Browse Articles

Relating the molecular phenotype of ulcerative colitis to the clinical course

Abstract The expanding portfolio of targeted therapies for ulcerative colitis (UC) suggests that a more precise approach to defining disease activity will aid clinical decision-making. This prospective study used genome-wide microarrays to characterize gene expression in biopsies from the most inflamed colon segments from patients with UC and analyzed associations between molecular changes and short-term outcomes while on standard-of-care treatment. We analyzed 141 biopsies—128 biopsies from 112 UC patients and 13 biopsies from eight inflammatory bowel disease unclassified (IBDU) patients. Endoscopic disease was associated with expression of innate immunity transcripts, e.g. complement factor B (CFB); inflammasome genes (ZBP1 and PIM2); calprotectin (S100A8 and S100A9); and inflammation-, injury-, and innate immunity-associated pathway analysis terms. A cross-validated molecular machine learning classifier trained on the endoscopic Mayo subscore predicted the endoscopic Mayo subscore with area-under-the-curve of 0.85. A molecular calprotectin transcript score showed strong associations with fecal calprotectin and the endoscopic Mayo subscore. Logistic regression models showed that molecular features (e.g. molecular classifier and molecular calprotectin scores) improved the prediction of disease progression over conventional, clinical features alone (e.g. total Mayo score, fecal calprotectin, physician global assessment). The molecular features of UC showed strong correlations with disease activity and permitted development of machine-learning predictive disease classifiers that can be applied to expanded testing in diverse cohorts.

Correction for Patel et al., Aspirin binds to PPARα to stimulate hippocampal plasticity and protect memory

Bicomponent nano- and microfiber aerogels for effective management of junctional hemorrhage

Abstract Managing junctional hemorrhage is challenging due to ineffective existing techniques, with the groin being the most common site, accounting for approximately 19.2% of potentially survivable field deaths. Here, we report a bicomponent nano- and microfiber aerogel (NMA) for injection into deep, narrow junctional wounds to effectively halt bleeding. The aerogel comprises intertwined poly(lactic acid) nanofibers and poly(ε-caprolactone) microfibers, with mechanical properties tunable through crosslinking. Optimized aerogels demonstrate improved resilience, toughness, and elasticity, enabling rapid re-expansion upon blood contact. They demonstrate superior blood absorption and clotting efficacy compared to commercial products (i.e., QuikClot® Combat Gauze and XStat®). Most importantly, in a lethal swine junctional wound model (Yorkshire swine, both male and female, n = 5), aerogel treatment achieved immediate hemostasis, a 100% survival rate, no rebleeding, hemodynamic stability, and stable coagulation, hematologic, and arterial blood gas testing.

Abstract P1162: Cardiac Magnetic Resonance Imaging Measures of Atrial Cardiomyopathy and Adverse Clinical Outcomes in the UK Biobank

Introduction: Atrial cardiomyopathy precedes atrial fibrillation (AF) and is a strong risk factor for downstream adverse clinical outcomes, but there is no census about the optimal method for assessing it. Cardiac magnetic resonance imaging (CMR) is the most accurate tool to assess atrial function and structure. Our objective was to evaluate the association between CMR measures of atrial cardiomyopathy, incident AF, and AF-related clinical complications. Hypothesis: We hypothesized that CMR measures of atrial cardiomyopathy are associated with AF, ischemic stroke, heart failure, and dementia, independent of established risk factors. Methods: In 44,591 participants who underwent CMR as part of UK Biobank Imaging Study and had no history of AF, we assessed atrial minimal and maximal volumes (indexed to body surface area) and ejection fraction. Cox proportional hazard models were used to evaluate the association of these CMR measures with incident AF, ischemic stroke, heart failure, and dementia, adjusting for established risk factors. Results: During a median follow-up time of 4.0 [IQR 2.9-5.4] years, 834 (2%) participants developed AF, 197 (0.4%) developed ischemic stroke, 278 (0.6%) developed heart failure, and 61 (0.1%) developed dementia. The mean [standard deviation] age was 65 [8] years and 51% were female. When evaluated as continuous variables, left atrial ejection fraction (LAEF) was significantly associated with the risk of new-onset AF, ischemic stroke, and heart failure, while left atrial minimal volume (LAVI min ) and maximal volume (LAVI max ) were associated with these outcomes as well as the risk of dementia (Table). In comparison, right atrial measures were associated with only AF and heart failure, and the magnitude of the associations was generally smaller. After further adjustment for time-varying AF, these associations remained significant. When categorized by quintiles, participants in the highest LAVI min group had a HR of 3.67(95%CI 2.93-4.60) for AF, 1.51(95%CI 1.02-2.25) for ischemic stroke, 2.71(95%CI 1.86-3.96) for heart failure, and 2.43 (95%CI 1.11-5.31) for dementia, compared to those in the lowest. Conclusion: CMR measures of atrial structure and function were associated with AF-associated clinical outcomes independent of risk of AF. These findings suggest that atrial cardiomyopathy may be an important target of future research efforts, with potential implications for screening patients at high risk for cardiovascular disease.

