change in cardiometabolic risk score (95% CI: -0.06, -0.004; Figure) across the same time period. In those with initially high sedentary time, associations were attenuated and not statistically significant (-0.02; 95% CI: -0.04, 0.004). Associations were stronger with more time reallocated (up to 3 hours) and similar in those with low and high MVPA. Conclusions: Model-based replacement of sedentary time with LPA was associated with attenuation of age-related decline in cardiometabolic health across midlife.
Abstract P3048: Relationships of Body Roundness Index and Triglyceride–glucose Index with 5-year All-cause Mortality in Patients with Diabetes and Comorbid Hypertension: Evidence from Two Prospective Cohort Studies
Aims: We aimed to characterise the complex relationships of body roundness index (BRI) and triglyceride-glucose index (TyG) with 5-year all-cause mortality in patients with diabetes and comorbid hypertension. Methods: 5,728 patients from the 1999–2014 US National Health and Nutrition Examination Survey (NHANES) cycles and 3,456 from the 2005–2010 China Kailuan cycles were included. BRI was calculated as 364.2−365.5×√(1−(waist circumference in centimeters/2π) 2 ÷(0.5×height in centimeters) 2 ). TyG was calculated as the logarithmic product of the fasting triglyceride and glucose concentrations. The cut-off values of BRI and TyG were based on median values. Results: The prevalence of 5-year all-cause mortality was 8.4% in the NHANES database and 9.2% in the Kailuan cohort. Multivariable Cox regression demonstrated that a BRI of >6.2 (HR: 2.53, 95% CI: 1.71–2.96) and TyG of >9.5 (HR: 1.64, 95% CI: 1.39–2.72) were independent predictors of 5-year all-cause mortality in diabetic patients with hypertension after adjusting forage, gender, marital status, education level, smoking status, history of myocardial infarction, stroke, urinary protein and CKD-EPI eGFR. These results were reconfirmed in the Kailuan cohort for BRI (HR: 2.91, 95% CI: 1.93–3.57) and TyG (HR: 2.13, 95% CI: 1.86–3.02). TyG was found to mediate the association between BRI and all-cause mortality, being responsible for 24.1% (16.8%-28.5%) in the NHANES database and 27.5% (22.7%-30.1%) in the Kailuan cohort. No significant additive interactions were found between BRI and TyG on 5-year all-cause mortality. Significant multiplicative effects were identified between TyG and BRI in the NHANES database alone (Additive: RERI = 0.05, 95% CI – 3.21–1.97; Multiplicative, HR = 1.27, 95% CI 1.13–1.95 in the NHANES database; Additive: RERI = 0.27, 95% CI – 2.17–5.29; Multiplicative, HR = 1.02, 95% CI 0.85–2.21 in the Kailuan cohort). Conclusions: BRI and TyG were independent risk factors for 5-year all-cause mortality in patients with diabetes and comorbid hypertension. TyG was found to mediate a considerable proportion of the effect of BRI on all-cause mortality in cohorts from both the United States and China. Interventions aimed at improving obesity and abnormal fat distribution might reduce the all-cause mortality risk associated with insulin resistance.
Abstract P2158: Neighborhood poverty, John Henryism, and incident cardiovascular disease events in the Jackson Heart Study
Background: John Henryism (JH), or high effort-coping, is common when facing adversity. Little is known about cardiovascular disease (CVD) risk when living in poverty and having to cope with adversity. Objective: Test whether JH moderates the association between neighborhood-level poverty and incident CVD events among African American participants in the Jackson Heart Study (JHS). Hypothesis: High JH will increase the risk of CVD among participants who live in neighborhoods with greater poverty. Methods: JHS participants with complete data and no CVD at baseline (2000-2004) were included (n=2,691, mean age: 52.5 years). We utilized % below poverty as a marker for neighborhood poverty. JH was defined using the 12-item measure for high-effort coping (range: 0 to 36). Three categories were created using a tertile distribution: low JH (<28), moderate JH (29-32) and high JH (>32). Coronary heart disease (CHD) and stroke events were adjudicated from baseline to 2016; heart failure (HF) events were adjudicated from 2005 to 2016. Hazard ratios (HR 95% confidence intervals - CI) estimated the association between neighborhood poverty and CVD, adjusting for demographics, psychosocial factors (i.e., optimism), and risk factors (i.e., diabetes). Moderation by JH was examined via interaction terms and stratification in adjusted models using a p-value <0.05. Results: Median follow-up time was approximately 13 years for CHD and stroke cases and 10 years for HF cases. By 2016, there were 126 CHD, 187 HF, and 93 stroke cases. Greater poverty was associated with a greater risk of CHD [HR 1.37 (95% CI 1.15,1.63)] and HF [HR 1.48 (95% CI 1.29,1.71)]. There was a significant interaction between poverty and JH for CHD (p=<0.0001) and HF (p=<0.001). However, low JH combined with greater poverty was associated with a greater hazard of CHD [HR 1.93 (95% CI 1.34, 2.78)] after full adjustment. Individuals with greater poverty also had a higher risk of HF when reporting low JH [HR 1.58 (95% CI 1.22, 2.03)] and moderate JH [HR 1.53 (95% CI 1.14, 2.06)]. No significant associations were identified for high JH or stroke. Conclusion: Residing in neighborhoods with greater poverty was associated with an increased risk of CHD and HF for individuals who reported low and moderate levels of coping. Low JH may represent lower motivation/ low psychosocial resilience and may increase the risk of heart disease when living in poverty.
Adeno-associated viruses for efficient gene expression in the axolotl nervous system
Axolotls are amphibian models for studying nervous system evolution, development, and regeneration. Tools to visualize and manipulate cells of the axolotl nervous system with high-efficiency, spatial and temporal precision are therefore greatly required. Recombinant adeno-associated viruses (AAVs) are frequently used for in vivo gene transfer of the nervous system but virus-mediated gene delivery to the axolotl nervous system has not yet been described. Here, we demonstrate the use of AAVs for efficient gene transfer within the axolotl brain, the spinal cord, and the retina. We show that serotypes AAV8, AAV9, and AAVPHP.eB are suitable viral vectors to infect both excitatory and inhibitory neuronal populations of the axolotl brain. We further use AAV9 to trace retrograde and anterograde projections between the retina and the brain and identify a cell population projecting from the brain to the retina. Together, our work establishes AAVs as a powerful tool to interrogate neuronal organization in the axolotl.