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Multilevel irreversibility reveals higher-order organization of nonequilibrium interactions in human brain dynamics
Information processing in the human brain can be modeled as a complex dynamical system operating out of equilibrium with multiple regions interacting nonlinearly. Yet, despite extensive study of the global level of nonequilibrium in the brain, quantifying the irreversibility of interactions among brain regions at multiple levels remains an unresolved challenge. Here, we present the Directed Multiplex Visibility Graph Irreversibility framework, a method for analyzing neural recordings using network analysis of time-series. Our approach constructs directed multilayer graphs from multivariate time-series where information about irreversibility can be decoded from the marginal degree distributions across the layers, which each represents a variable. This framework is able to quantify the irreversibility of every interaction in the complex system. Applying the method to magnetoencephalography recordings during a long-term memory recognition task, we quantify the multivariate irreversibility of interactions between brain regions and identify the combinations of regions which showed higher levels of nonequilibrium in their interactions. For individual regions, we find higher irreversibility in cognitive versus sensorial brain regions while for pairs, strong relationships are uncovered between cognitive and sensorial pairs in the same hemisphere. For triplets and quadruplets, the most nonequilibrium interactions are between cognitive–sensorial pairs alongside medial regions. Combining these results, we show that multilevel irreversibility offers unique insights into the higher-order, hierarchical organization of neural dynamics from the perspective of brain network dynamics.
Abstract P1082: Estimating the Burden of Undiagnosis HFpEF in the Community
Objective: Over 3 million Americans have heart failure with preserved ejection fraction (HFpEF). Effective guideline directed medical treatments (GDMT) are increasingly available but patients with HFpEF are likely under-detected (particularly women) and not receiving GDMT. Limited data are available informing the extent of HFpEF under-detection in the community. Hypothesis: Among patients with undifferentiated dyspnea and a high risk for unrecognized HFpEF, fewer than 50% will receive a HFpEF diagnosis during two years of follow-up; underrecognition will be greater among women. Methods: We identified 22,134 patients aged ≥30 in the Rochester Epidemiology Project (a medical records linkage system comprising a 27-county region of southeastern Minnesota and western Wisconsin) with evidence of unexplained dyspnea (≥2 ICD codes for dyspnea separated by >1 day) without prior documented etiology including HF or lung disease, during the time period 2018-2022. We calculated the recently validated HFpEF-Age-BMI-Atrial Fibrillation (HFpEF-ABA) score to estimate the probability of underlying HFpEF. Cox proportional hazards models regressed risk for incident HFpEF diagnosis on HFpEF-ABA score (dichotomized as ≥80% vs. <80%) with multivariable adjustment for sex, race and ethnicity. HRs(95%CIs) are presented. Results: Patients were 59±16 yrs, 50.8% women, 88.6% white, 3.1% Black, 3.7% other race, 4.6% Hispanic. Atrial fibrillation prevalence was 9.4% and mean BMI=31.4±7.8. Prevalence of HFpEF-ABA≥80% was 22.4%(n=4,958): 22.7% among women and 22.1% among men. The cumulative incidence of clinically-recognized HFpEF diagnosis at two years follow-up was 9.7% among women and 12.8% among men (log-rank p<0.01). HFpEF incidence was elevated with high HFpEF-ABA scores(≥80%): HR(95%CI) among women=3.72 (3.35, 4.14), and men=3.42 (3.11, 3.76). Among those with clinically diagnosed HFpEF during follow-up, mean time from date of first dyspnea ICD code to HFpEF diagnosis was 1.26 years overall: 1.31 and 1.21 years in women and men, respectively (p=0.05). Conclusions: One in five patients with undifferentiated dyspnea have probable undiagnosed HFpEF, and of that group, only 30% receive a clinical diagnosis, requiring an average of over 1 year to be recognized. The rate of diagnosis is even lower among women than men. Further study is warranted to implement evidence-based algorithms supporting detection of undiagnosed HFpEF in the community, especially in women.