Abstract P1069: Health Care Professional Perspectives on IMPLEMENT-HF: A Qualitative Study Examining Successes, Facilitators, and Barriers in a Quality Improvement Program for Patients with Heart Failure

Introduction: Heart failure (HF) leads to over 1 million hospitalizations and 450,000 related deaths annually, yet there are substantial quality gaps in care. In 2021, the American Heart Association launched IMPLEMENT-HF (I-HF), a 3-year national Quality Improvement (QI) initiative, to improve care and outcomes for patients with HF. Several QI strategies were used and evaluated over the course of this initiative. Purpose: Focus groups were conducted to gather health care professional (HCP) perspectives on I-HF implementation. Results will assist in determining overall program impact and to identify successes, barriers, and facilitators to inform implementation of future QI programs. Methods: This study involved virtual focus groups (n=8) with HCPs (n=25) recruited from the 111 sites enrolled in I-HF. A semi-structured focus group guide was developed to facilitate the 60-minute sessions. Focus groups were recorded and transcribed, and inductive and deductive thematic analyses conducted in NVivo identified key high-level themes and subthemes. Results: HCPs felt I-HF improved their care team’s knowledge of HF treatment options and their confidence in treating patients with HF. They reported improvements in prescribing guideline-directed medical therapy (GDMT), medication adherence, and follow-up appointment attendance during the program period. HCPs appreciated the flexibility and variety of I-HF’s educational offerings, opportunities to learn from other HCPs, and the benefits of the Get With The Guidelines® program on patient care. Commonly cited implementation barriers included high staff turnover, clinical roles taking precedence, and a lack of leadership and organization within their sites, which hindered full engagement with I-HF. The cost of and lack of insurance coverage for GDMT was frequently cited as a major burden for patients and a barrier to uptake. Conclusions: QI programs like I-HF can improve care and outcomes for patients with HF and increase HCP knowledge and confidence in providing appropriate treatments. Several cited implementation facilitators, such as flexible educational offerings, can be replicated in future programs. Some reported barriers, such as limited staff capacity, will be challenging to address. However, future initiatives can offer additional guidance on program implementation and recommend assigning a point person at each site to enhance internal organization and support more comprehensive adoption of program activities.

Abstract P3146: Racial Disparities in the Association of Adiposity Measures with Cardiovascular Disease Mortality

Introduction: Body Mass Index (BMI) has been generally used to measure adiposity, but it can be inaccurate when examining diverse race groups. We examined how the association between cardiovascular disease (CVD) mortality and adiposity – as measured by BMI, Waist-to-Height Ratio (WHtR), and Body Roundness Index (BRI) – differed by race. Hypothesis: We hypothesized that BRI would have the strongest association with obesity-related mortality risk with the association being more pronounced among Non-White race groups. Methods: We use 2019 National Death Index Linked Mortality data combined with the pooled adult sample of the 2007-2018 National Health and Nutrition Examination Survey (N = 31,244). We examined four race groups: Non-Hispanic White (n=12,684), Hispanic (n=8,043), Non-Hispanic Black (n=6,669), and Other Races (n=3,848). BMI, WHtR, and BRI were calculated using established equations and scaled by 0.05 increments to improve interpretability for regression analyses. We examined the association between each adiposity measure and CVD-related morality by race using Cox Regression. Results: Each race group had increased risk of CVD-related mortality for increasing adiposity for all measures (Figure). For BMI, people of “Other Race” had the highest risk (HR = 1.04). Non-Hispanic Black people had the lowest risk (HR = 1.01). For WHtR, Hispanic people had the highest risk (HR = 1.16), while Non-Hispanic Black people had the lowest risk (HR = 1.08). Finally, for BRI, Hispanic people had the highest risk (HR = 1.16) while Non-Hispanic Black people had the lowest risk (HR = 1.06). Conclusions: While increased adiposity is associated with heighted risk of mortality for all race groups, the association may be stronger for Hispanic people. Further investigation is needed into which adiposity measure is best for assessing CVD risk and mortality.

