Browse Articles

Catabolism of serine enantiomers represses enterohemorrhagic <i>Escherichia coli</i> virulence factors via modulation of the nitrogen stress response

Attaching and effacing pathogens, including enterohemorrhagic Escherichia coli (EHEC), colonize their preferred intestinal niche by sensing diverse host-, diet-, and microbiota-derived signals and coordinating the expression of virulence factors. D-serine, a host metabolite abundant in urine but scarce in the intestine, restricts EHEC colonization by transcriptionally repressing the type 3 secretion system (T3SS) while activating the SOS stress response. However, the mechanism underlying virulence regulation by D-serine remains unestablished. Here, we show that multiple amino acids, including L-serine converge on this pathway, repressing the T3SS without inducing the SOS response. Transcriptomic analyses showed a common response to D- and L-serine dominated by repression of nitrogen stress response genes. Mutational analysis identified the response regulators NtrC and Nac as essential mediators of T3SS repression by both serine enantiomers. Disruption of L-serine deaminase enzymes crucially revealed that T3SS repression depends on cytoplasmic ammonia/ammonium release rather than sensing of intact serine. While EHEC lacks canonical D-serine catabolic capacity, through metabolomics we provide evidence of oxidative deamination activity, capable of producing this regulatory signal. Together, these findings establish a mechanistic link between amino acid catabolism, nitrogen stress signaling, and virulence regulation in EHEC, highlighting how metabolic flux fine-tunes pathogen adaptation to intestinal niches.

Abstract 09: Healthcare Interactions, Diagnoses, and Service Utilization Preceding Cardiovascular Mortality Associated with Homelessness

Background: Cardiovascular disease (CVD) persists as the leading cause of death among U.S. adults. Persons experiencing homelessness (PEH) face a disproportionate burden with earlier onset and premature mortality. The average age of CVD death among PEH is 58–62 years, while 83% of CVD deaths occur after 65 in the general population. This disparity reflects combined effects of traditional risk factors, housing instability, barriers to care, and structural inequity. It is hoped that examining healthcare and service interactions and diagnostic patterns preceding CVD death may inform interventions to reduce PEH mortality. Methods: This study analyzed medicolegal records of PEH deaths reported by a large urban county medical examiner between 2021-2024. Decedent data from 2021-2023 were linked with a community-based (PCIC; n=199) and health information exchange (HTX; n=384) to evaluate temporal trends in healthcare, service utilization, comorbidities, social determinants, and clinical factors preceding death. Results: From 2021-2024, CVD accounted for 29.1%, 29.8%, 28.9%, and 26.9% of PEH deaths. Healthcare and service use increased near-exponentially in the months before death across EMS, clinics, hospitals, social services, and law enforcement. In the year before death, circulatory system disease (CSD) was the second most common diagnosis in PCIC (n=57) and third in HTX (n=138). Excluding F and Z codes, PCIC commonly recorded pain not elsewhere classified (G89; n=41) and hypertension (HTN) (I10; n=30); HTX included HTN (n=84), and CVD-related conditions such as heart failure (I50; n=42), abnormal breathing (R06; n=50), and respiratory failure (J96; n=45). Including F and Z codes, frequent diagnoses were HTN (n=38), housing instability (Z59; n=25), heart failure (n=24), electrolyte imbalance (E87; n=22), and chest/throat pain (R07; n=22). Conclusion: Stable CVD mortality among PEH reflects an ongoing burden. CSD consistently ranked among the top diagnoses preceding death, with pain, HTN, heart failure, abnormal breathing, and respiratory failure observed as contributors to CVD morbidity and mortality. Housing instability was commonly, but not universally documented, underscoring the need for integrated medical and social interventions. Rising service utilization before death suggests crisis-driven care. Strengthening coordination, care continuity, and community-based interventions may enable early detection and management of CVD, reducing preventable deaths.

Abstract MPTH64: High-Intensity Interval Training Provides Greater Gains In Quality of Life Than Moderate-Intensity Continuous Training in Post-Myocardial Infarction Patients: A Systematic Review of Randomized Controlled Trials