Abstract MP23: Environmental Justice and Atherosclerotic Cardiovascular Disease Risk among Asian American, Native Hawaiian, and other Pacific Islander Subgroups: The PANACHE Study
Introduction: Environmental pollution is a risk factor for cardiovascular disease. Few environmental justice studies have examined the burden of pollution among Asian American, Native Hawaiian, and other Pacific Islander (AANHPI) subgroups. The California Environmental Protection Agency CalEnviroScreen is an environmental justice mapping tool that identifies disadvantaged communities with a high burden of multiple pollutants. Methods: The study included 562,538 AANHPI and 1,891,203 non-Hispanic White adults aged ≥30 years who received health care from Kaiser Permanente Northern California during 2012-2022 and had no prior cardiovascular disease. We linked the CalEnviroScreen 2.0 score to the census tract of each person in the study at baseline. CalEnviroScreen designates “disadvantaged communities” as the census tracts with the highest statewide quartile of the score. Atherosclerotic cardiovascular disease (ASCVD) events were ascertained through 2023 using discharge diagnosis codes and death certificates. We fit Cox proportional hazards models to examine the association between statewide quartiles of the CalEnviroScreen score with incident ASCVD, adjusting for age, sex, AANHPI subgroups, diabetes, hypertension, dyslipidemia, chronic kidney disease severity, body mass index, and current and former tobacco use. Results: CalEnviroScreen scores differed by AANHPI subgroups (p-value <0.0001). The Southeast Asian subgroup had the highest percentage of adults living in a CalEnviroScreen disadvantaged community (23.0%), followed by Native Hawaiian/Pacific Islander (12.9%), Vietnamese (11.7%), and Filipino (8.5%; Figure ). In contrast, only 6.9% of non-Hispanic White adults lived in a CalEnviroScreen disadvantaged community. Living in a disadvantaged community was associated with a 23% increased risk of incident ASCVD (adjusted hazard ratio 1.23, 95%CI 1.19-1.27) compared to the lowest quartile of the CalEnviroScreen score, adjusting for demographics and clinical cardiovascular risk factors. Conclusions: In a large, community-based AANHPI cohort in California, we found differences in the burden of pollution across AANHPI subgroups. Living in a community with a high pollution burden was associated with an increased adjusted risk of incident ASCVD. Environmental pollution may be a factor contributing to disparities in ASCVD among AANHPI subgroups.
Abstract P1111: Metabolomic Architecture of Different Composition of Fat, Carbohydrates, and Proteins in Randomized Weight-Loss Diet Intervention Trial
Background and Aims: Low-calorie weight loss diets with different macronutrient compositions have shown to result in clinically meaningful long-term weight loss. We aimed to identify plasma metabolites that significantly changed over two years in an intervention trial of low-calorie weight-loss diets with varying amounts of fats, carbohydrates, and proteins, and to investigate which changes in plasma metabolites are linked to better long-term weight loss. Materials and methods: The present study included participants who were randomly assigned to one of 4 diets in the POUNDS Lost trial. Untargeted plasma metabolomics was performed; changes in 856 metabolites across various metabolic pathways from baseline to the end of the two-year intervention were calculated in 533 participants. Results: We observed 571 metabolites (67%) showing statistically significant changes ( P- FDR < 0.05) following the two-year diet intervention (Figure panel a). We also identified core metabolites that significantly changed across all diet groups as well as specific metabolites that changed only in each of the 4 diet groups (panel b). Of the significantly modified metabolites by diets, 239 were significantly associated with 2-year weight changes, while others were not linked to weight loss (panel c). When stratifying by diet group, we identified 230 metabolites related to weight loss in response to one of the 4 diet interventions, including 22 metabolites within the lactoyl amino acid pathways, which showed the strongest sub-pathway associations with weight changes over two years in all diet groups. Conclusion: Our study identified core and specific metabolic pathways associated with changes in all or each of three macronutrients that contribute to better long-term weight loss.
Input-driven circuit reconfiguration in critical recurrent neural networks
Changing a circuit dynamically, without actually changing the hardware itself, is called reconfiguration, and is of great importance due to its manifold technological applications. Circuit reconfiguration appears to be a feature of the cerebral cortex, so understanding the dynamical principles underlying self-reconfiguration may prove of import to elucidate brain function. We present a very simple example of dynamical reconfiguration: a family of networks whose signal pathways can be switched on the fly, only through use of their inputs, with no changes to their synaptic weights. These are single-layer convolutional recurrent network with local unitary synaptic weights and a smooth sigmoidal activation function. We generate traveling waves using the high spatiotemporal frequencies of the input, and we use the low spatiotemporal frequencies of the input to landscape the ongoing activity, channeling said traveling waves through an input-specified spatial pattern. This mechanism uses inherent properties of marginally stable, dynamically critical systems, which are a direct consequence of their unitary convolution kernels: every network in the family can do this. We show these networks solve the classical connectedness detection problem, by allowing signal propagation only along the regions to be evaluated for connectedness, and forbidding it elsewhere.
Abstract P2137: Depressive symptoms during late pregnancy are associated with higher cardiovascular disease risk 2-7 years after delivery.