Light-matter coupling via quantum pathways for spontaneous symmetry breaking in van der Waals antiferromagnetic semiconductors

Abstract P2014: Baseline Sex Hormone Binding Globulin Level Modifies Intensive Lifestyle Intervention Effect on Blood Pressure in Post-Menopausal Females

Background: The Look AHEAD (Action for Health in Diabetes) randomized controlled trial showed that Intensive Lifestyle Intervention (ILI) targeting weight loss caused greater reductions in systolic and diastolic blood pressure (SBP and DBP) than Diabetes Support and Education (DSE) in patients with body mass index (BMI) 25 kg/m 2 and type 2 diabetes (T2D). Nonetheless, treatment assignment alone did not explain the individual variations in BP improvement. We hypothesize that baseline sex hormone binding globulin (SHBG), which is inversely associated with hypertension in both males and females, might modify the effect of ILI on BP. Methods: We selected a random sample of 1167 post-menopausal females and 1167 males from the Look AHEAD trial in our analysis. We retained the randomized design and created sex-stratified linear mixed models to examine whether log-transformed baseline SHBG levels modify the treatment effects (i.e., absolute difference between ILI and DSE) on SBP and DBP reduction after 1 year, adjusting for age, race, study site, baseline BMI and use of anti-hypertensive medications. Results: In our study sample (age: 60.0 [SD, 6.2] years; 14.8% black; 50% female), median [IQI] baseline SHBG levels were 32.9 [22.2-54.0] nmol/L in females and 29.0 [19.9-44.8] nmol/L in males. Mean (SD) baseline SBP and DBP were 130 (17.3) and 67.6 (9.2) mmHg for females, 128.6 (16.3) and 73.1 (8.9) mmHg for males. Females with 2-fold higher baseline SHBG had 3.0 (95%CI: 1.0, 5.0) mmHg and 1.3 (95%CI: 0.3, 2.2) mmHg greater reduction in SBP (Figure, panel A) and DBP (panel B), respectively, due to ILI compared to DSE. However, treatment effects in males did not vary significantly with baseline SHBG (heterogeneity p-values: 0.81 SBP, 0.98 DBP). Conclusion: Females with higher baseline SHBG had more BP lowering due to ILI, compared to DSE, but this effect was not seen in males. Future research is needed to confirm if baseline SHBG can identify female patients with T2D who benefit most from ILI, and to determine whether those with low SHBG levels need more aggressive BP management in combination with ILI.

Abstract P1160: Gut Microbiota, Circulating Inflammatory Markers, and Cardiac Dysfunction In Women Living With HIV

Introduction: The relationships among gut microbial alterations, host inflammation, and cardiac dysfunction remain understudied, particularly in the context of HIV. Hypothesis: We hypothesized that higher abundance of pro-inflammatory gut bacteria is associated with higher levels of host circulating inflammatory makers and cardiac dysfunction. Methods: We examined associations of gut microbial features (16S rRNA sequencing) with cardiac dysfunction (Echocardiography) in 973 women from the MACS/WIHS Combined Cohort Study. Cardiac dysfunction was defined as the presence of left ventricular systolic (LV ejection fraction<54%) or diastolic (ASE 2016 criteria) dysfunction. In a subset (n=397), we further integrated cardiac dysfunction-associated microbial features (Shotgun metagenomics sequencing) with serum proteomic inflammatory markers (Olink platform inflammation panel) in relation to cardiac dysfunction. Results: The potentially pathogenic bacteria Streptococcus, Eggerthella and Anaeroglobus , were positively associated with cardiac dysfunction, while the beneficial genera Roseburia and Alistipes were linked to lower odds of cardiac dysfunction ( Fig. 1A ). Results were consistent in women with and without HIV. These cardiac dysfunction-associated bacteria were associated with a number of circulating proteomic inflammatory markers ( Fig. 1B ). For example, the pathogenic Streptococcus was positively associated with the pro-inflammatory cytokines IL-8 and IL-6, the chemokine MCP-3 (linked to immune response and atherosclerosis), and the inflammatory mediator OSM (associated with vascular inflammation and heart failure). Proteomic inflammatory scores were generated for each genus based on their specific inflammatory marker profiles. The inflammatory score for Streptococcus was significantly associated with cardiac dysfunction ( Fig. 1C ). Associations between bacterial genera and cardiac dysfunction were attenuated after further adjustment for specific microbial associated inflammatory markers ( Fig. 1D ). Conclusion: Among women living with or at risk of HIV, we identified gut microbial features associated with cardiac dysfunction, with certain microbiota-related inflammatory markers partially explaining these associations.