Background: Cardiac rehabilitation (CR) is emerging as an essential aspect of secondary prevention in patients recovering from acute myocardial infarction (AMI) or coronary artery disease (CAD). Exercise-based rehabilitation involves high-intensity interval training (HIIT), moderate-intensity continuous training (MICT), and maximum intensity interval training (MIIT). These are integral to improving cardiopulmonary fitness, cardiovascular outcomes, and affect health-related quality of life (HRQoL). HIIT is presumed to show better outcomes, though comparative evidence across exercise types remains inconsistent. Clarifying the differential impact of HIIT, MIIT, and MICT on physical and psychosocial outcomes is vital for optimizing CR. Methods: 5 studies involving 650 post-AMI adults enrolled in CR were included. Most studies compared HIIT and MICT; one study also included maximal-intensity interval training (MIIT), and all others used usual care as a control. Outcomes included cardiorespiratory fitness (VO2 max), functional capacity (6-minute walk test [6MWT]), HRQoL (EQ-5D-5L, MacNew), mental health (PHQ, vitality), sleep quality (PSQI), fatigue (FSS), and physiological measures (blood pressure (BP), lipid profile, stroke volume, VE_peak). A qualitative synthesis of findings was performed due to heterogeneity across studies. Results: All 5 studies indicated that structured exercise improved outcomes. HIIT led to greater gains in VO2max compared to MICT. MIIT, assessed in one study, showed the largest VO2max improvements. HRQoL improved in all modalities across EQ-5D-5L, MacNew, PHQ, and visual analog scales. Functional metrics (6MWT, PPO) and cardiovascular parameters (HDL-C, HR recovery) improved more with HIIT. BP, BMI, and HbA1c improved similarly across groups. In several studies, HIIT had a stronger effect on physical functioning and emotional health. Only HIIT led to a significant drop in depression scores. HDL cholesterol improved more with HIIT. Conclusion: HIIT provides superior gains in cardiorespiratory fitness and physical function compared to MICT or MIIT in CR participants, without compromising safety/quality of life. Mental health, HRQoL, and physiological parameters improve comparably across exercise modalities. These findings support that HIIT is an effective, time-efficient option in contemporary CR planning. Future standardized, large-scale, and long-term studies are needed to assess sustained clinical impact and cardiovascular event reduction.

Abstract MPTU16: Individual-level Social Determinants of Health and High-Risk Behavioral Engagement Among Puerto Rican Young Adults: PR-OUTLOOK Study

Introduction: High-risk behaviors, such as tobacco use, physical inactivity, and excessive alcohol consumption contribute to chronic diseases, including cardiovascular disease and cancer. Social determinants of health (SDOH), including economic stability, housing, education, and healthcare access, shape these behaviors. In Puerto Rico (PR), longstanding economic instability, natural disasters, and COVID-19 have exacerbated social vulnerability. This study examines high-risk behaviors and their association with individual-level SDOH among PR adults aged 18-29 years, using baseline survey data from the PR-OUTLOOK cohort. We assessed the hypothesis that greater individual-level social disadvantage is associated with engagement in high-risk behaviors. Methods: The analytic sample included 2,484 participants from the baseline PR-OUTLOOK cohort (2020–2023), based on data available at the time of request and excluded those with missing data. Five binary high-risk behaviors were analyzed: cigarette smoking, e-cigarette use, recreational marijuana use, moderate alcohol use, and physical inactivity. Individual-level SDOH was derived using factor analysis of 10 indicators (e.g., “how difficult or easy is it currently for your household to make ends meet?”, educational attainment), with higher values indicating greater disadvantage and were categorized into tertiles (least, moderate, and most disadvantage). Adjusted prevalence ratios (aPR) comparing most vs. least disadvantaged SDOH groups were estimated using Poisson regression with robust standard errors, adjusting for sex, age, and marital status. Results: Participants were on average 22 years old (SD=3.2), and 61.3% were female. Overall, 34.1% reported one high-risk behavior, and 42.3% reported two or more behaviors. High-risk behaviors were most prevalent in the most disadvantaged SDOH group (p&lt;0.01). Compared to the least disadvantaged, the most disadvantaged tertile had 68% higher prevalence of cigarette smoking (aPR: 1.68, 95% CI: 1.20-2.35), 14% higher prevalence of e-cigarette use (aPR: 1.14, 95% CI: 1.01-1.28), and 27% higher prevalence of physical inactivity (aPR: 1.27, 95% CI: 1.13-1.41) (Table 1). Conclusions: Individual-level social disadvantage was associated with multiple behaviors elevating cardiovascular risk among young adults in PR. Findings underscore the need for equity-focused strategies addressing upstream social conditions to reduce early behavioral risks for cardiovascular disease.