Background: Adverse pregnancy outcomes (APOs) are risk factors for future cardiovascular disease (CVD). APOs are more common among individuals who experience depression during pregnancy, and depression is a well-established CVD risk factor in non-pregnant populations. The purpose of the present study was to evaluate the relationship between depressive symptoms in pregnancy and future CVD risk, and to determine whether this relationship was mediated by APOs. Methods: This secondary analysis of the multisite prospective nuMoM2b-Heart Health Study included 4,050 participants (M age =27.6±5.6 years), with complete longitudinal data for variables from early pregnancy to 2-7 years post-delivery. Participants self-reported depressive symptoms on the Edinburgh Postnatal Depression Scale (EPDS) at 6-13 (early pregnancy) and 22-29 (mid-pregnancy) weeks of gestation. APOs were collected prospectively and adjudicated and included small-for-gestational-age birth, hypertensive disorders of pregnancy, gestational diabetes mellitus, placental abruption, and preterm birth. CVD risk factors, assessed at 2-7 years after delivery (follow-up interval M =3.2±0.9 years), were modeled as a higher order latent factor indicated by intermediate latent factors: insulin resistance (glucose and insulin), adiposity (waist circumference and BMI), blood pressure (SBP and DBP), and dyslipidemia (triglycerides and HDL cholesterol). Structural equation modeling was used to test whether APOs (present or absent) mediated the relationship between mid-pregnancy EPDS scores and latent CVD risk 2-7 years post-delivery, covarying for EPDS scores in early pregnancy (approximating pre-pregnancy), length of follow-up interval, smoking history, age, education, and income. Results: The model adequately fit the data (CFI=.96; RMSEA=.058; SRMR=.04). The direct effects of APOs ( β =.26, p <.01) and late pregnancy EPDS scores ( β =.13, p <.01) on latent CVD risk were significant. BMI ( r =.16), waist circumference ( r =.15), and HDL cholesterol ( r =-.13) were the CVD risk factors most strongly associated with late pregnancy EPDS scores ( r range=|.04-.16|). The indirect effect of EPDS scores on CVD risk through APOs was not significant ( p >.6). Discussion: Depressive symptoms in mid-pregnancy were associated with higher CVD risk 2-7 years after delivery, but this effect was not mediated by experiencing APOs. Future studies should evaluate whether pregnancy interventions to improve mood reduces subsequent risk of CVD.
Abstract P2087: Sex Disparities in Acute Myocardial Infarction Identification and Treatment.
Background: Early identification and diagnosis are pivotal in the management of patients with acute myocardial infarction (AMI). The American Heart Association / American College of Cardiology (AHA/ACC) guidelines recommend obtaining an electrocardiogram (ECG) for patients who present to the emergency department (ED) with ischemic symptoms within 10 minutes of arrival. This is an important step in ensuring early administration of reperfusion therapy for those with an ST-elevation myocardial infarction (STEMI). A goal of ≤90 min or ≤ 120 min when transfer is involved is recommended for door-to-balloon (DTB) procedure time to reduce the risk of poor outcomes. However, past research has shown that sex disparities exist in ED triage and timely treatment of patients experiencing an AMI. The aim of this study was to assess sex differences in timely identification and treatment of patients presenting to the ED with AMI. Methods: We performed a retrospective cross-sectional analysis of 874 STEMI (234 females and 640 males) and 1,650 Non-STEMI (NSTEMI; 556 females, 1095 males) patients that presented to two urban EDs between January 1, 2022, and March 31, 2024. Sex differences in time to ECG (STEMI and NSTEMI) and DTB (STEMI only) were compared continuously, as well as categorically based on AHA/ACC recommendations (ECG delay: >10 min, DTB delay: >90 min or >120 min with transfer). Continuous variables were compared using a multi-factor analysis of variance and categorical variables were tested using chi-square test of association. Results: Median time to ECG was 4.0 min longer for female compared to male STEMI patients, and 2.5 min longer for female vs male NSTEMI patients (ECG delay: 20.3% of female vs. 11.6% of male STEMI patients and 29.3% female vs. 20.3% of male NSTEMI patients). EMS activation time to ECG was also longer in females (+7.4 min for female STEMI patients and +2.9 min for female NSTEMI patients, compared to male counterparts). Similarly, DTB was 28.0 min longer when no transfer was involved and 15.2 min longer with transfer in female compared to male STEMI patients (DTB delay: 40.6% female vs. 37.0% male STEMI patients). Conclusion: In AMI patients presenting to the ED, female sex was associated with a significantly longer time to ECG. Female STEMI patients also had longer DTB times, which is associated with poorer outcomes. Initiatives are needed to understand these sex disparities and achieve the AHA/ACC guidelines for both time to ECG and DTB.
Abstract P1176: The Association of Urinary Incontinence, Physical Activity, and Cardiovascular Disease Risk in Women
Introduction: Urinary incontinence (UI) is a common condition among women. Emerging evidence indicates UI might contribute to lower physical activity (PA) levels. Thus, women with UI may have increased risk for inactivity and related cardiovascular disease (CVD). Hypothesis: Women with UI, compared to women without UI, will 1) have higher odds of being inactive or insufficiently active, and 2) have higher odds of cardiovascular risk factors or diagnosed cardiovascular disease. Methods: This retrospective observational study used electronic medical records to capture data on UI diagnosis, self-reported moderate-to-vigorous PA using the Exercise Vital Sign, Atherosclerotic Cardiovascular Disease (ASCVD) risk factor components and the diagnosis or management of CVD using ICD-10 codes, and demographic information. Multinomial logistic regression assessed the association of UI and PA classification (inactive: 0 min/week, insufficiently active: 1-149 min/week, and active ≥150 min/week). Multiple variable logistic regression models assessed associations of UI with CVD risk calculator components and diagnosed CVD. All models adjusted for age, race, body mass index, and tobacco use. Results: Of 20,155 women who were included in analysis (mean age 50.36±16.42 years), 1,085 (5.4%) had a UI diagnosis. Women with UI were on average 11.4 years older than those without UI. A greater proportion of those with UI were current or former smokers compared to those without UI. Activity classification did not differ in those with and without UI. Those with UI had greater odds of type 2 diabetes (aOR 1.25, 95% CI: 1.06-1.48), dyslipidemia (aOR 1.37, 95% CI: 1.19-1.58), stroke (aOR 1.55, 95% CI: 1.06-2.25), and coronary artery bypass grafts (aOR 3.17, 95% CI: 1.45-6.95) than those without UI (Table 1). Conclusions: UI was not associated with PA classification; future studies should investigate whether increasing PA among women with UI can mitigate associations of UI and CVD risk. Women with UI also present with risk factors for CVD and the association should be further studied. Additionally, women with CVD should be screened for UI.