Abstract 034: Proteomic Profiles of Obesity-Related Phenotypes are Independently Associated with Incident Cardiovascular Events

Background: Obesity is a critical modifiable risk factor for adverse cardiovascular events, yet traditional measures like Body Mass Index (BMI) have limitations in capturing the complexities of adiposity and its associated cardiovascular disease risk. Proteomics may improve the understanding of the molecular underpinnings of obesity and its implications for cardiovascular health. Methods: Proteomic profiling was performed using the Olink Explore 3072 platform on blood plasma samples from a subset of the UK Biobank participants. The relative protein abundance was normalized using rank-based inverse normalization. A total of 15,652 healthy participants without prevalent or incident diabetes, cardiovascular disease, renal disease, and cancer were included for training and testing of the protein-predicted obesity phenotypes, including BMI, body fat percentage (BFP), and waist-hip ratio (WHR). An additional 24,999 participants without prevalent stroke or coronary artery disease were included in predicting major adverse cardiovascular events (MACE). Protein-predicted scores of BMI, BFP, and WHR were generated using the least absolute shrinkage and selection operator (LASSO) algorithm with cross-validation among the healthy participants. Associations between these protein-predicted scores and MACE were evaluated using Fine and Gray's competing risk model accounting for all-cause death as competing risk, adjusting for lipids, blood pressure, estimated glomerular filtration rate, diabetes, smoking, blood pressure-lowering medication, cholesterol-lowering medication, and the measured obesity-related phenotypes. Results: Strong correlations were observed between protein-predicted obesity phenotypes and their measured counterparts (R 2 : BMI = 0.78, BFP = 0.85, WHR = 0.63). A standard deviation of elevated protein-predicted scores for BFP and WHR, but not for BMI, was significantly associated with an increased risk of MACE (Hazard Ratio [HR] 1.25, 95% CI 1.14 - 1.38, p <0.0001; HR 1.15, 95% CI 1.06 - 1.24, p = 0.001, respectively), independent of established cardiovascular risk factors and outperformed the measured obesity-related phenotypes. Conclusion: Proteomic markers can improve the assessment of obesity-related risks for cardiovascular outcomes. Integrating proteomic data into clinical practice complements current metrics for adiposity and has the potential to facilitate personalized preventive strategies for adverse cardiovascular outcomes.

VDAC2 and Bak scarcity in liver mitochondria enables targeting hepatocarcinoma while sparing hepatocytes

Abstract P2078: Extreme Lipoprotein(a) Levels and the Hazard of Acute Myocardial Infarction Among Standard Modifiable Cardiovascular Risk Factors in the United States

Background: Lipoprotein(a) [Lp(a)] is a risk factor for atherosclerotic cardiovascular disease, including acute myocardial infarction (AMI). Currently, no Lp(a) targeted pharmaceutical treatments are available in the U.S. While Lp(a) has previously shown prognostic value among patients without standard modifiable risk factors (SMuRFs), data is limited among patients with SMuRFs. This study examined the variation in Lp(a) and AMI association by SMuRFs’ number. Hypothesis: We hypothesized that the association between extremely high Lp(a) (XHI) levels and AMI among U.S. adults would differ by SMuRFs’ number with an increased AMI hazard among those with more SMuRFs. Methods: This retrospective study included U.S. adults with ≥1Lp(a) lab result between 01/01/2016-01/31/2023 identified in the Veradigm Network Electronic Health Records (VNEHR) linked to closed claims. Patients had EHR/claims activity ≥13 months prior to and ≥12 months following the index date (30 days post-first Lp(a) test). Patients were stratified by Lp(a) value into low (LO, <50 th percentile) and XHI (>90 th percentile) cohorts. SMuRFs at baseline were defined as hypertension, dyslipidemia, diabetes, chronic kidney disease, current or former smoker, alcohol use disorder, and BMI <18.5 or ≥25. Descriptive analyses were completed in SQL and SAS. Multivariable analyses are ongoing to examine AMI’s association with XHI Lp(a) by the number of SMuRFs. Results: Among the 17,819 patients meeting the inclusion criteria, 1,776 and 8,999 were assigned to the XHI and LO cohorts. Patients overall were 52.9 years old, 59% female, and 59% white. The XHI cohort had a greater proportion of patients with 3 SMuRFs (23.4% vs. 19.0%) and > 4 SMuRFs (15.7% vs. 11.5%) and a lower proportion with 0 SMuRFs (6.6% vs. 11.0%) vs. the LO cohort (all p<0.001). Baseline dyslipidemia (84.0% vs. 74.2%), hypertension (42.1% vs. 35.3%), and diabetes (19.5% vs. 15.7%) were observed more commonly among XHI vs. LO patients (all p<0.001). During a mean follow-up of 3.9-years, AMI incidence was low (<1.5%) and did not differ between Lp(a) cohorts. Conclusions: Patients in the XHI cohort were more likely to have ≥3 SMuRFs and baseline risk factors vs. the LO cohort. Although few patients had an AMI during the follow-up period, the higher presence of SMuRFs and risk factors within the XHI cohort underscore a pressing public health need. Additionally, a longer follow-up period may help better understand SMuRFs’ contribution to AMI hazard.

Abstract 065: Lower Acute Healthcare Utilization Associated with Virtual Cardiometabolic Health Programs

Background: Type 2 diabetes and hypertension are common and costly conditions that increase risk for hospitalization. Lifestyle-focused virtual health programs may offer an effective and accessible self-management solution for these conditions and reduce future high-cost acute care encounters. The purpose of this study was to evaluate the differences in inpatient and emergency room (ER) healthcare utilization between patients enrolled in a virtual health program (VH) for cardiometabolic lifestyle management vs. usual care (UC) controls at 6 and 12 months. Methods: We conducted a real-world, retrospective secondary analysis of healthcare claims incurred between July 2019 and May 2023 from multiple payers. Inclusion criteria included continuous coverage for ≥6 months pre- and post-index, an age range of 18-64 years, and having commercial insurance. Index date was defined as the program enrollment date for VH patients or an outpatient claim with a type 2 diabetes and/or hypertension diagnosis code for UC patients. VH patients were enrolled in Omada for Diabetes (DM; n=317), Hypertension (HTN; n=1,102), or Diabetes&Hypertension (DM+HTN; n=315) program and 1:3 propensity score matched (demographics, clinical characteristics and pre-index costs) to UC controls (n=951, n=3,306, and n=945, respectively). Mean differences in post-index inpatient, ER, and acute (inpatient+ER) encounter counts were compared at 6 and 12 months using t-tests. Results: After matching, the VH and UC groups had no statistically significant differences in pre-index characteristics. VH patients across all programs had fewer inpatient, ER, and acute encounters at 6 and 12 months vs. UC (absolute mean difference range -0.01 to -0.33, relative difference range: -5% to -63%). Specifically, DM VH patients had 63% lower inpatient utilization at 12 months, 46% lower ER utilization at 6 months, and 54% and 52% lower acute utilization at both 6 and 12 months vs. UC (all p<.05). HTN VH patients experienced significant reductions at both 6 and 12 months for ER and acute utilization vs. UC (ER: -56%, -43%; Acute: -51%, -40%; all p<.05). Finally, DM+HTN patients had 43% lower ER utilization at 6 months vs. UC (p=.04). Conclusions: Using a lifestyle-focused virtual health program to support cardiometabolic disease management may lead to meaningful reductions in high-cost acute care encounters, indicating the value of using virtual solutions as an effective and accessible approach to between-visit care.

Abstract P2111: Analysis of C-reactive protein omics-measures associates methylation risk score with obstructive sleep apnea-related measures