Evolution of the <i>JULGI–SMXL4/5</i> module for phloem development in angiosperms
Bifacial cambium, which produces xylem and phloem, and monopodial architecture, characterized by apical dominance and lateral branching from axillary buds, are key developmental features of seed plants, consisting of angiosperms and gymnosperms. These allow seed plants to adapt to diverse environments by optimizing resource allocation and structural integrity. In seed plants, SUPPRESSOR OF MAX2-LIKE ( SMXL ) family members function in phloem development and strigolactone-induced inhibition of axillary bud outgrowth. Although strigolactone signaling regulates most SMXL family members, the only known regulator of SMXL4 and SMXL5 is the RNA-binding protein JULGI. We demonstrate that in angiosperms, by directly regulating SMXL4/5 expression, JULGI uncouples SMXL4/5 activity from strigolactone signaling. JULGI and ancestral SMXL s from seedless vascular plants or SMXL4/5 from seed plants are coexpressed in the phloem tissues of vascular plants, from lycophytes to angiosperms. Core angiosperm SMXL4/5 mRNAs contain a G-rich element in the 5′ untranslated region (UTR) that serves as a target sequence for JULGI to negatively regulate SMXL4/5 expression. Heterologous expression of JULGI s from various angiosperms rescued the Arabidopsis jul1 jul2 mutant. Expressing SMXL4/5 s from seed plants and ancestral SMXL s rescued Arabidopsis smxl4 smxl5 . Angiosperm SMXL4/5s lack an RGKT motif for proteasomal degradation. Indeed, treatment with the synthetic strigolactone analog rac -GR24 induced proteasomal degradation of SMXL from ferns and SMXL5a from gymnosperms, but not SMXL4/5 from angiosperms. These findings suggest that in ancestral angiosperms, the 5′ UTR of SMXL4/5 gained G-rich elements, creating a regulatory module with JULGI that allows the phloem development pathway to act independently of strigolactone signaling.
Abstract P2141: Developing a Targeted Educational Intervention Addressing Barriers to Home Blood Pressure Monitoring for Pregnant People with Hypertensive Disorders of Pregnancy
Introduction: Hypertension (HTN) is a leading cause of maternal morbidity and mortality. Home blood pressure monitoring (HBPM) is essential in pregnancy due to blood pressure variability, limited medication options, and high rates of Whitecoat HTN. However, there is no standard for counseling, and utilization is inconsistent. Hypothesis: To identify patient- and provider-reported barriers to HBPM in pregnancies complicated by hypertensive disorders (HDP) to guide the development of a targeted educational intervention. Methods: From April to August 2023, pregnant participants (n = 21, mean age 31.6 years, SD 5.3) with HDP and perinatal healthcare providers (n = 4) were recruited from an academic tertiary care center. In-person interviews explored experiences with HBPM, identified barriers, and gathered recommendations for change. Qualitative analysis was used to generate and reconcile themes and subthemes. Discrepancies were resolved by consensus. Root cause analysis was conducted using the "5 Why Technique," and a Plan-Do-Study-Act (PDSA) cycle informed the design of our intervention. Results: Of the 21 participants, 71.4% utilized HBPM, but only 13.3% received guidance from providers. The average confidence level in HBPM was 6.67 (SD 3.4) on a 0-10 Likert scale. The major root causes leading to decreased confidence in utilizing HBPM included: 1) no standardized guidance or resources for providers and patients regarding HBPM and alert values during pregnancy; 2) no streamlined process recommended or taught to patients; and 3) no consolidated resources on available validated cuffs for this patient population. To address these issues, we developed a patient-centered educational intervention, including physical pamphlets, a video guide, and online links to a template log and validated cuffs currently accessible for this patient population. Conclusion: In conclusion, we identified critical barriers to HBPM in pregnancies with HDP, including insufficient guidance, inadequate access to resources, and absence of standardized processes. A new targeted educational intervention, including patient-focused materials and provider resources, was developed to address these barriers. Ongoing post-intervention data collection aims to refine and optimize the intervention for broader reach and improved confidence in HBPM practices. Targeted solutions like this may ultimately improve maternal outcomes and reduce risks associated with hypertensive disorders in pregnancy.