Introduction: DNA methylation (DNAm) predictors of high sensitivity C-reactive protein (CRP) offer a stable and accurate means of assessing chronic inflammation, bypassing the CRP protein fluctuations secondary to acute illness. Poor sleep health is associated with elevated inflammation and blood CRP levels which may explain associations of sleep insufficiency with metabolic, cardiovascular and neurological diseases. Our study aims to characterize the relationships obstructive sleep apnea (OSA)-associated phenotypes and CRP markers —blood, genetic, and epigenetic indicators—within the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). Methods: Multiple polygenetic risk score (PRS)-CRP scores were evaluated for their association with circulating CRP in the Multi-Ethnic Study of Atherosclerosis (MESA) cohort to select the best-performing PRS-CRP for association analysis in HCHS/SOL. Methylation risk scores (MRS)-CRP and PRS-CRP were constructed separately in HCHS/SOL for each individual as weighted sums of methylation beta values or allele counts, respectively. OSA-related phenotypes were measured using self-reported questionnaires and objective measurements. Survey-weighted linear and logistic regressions estimated the associations between OSA-related phenotypes (apnea-hypopnea index (AHI), minimum oxyhemoglobin saturation during sleep (min SpO2), and excessive daytime sleepiness (EDS)), diabetes and hypertension with CRP markers while adjusting for age, sex, BMI, study center, and the first five principal components of genetic ancestry. Results: We included 2221 HCHS/SOL participants (age range 37-76 yrs, 65.7% female) in the analysis. Both the MRS-CRP (95% confidence interval (CI): 0.32-0.42, p = 3.3 x 10 -38 ) and the PRS-CRP (95% CI: 0.15-0.25, p = 1 x 10 -14 ) were associated with blood CRP level. MRS-CRP was associated with AHI, min SpO2, diabetes and hypertension, while PRS-CRP markers was not. EDS was associated only with circulating CRP levels, while diabetes was associated with both circulating and MRS-CRP. Associations between OSA traits and metabolic comorbidities weakened after adjusting for MRS-CRP, with a strong impact of diabetes. Conclusions: MRS-CRP is a promising estimate for systemic and chronic inflammation, which either mediates or serves as a common cause of the association between OSA-related phenotypes and related comorbidities, especially diabetes.

DeltaC and DeltaD ligands play different roles in the segmentation clock dynamics

Abstract 043: Circulating Monocyte Gene Expression Profiles of Cardiac Remodeling and Incident Heart Failure: the Multi-Ethnic Study of Atherosclerosis

Introduction: The role of circulating monocytes in non-ischemic cardiac remodeling and heart failure (HF) is complex and unclear, due in part to monocyte heterogeneity and plasticity. We assessed the hypothesis that monocyte gene expression profiles reflecting activation and tissue inflammation are associated with cardiac structure and function and incident adjudicated HF in the Multi-Ethnic Study of Atherosclerosis. Methods: Monocytes were isolated from peripheral blood, and RNA was quantified using an Illumina BeadChip microarray. Cardiac magnetic resonance was performed concurrently. We used multivariable linear regression to estimate cross-sectional associations between gene expression levels and cardiac structure and function and Cox regression to estimate associations with time to incident HF. Results: We studied 12,369 transcripts mapping to 9,430 genes among 813 participants (mean age 69±9 years; 50% female; 22% Black; 29% Hispanic). Independent of traditional risk factors, expression levels of 55 transcripts were associated with left ventricular (LV) ejection fraction, 1136 with LV strain, 16 with LV geometry, 1020 with myocardial interstitial fibrosis, and 483 with left atrial size (FDR<0.05). Enrichment analysis implicated T and B cell activation, cytokine production, phagocytosis, wound healing, oxidative stress, and cell migration. Expression levels of three genes—PCCB, MTCP1, and VIM—were associated with more than one cardiac metric as well as time to clinical HF ( n =45 events over a median follow-up of 7.7 years). Conclusion: These unique data support an association between monocyte-mediated immune processes and subclinical cardiac remodeling and incident HF in the absence of ischemic injury. Agnostically identified profiles were enriched for processes related to both pro-inflammatory and pro-resolving activated monocyte function and immunometabolism, as well as tissue migration and homeostasis. These insights may help generate hypotheses toward novel therapeutic targets for HF.

Abstract P1004: Epigenetic Age Acceleration Predicts All-cause and CVD-specific Mortality over 20-years in a national-representative population

Background: Epigenetic age acceleration (EAA), the difference between DNA methylation-calculated age (DNAmAge) and chronological age, reflects biological aging. However, few studies have examined the prospective association of EAA with mortality in a national-representative sample. This study aims to investigate whether EAA is predictive of all-cause and cardiovascular disease (CVD) specific mortality over 20-year follow-up in the National Health and Nutrition Examination Survey (NHANES, cycle 1999–2002). Methods: We included 2,353 participants aged over 50 who had DNA methylation data at baseline and have been linked to the National Death Index in 2019. EAA was calculated by regressing DNAmAge on age and cell composition, using six estimators (Horvath, Hannum, SkinBlood, PhenoAge, GrimAgeMort, GrimAge2Mort). CVD deaths were identified by specific ICD-10 codes. Survival month was defined as the interval between baseline and the time of death or censorship. Cox proportional hazards models, adjusted for demographics, socioeconomic status, smoking, BMI, and chronic diseases, were used. Analyses were stratified by pre-existing CVD and BMI. Results: Over a median follow-up of 207 months, 1,210 deaths (385 CVD-specific) occurred. All EAA measures were significantly associated with increased all-cause mortality (except for SkinBlood-EAA) and CVD-specific mortality (except for Horvath-EAA). For instance, per 5-year increment of Hannum-EAA was associated with a 13% higher risk of all-cause mortality (HR: 1.13, 95% CI: 1.07 – 1.21), and 25% higher risk of CVD-specific mortality (HR: 1.25, 95% CI: 1.12 – 1.40). In those with pre-existing CVD, all EAA measures (excluding Horvath-EAA) were significantly associated with CVD mortality (e.g., PhenoAge-EAA HR: 1.13, 95% CI: 1.02–1.24), while no significant associations were found for participants without pre-existing CVD (e.g., Hannum-EAA HR: 1.08, 95% CI: 0.88–1.32). Stratified by BMI, obese individuals showed the highest hazard ratios. For instance, Hannum-EAA in obese participants was associated with an HR of 1.17 (95% CI: 1.04–1.32), compared to normal-weight (HR: 1.12, 95% CI: 1.00–1.25) and overweight participants (HR: 1.06, 95% CI: 0.95–1.18). Conclusion: Accelerated biological aging, as indicated by epigenetic clocks, was associated with increased all-cause and CVD-specific mortality risk in a US representative sample over 20 years. Associations were stronger among those with pre-existing CVD or obesity.

Abstract P2134: Fatigue category, quality of life, and risk of incident clinical heart failure in those with stage B heart failure in the Atherosclerosis Risk in Communities (ARIC) Study.

Background: General and exertional fatigue are common in clinical heart failure (HF) and associated with worse quality of life (QOL) and increased risk of HF re-admission and mortality. However, little is known about general and exertional fatigue in those with pre-HF. Methods: We included 2,972 individuals at Visit 5 (2011-13) of the ARIC study without clinical HF but meeting criteria for pre-HF (stage B HF per ACC/AHA guidelines) by echocardiography or elevated cardiac biomarkers, and with complete fatigue data. Using previously defined PROMIS fatigue (general fatigue) and MRC Breathlessness (exertional fatigue) scale score thresholds, individuals were cross categorized into 4 groups: low/no fatigue, high general fatigue, high exertional fatigue, and the co-occurrence of high general and high exertional fatigue. Adjusting for sociodemographic and clinical characteristics, we determined the cross-sectional association of fatigue category with physical and mental QOL (SF-12 scale) using linear regression, and prospective associations with incident clinical HF using Cox regression. To reduce the contribution of indolent HF to results, we conducted a sensitivity analysis excluding individuals with an outpatient diagnosis of clinical HF from Centers for Medicare and Medicaid Services claims data. Results: Participants were 60% female, 18% Black, and had a mean age of 76 years. Compared to the low/no fatigue category, all individuals in higher fatigue categories had lower physical QOL scores. The co-occurrence of high general and exertional fatigue was associated with the lowest QOL [β (95% CI) = -11 (-13, -10)] (Table). More modest, but significant, associations were seen for fatigue categories with mental QOL. Compared to the low/no fatigue category, those with high exertional fatigue, and those with the co-occurrence of high general and high exertional fatigue, had higher risk of incident clinical HF [HRs (95% CI) = 1.9 (1.4, 2.5) and 2.2 (1.5, 3.2), respectively]. Associations were similar after excluding individuals with an outpatient clinical HF diagnosis. Conclusions: In those with pre-HF, worse fatigue category was associated with worse QOL and increased risk of incident clinical HF, independent of traditional risk factors. Assessment of general and exertional fatigue may provide prognostic information in individuals with pre-HF.

Correction for Liu et al., Cytoskeleton remodeling mediated by circRNA-YBX1 phase separation suppresses the metastasis of liver cancer

Designing polymersomes with surface-integrated nanoparticles through hierarchical phase separation