Abstract 004: Longitudinal Change in Cardiovascular Health by Repeated Measures of Self-Reported Sexual Orientation Discrimination in the CARDIA Study Cohort
Introduction: Few studies have investigated the association of self-reported discrimination based on sexual orientation with cardiovascular health. Objective: We assessed if repeated self-reported sexual orientation discrimination was associated with longitudinal cardiovascular health among males and females in the CARDIA study. Methods: CARDIA participants completed cardiovascular health assessments and sexual orientation discrimination measures in 1992-1993 (Year 7 Exam), 2015-2016 (Year 30 Exam), and 2020-2022 (Year 35 Exam). For each exam, participants reported if they experienced discrimination attributable to sexual orientation in 6 different contexts (at school, getting a job, at work, at home, getting medical care, and in public settings). The number of reported discrimination contexts was summed at each time point and assigned to one of four levels (0, 1, 2, or 3 or more experiences). Multiple imputation by chained equations was used to estimate missing exposure and outcome variables. Linear mixed models stratified by sex were used to estimate the associations between age, sexual orientation discrimination, and Life’s Simple 7 (LS7). The interaction of age and discrimination was used to estimate differences in change in LS7 over time (i.e., age) by levels of discrimination. Results: Median participant age was 54 years (SD 12.7 years), 55.3% of participants were female, and 49.7% were Black. Combining participant reports of females across all 3 exams, 83.5% reported 0, 4.8% reported 1, 2.6% reported 2, and 4.2% reported 3 or more contexts of sexual orientation discrimination. Among males, these percentages were 84.7%, 4.6%, 2.4%, 4.2%, respectively. The mean LS7 score across all visits for all participants was 7.68 (SD 1.78). Females who reported 3 or more sexual orientation discrimination contexts had significantly lower cardiovascular health than those who reported no sexual orientation discrimination (b = -0.60, p=0.008), but no significant difference in their rate of LS7 change from Year 7 to Year 35 Exam (b=0.02, p=0.15). There was no significant association between sexual orientation discrimination and cardiovascular health in males. Conclusions: Among females, sexual orientation discrimination was inversely associated with cardiovascular health. No significant differences were detected in males. Future studies will investigate if these findings vary by sexual identity and race.
Abstract P3012: Increased Circulating Concentrations of Soluble Cell Adhesion Molecules and Fibrin-D-Dimer in Adults with Periodontal Disease
Periodontal disease, specifically periodontitis, is a progressive multidimensional inflammatory disease of the oral cavity. In addition to adverse oral health consequences, periodontitis is associated with increased risk of atherothrombotic cardiovascular disease and events. Importantly, periodontitis affects >40% of adults in the United States over the age of 30 years. Despite improved management of many of the oral health consequences associated with periodontitis, factors that initiate and promote increased atherothrombotic risk and events are poorly understood. Elevated levels of circulating soluble cell adhesion molecules and fibrin D-dimer are markers of a proatherogenic vascular environment and strong prognostic indicators of atherothrombotic events. We tested the hypothesis that circulating levels of soluble cell adhesion molecules and fibrin D-dimer are elevated in adults with periodontitis, which, in turn, may contribute to the heightened risk of vascular disease and events in this population. Peripheral blood was collected from 26 middle-aged adults: 13 without periodontitis (9 M/4F; age: 49 + 3 yr; BMI: 28.5 + 0.9 kg/m 2 ) and 13 clinically diagnosed with periodontitis (7 M/6 F; 54 + 4 yr; 26.0 + 1.6 kg/m 2 ). All subjects were free of overt cardiovascular and metabolic disease. Plasma concentrations of extracellular soluble adhesion molecules (intracellular adhesion molecule-1 [sICAM-1], vascular adhesion molecule-1 [sVCAM-1], platelet endothelial cell adhesion molecule-1 [sPECAM-1] and E-selectin) and fibrin D-dimer were determined by immunoassay. sICAM-1 (265±14 vs 218±11 ng/mL), E-selectin (48±4 vs 36±3 ng/mL) and fibrin D-dimer (408±47 vs 278±31 ng/mL) were significantly higher (~25-50%) in adults with periodontitis. There were no significant group differences in either sVCAM-1 (595±38 vs 596±53 ng/mL) or sPECAM-1 (10±1 vs 9±1 ng/mL). Elevated circulating levels of sICAM and sE-selectin are sensitive biomarkers of vascular endothelial cell activation and adhesion and have been linked with increased risk of atherogenesis; in addition, elevated fibrin D-dimer is a direct indicator of thrombotic activity. Thus, the increased risk and prevalence of atherothrombotic events in adults with periodontitis may be mediated, in part, by increased expression of cell adhesion molecules and a prothrombotic environment as indicated by elevated soluble cell adhesion molecules and fibrin D-dimer levels.
State-dependent motion of a genetically encoded fluorescent biosensor
Genetically encoded biosensors can measure biochemical properties such as small-molecule concentrations with single-cell resolution, even in vivo. Despite their utility, these sensors are “black boxes”: Very little is known about the structures of their low- and high-fluorescence states or what features are required to transition between them. We used LiLac, a lactate biosensor with a quantitative fluorescence-lifetime readout, as a model system to address these questions. X-ray crystal structures and engineered high-affinity metal bridges demonstrate that LiLac exhibits a large interdomain twist motion that pulls the fluorescent protein away from a “sealed,” high-lifetime state in the absence of lactate to a “cracked,” low-lifetime state in its presence. Understanding the structures and dynamics of LiLac will help to think about and engineer other fluorescent biosensors.
Abstract P2151: Good Sleep Health Is Associated With Better Cardiometabolic Health In Adolescents: A Multidimensional-Multimethod, Factor-Analytic Approach
Background: Life’s Essential 8 highlights the importance of adequate sleep duration in for cardiovascular health. Current evidence demonstrates that health is also influenced by the quality, consistency, and timing of sleep within the 24-hour day. However, no studies have explored which sleep variables contribute to adolescent cardiometabolic health. Hypothesis: The quality, consistency, and timing of sleep will contribute differently to metabolic syndrome (MetS) and each of its components in adolescents. Methods: 307 adolescents (16 yr; 47% female; 23% racial/ethnic minority) from the Penn State Child Cohort had at least 3-nights of actigraphy (ACT), in-lab 9h polysomnography (PSG), self-reported (SR) insomnia symptoms, daytime sleepiness, sleep schedules, completed a physical exam, and a fasting blood draw. A continuous MetS (cMetS) score was calculated as the sum of sex-and age adjusted z-scores of waist circumference (WC), mean arterial pressure (MAP), HDL, triglycerides, and HOMA-IR. Common factor analysis was performed to understand the factor and correlation structure of 58 standardized sleep variables. LASSO Regression selected sleep variables and assessed their importance to cMetS and its components, independently. Results: Factor analysis identified five sleep domains: 1. Timing and Irregularity: means and standard deviations of SR bedtime and waketime, ACT sleep midpoint, and PSG sleep midpoint; 2. Efficiency: means of ACT sleep efficiency (SE), wake after sleep onset (WASO), sleep onset latency (SOL), and number of awakenings; 3. Duration: mean ACT total sleep time (TST), time in bed (TIB), and SR habitual bedtime; 4. Catch-up and Social Jetlag: differences in weekday and weekend SR waketime and TIB and ACT TST and sleep midpoint; 5. Physiologic Sleep Disturbance: PSG TST, SE, SOL, WASO, apnea-hypopnea index (AHI). Results from LASSO indicate that lower PSG AHI contributed to lower cMetS, WC, MAP, triglycerides, and higher HDL, while longer PSG TST contributed to higher HDL and lower MAP. Earlier sleep midpoint contributed to higher WC, HDL and higher sleep regularity contributed to lower HDL. Longer catch-up sleep contributed to lower MAP, and lower social jetlag contributed to lower MAP. Conclusions: Objective measures of sleep contribute most to cardiometabolic health in adolescents, while subjective sleep measures do not contribute to the same extent. These findings highlight the multidimensional association of sleep and cardiometabolic health.
Abstract 037: Proteo-Transcriptional Characterization of Aortic Stenosis Prioritizes Novel Targets Relevant to Heart Failure
Background: Aortic stenosis (AS) initiates a series of molecular alterations that predate cardiac remodeling and development of heart failure (HF). We hypothesized that integrating circulating mediators (proteome) from large-scale epidemiological cohorts with their cell-specific gene expression in the heart (transcriptome) may prioritize novel targets in human AS. Methods: Among individuals with severe AS, we measured the circulating proteome (Olink) and examined associations with myocardial structure/function (N=519), cardiac MRI-based tissue fibrosis (N=145), and clinical outcomes (N=802). We constructed proteomic signatures of cardiac remodeling and tested their association with mortality and HF in the UK Biobank (UKBB; N=36,668). We then examined a "remodeling proteome” prioritized by proteome-phenotype relations at the transcriptional level via single nuclear RNA-sequencing in 20 human hearts (11 with AS at the time of SAVR and 9 donor hearts unused for transplant). Results: We identified three principal components (PCs) of cardiac remodeling (across 12 echocardiographic measures in 503 patients with severe AS) loaded on cardiac morphology, systolic, and diastolic function traits. Proteins associated with these PCs specified both known and novel mediators of fibrosis, LVH, and oxidative stress. Proteomic signatures were strongly linked to mortality (AS cohort, UKBB) and incident HF (UKBB). At a myocardial level, we observed cell-specific differential gene expression, particularly prominent in fibroblasts, cardiomyocytes, and endothelial cells, featuring convergent fibrosis pathways ( WNT9A , ITGA6 , AGRN , CRIM1 , SEMA4C , LAYN, PTX3 , HMOX1 ) and metabolic-inflammatory signaling ( ENPP2/ATX, TNF), among others. Conclusions: Proteo-transcriptional prioritization in human AS identifies both known and novel targets that are mechanistically relevant to HF pathogenesis. Future integrative studies that link longitudinal circulating biomarkers in large-scale cohorts directly to myocardial tissue are warranted to inform pathways of HF progression.
Abstract P3062: Active Screening in Black, Hispanic/LatinX, Asian/Pacific Islander, and Native American Individuals Reduces Racial Disparities in Abdominal Aortic Aneurysm Diagnosis
Introduction: Abdominal aortic aneurysm (AAA) screening and diagnosis in Black, Hispanic/LatinX, Asian/Pacific Islander and Native American people is challenging given the asymptomatic clinical presentation necessitating access to and utilization of the healthcare system. While previous studies report higher AAA risk in patients who identify as White, institutionalized racism and mistrust of the healthcare system limits representation of non-White individuals biasing AAA risk assessments. Large scale analysis of diverse patient cohorts is essential to understand the true incidence of AAA. Objective: To evaluate the impact of race on diagnosis rates for AAA in a diverse patient population. Methods: Patients over the age of 65 seen at the Mount Sinai Healthcare System were retrospectively reviewed from 2002 to 2024 to assess diagnosis rates in patients eligible for screening by U.S. Preventative Services Task Force (USPSTF) guidelines and those with aortic ultrasound screening. Multivariate logistic regression with interaction factors between patient reported race/ethnicity, screening eligibility, and aortic ultrasound (US) screening were included to assess the impact of US screening and race on AAA diagnosis. Results: A total of 1,070,367 patients were evaluated during the study period of which 54.6% self-identified as female, 11.4% Black, 42.9% White, 10.4% Hispanic/LatinX, 4.6% Asian, 0.08% Native American, 0.54 Pacific Islander, and 9.5% as Other Race. The diagnosis rate in men over 65 who smoked was slightly higher than the diagnosis rate for individuals who did not meet USPSTF guidelines (OR=3.087, 97.5% CI = 0.8-10.36, p=.075). Overall, after adjusting for race/ethnicity, eligibility, and US screening, diagnosis was significantly impacted by race (p<.05), screening (p=0.001), and the interaction effect between race and US screening (p=.008). Contrary to the results of previously studies, the significance of race and screening on diagnosis was driven by ~20% higher odds of a positive AAA diagnosis from screening Black or Hispanic/LatinX patients compared to White patients. Conclusion: AAA incidence in people who identify as Black, Hispanic/LatinX, Asian/Pacific Islanders, and Native Americans is likely much higher than previously reported. With the historic barriers to healthcare access and under representation, active AAA screening programs in these communities could drastically increase diagnosis rates leading to decreased mortality due to ruptured AAA.
Abstract P3053: Disparities in the Association Between Diabetes Mellitus and All-Cause Mortality Among Asian American Subgroups: Findings From the National Health Interview Survey (NHIS) (1997–2018)
Introduction: The prevalence of diabetes mellitus (DM), a well-established mortality risk factor, is higher among Asian Americans collectively than non-Hispanic White (NHW) populations. Despite known racial/ethnic differences in diabetes-related outcomes, Asian Americans are often studied as a homogeneous group. This study investigates the disparities in the association between DM and all-cause mortality rates among different Asian American subgroups relative to NHWs. Hypothesis: We assessed the hypothesis that the associations between diabetes mellitus and all-cause mortality rates differ among Asian American subgroups compared to NHWs. Methods: Data from the National Health Interview Survey (NHIS) (1997–2018) was linked with the 2019 National Death Index (NDI). A total of n = 418,681 individuals were analyzed, with diabetes prevalence and all-cause mortality rates compared among Asian Indian (n = 5,478), Chinese (n = 5,848), Filipino (n = 6,419), and NHW (n = 400,936) groups. Hazard ratios (HRs) were calculated using weighted Cox proportional hazard modeling controlling for demographic and socioeconomic determinants of health. Results: Compared to NHW individuals (8.3%, 95% CI [8.2-8.4]), the prevalence of diabetes was higher in Filipino individuals (9.7%, 95% CI [8.9-10.6]) and Asian Indian individuals (7.7%, 95% CI [6.9-8.6]) but lower in Chinese individuals (4.7%, 95% CI [4.1-5.4]). Among individuals with diabetes, the adjusted hazard ratios for all-cause mortality rates were lower for Chinese (HR = 0.85, 95% CI [0.76-0.96]), Filipino (HR = 0.75, 95% CI [0.71-0.79]), and Asian Indian (HR = 0.65, 95% CI [0.45-0.93]) populations compared to NHW individuals. Conclusion: Asian Americans with diabetes experienced a lower mortality risk compared to NHW individuals with diabetes, despite some Asian subgroups having a higher prevalence of the disease. Variations in determinants of all-cause mortality, such as education, income, and nativity, likely contribute to these differences, underscoring the need for targeted interventions.
Abstract P2039: Disease Progression in patients with Chagas Disease treated with Benznidazole or Nifurtimox: A Systematic Review and Meta-analysis
Introduction: Most studies evaluated the efficacy of treatment for chagas disease with the reduction of parasite detection as a primary outcome. However, little is known about the mortality rate associated with benznidazole or nifurtimox in chagas disease patients. Thus, we aimed to investigate all-cause mortality and cardiovascular-related mortality among chagas disease patients treated with benznidazole or nifurtimox. Method: Systematic review and meta-analysis were conducted including randomized control trial studies and cohort studies in patients who received benznidazole or nifurtimox for chagas disease treatment, using online databases including PubMed, Embase, CENTRAL, LILAC, and sciELO up to May 1, 2024. The primary outcomes were all-cause mortality or cardiovascular-related mortality. Studies focused on patients with HIV-coinfection were excluded. Result: We included 15 studies involving 3837 patients, with 14 studies on benznidazole (n=3552) and 3 studies (n=285) on nifurtimox. Overall, all-cause mortality over follow-up was 1.96% [95% Confidence Interval (CI): 0.58-3.93], and 2.21% [95% CI: 0.45-4.89] for cardiovascular-related mortality. All-cause mortality was 1.04% [95% CI: 0.00-4.61] for the nifurtimox group and 2.07% [95% CI: 0.51-4.39] for the benznidazole group. Cardiovascular-related mortality was 3.03% [95% CI: 0.00-9.25] for the nifurtimox group and 2.10% [95% CI: 0.25-5.16] for the benznidazole group. Conclusion: This study is one of the first studies that conducted a meta-analysis to provide mortality outcomes in chagas disease patients. Our study estimated an increase in individuals of all-cause mortality and cardiovascular-related mortality over the study period. Further investigations are needed to understand mortality by phase of chagas disease, comorbidities, and cardiomyopathy-related signs to better understand the long-term effect of patients treated for chagas disease.
Abstract P2065: A Comparative Study Of Social Determinants, Hypertension, And Life Essential Factors In Alabama And Colorado From The 2021 Behavioral Risk Factor Surveillance System
Background: Hypertension is an important modifiable risk factor for cardiovascular disease, which disproportionately impacts racial/ethnic minorities in the US. Currently, Equity in Prevention of Hypertension (EPIPHANY, 2024) a program funded by the American Heart Association(AHA) is focusing on and engaging the Black belt of Alabama to mitigate hypertension by targeting adults with prehypertension, a new strategy to reduce the prevalence of hypertension. This project was meant to test the hypothesis of no difference in the risk of hypertension between two US States and to generate evidence for implementation. Objective: To compare the social determinant of health (SDOH), hypertension, and the AHA life's essential factors among adults in Colorado and Alabama in the 2021 Behavioral Risk Factor Surveillance System (BRFSS) Methodology: This was a cross-sectional survey of adults enrolled in the US 2021 BRFSS study. Data analysed compared Colorado and Alabama to determine the essential life factors among the two states. Elevated blood pressure (hypertension) and the included variables were based on the answers from the diagnosis of the healthcare professional given to the participants in the US BRFSS 2021. Data analysis used regression and risk ratios from the BRFSS WEAT to calculate the logistic regression and adjusted odds ratios (CDC, 2024). Results: In 2021, the racial proportion of adults with hypertension in Alabama was 41.8% for White vs 48.4% for the Black population (overall proportion=42.6 %), while in Colorado, 27.6% of White vs 36.1% of the Black adult population had hypertension(Overall proportion=25.9%) [Figure 1]. Compared to Colorado, AL has 1.83 times higher AOR of hypertension (p<0.0001). Fruit consumption, physical activity, and disability status significantly differed between Alabama and Colorado (p<0.0001)[Table 1, Figure 2]. Surprisingly, there was no difference in healthcare access between AL and CO (0.7872) [Table 1] Conclusion: Though Colorado has the lowest prevalence of hypertension in the United States, disparities still persist. However, Alabama demonstrated much higher disability status, lack of physical activity, and consumption of vegetables and fruits of <1 time/day (p<0.0001). Recommendations: The high burden of hypertension among ethnic minorities deserve attention and more evidence can be assessed to further understand the enabling factors that led to CO having the lowest proportion of hypertension.
<i>Dux</i> cluster duplication ensures full activation of totipotent genes
Zygotic genome activation (ZGA) confers to the mouse two-cell (2C) embryo a unique transcriptional profile characterized by transient up-regulation of many totipotency-related genes and MERVL retrotransposons. Intriguingly, those genes are duplicated and clustered in the genome during evolution, including Dux cluster, Obox, and Zscan4 family members in mice. However, the contribution and biological significance of the totipotency-related gene duplication events in early embryo development remain poorly understood. Here, we focus on Dux cluster, the master regulator of ZGA that is necessary and sufficient for the induction of 2C-like cells and activation of totipotency-related genes in mouse embryonic stem cells (mESCs). By reducing Dux gene copies from 31 to 0 or 1 through CRISPR-Cas9 technology, we generate Dux -KO and Dux (n = 1) mESC lines, respectively. We uncover that the totipotency-related gene transcriptional profile is awakened to a much lesser extent in Dux (n = 1) mESCs compared to wild type mESCs following global DNA demethylation reprogramming or induction of DNA damage, mimicking the intrinsic events in preimplantation development. Together, Dux cluster duplication is critically required for full activation of ZGA transcripts.