<i>N</i> -glucosylation of indole-3-acetyl amino acids modulates auxin metabolism and growth traits in <i>Oryza sativa</i>

Dynamic regulation of auxin (indole-3-acetic acid; IAA) levels is crucial for proper plant growth and development and is finely regulated through biosynthesis, transport, metabolic inactivation, and signal transduction. While O -glucosylation of IAA is well established, the physiological significance of N -glucosylation pathways acting on IAA-amino acid conjugates remains largely unexplored. Here, we identify a UDP-glucosyltransferase in rice ( Oryza sativa ), designated IAAspGT, that catalyzes the N -glucosylation of indole-3-acetyl (IA) amino acid conjugates. Functional analysis revealed that natural allelic variants of IAAspGT differ markedly in enzymatic activity, with the high-activity allele prevalent in indica and the low-activity allele in japonica cultivars. Mutational analysis identified key residues within the glucose-accepting substrate-binding domain that account for this variation. A metabolic perturbation experiment demonstrated that IAAspGT competes with the DAO-mediated oxidation, thereby affecting active auxin levels. Plants harboring the high-activity allele exhibited enhanced root elongation under nutrient-deficient conditions and altered growth allocation between the panicle and other above-ground organs. Haplotype analysis indicated that the high-activity allele is ancestral and widely retained in the wild relatives. These findings establish IA-amino acid N -glucosylation as a previously overlooked metabolic branch that modulates auxin availability and contributes to environmental responses and growth plasticity in rice.

Abstract MPTH59: Cumulative Blood Pressure Burden Above Optimal Level and Risk of Cardiovascular Disease in Patients with Diabetes

Introduction: The 2025 AHA/ACC Blood Pressure (BP) Guidelines recommend a systolic BP (SBP) goal of &lt;130 mm Hg, with encouragement to &lt;120 mm Hg, and a diastolic BP (DBP) goal of &lt;80 mm Hg for adults with diabetes and hypertension. We hypothesized that greater cumulative exposure to BP above optimal level over time was associated with higher risk of cardiovascular disease (CVD) events, including atherosclerotic CVD (ASCVD) and heart failure (HF), in adults with diabetes, but data are scarce. Methods: Among adults aged 30-79 years who participated in the 2009-2013 Korean National Health Insurance general health screening, we included those who had diabetes for ≥5 years, ≥3 BP-measuring visits over the past 5 years, and no prior CVD. For each participant, cumulative BP burden was calculated as the area under the interpolated BP curve above optimal level (SBP ≥120 mm Hg; DBP ≥80 mm Hg), annualized by dividing by the total exposure years, and analyzed in quintiles or as a continuous variable using linear or restricted cubic spline terms. Outcomes were incident total CVD (composite of ASCVD or HF), ASCVD (myocardial infarction, fatal coronary heart disease, or fatal/nonfatal stroke) and HF. Results: Among the 485,642 participants included, the mean±SD age was 60.3±9.7 years, and 40.0% were women. Over a median follow-up of 12.6 years, 90,350 CVD events, 51,252 ASCVD events, and 50,958 HF events occurred. Cumulative incidence and multivariable-adjusted HRs of all outcomes increased monotonically toward higher quintiles of cumulative SBP and DBP burden. Each 10 mm Hg higher SBP above 120 mm Hg and 5 mm Hg higher DBP above 80 mm Hg, respectively, when sustained over time, was associated with 11% (HR, 1.11; 95% CI, 1.10–1.12) and 10% (HR, 1.10; 95% CI, 1.09–1.11) higher hazard of total CVD; 18% (HR, 1.18; 95% CI, 1.16-1.19) and 15% (HR, 1.15; 95% CI, 1.14-1.16) higher hazard of ASCVD; and 11% (HR, 1.11; 95% CI, 1.10-1.12) and 6% (HR, 1.06; 95% CI, 1.05-1.07) higher hazard of HF in a dose-dependent manner (Figure). Similar findings were observed for cumulative SBP burden above 130 mm Hg and cumulative DBP burden above 70 mm Hg. Conclusions: In patients with diabetes, a higher cumulative BP burden above optimal level was associated with an increased risk of CVD, ASCVD, and HF, highlighting the importance of sustained maintenance of optimal blood pressure below 120/80 mm Hg for the primary prevention of CVD in diabetes.

Abstract MPTU03: A “numerical autopsy” of out-of-hospital cardiac arrest: reclassifying unknown etiologies from five years of nationwide health data

Background: Out-of-hospital cardiac arrest (OHCA) remains a major public health issue. However, most cases are classified as having “unknown” etiologies, because the majority of patients die on scene after unsuccessful or not initiated resuscitation. This limitation is compounded by the low autopsy rate in France, can make it difficult both family screening and epidemiological understanding. We developed a semi-supervised machine learning framework to retrospectively infer the most likely cause of OHCA from patients’ longitudinal healthcare histories. Methods: We included 22170 adults OHCA cases recorded in the Sudden Death Expertise Center registry between 2011 and 2020, of whom 18817 (84.9 %) had an unknown etiology at the time of inclusion. Using the French National Health Insurance Database (SNDS), we extracted all hospital discharge diagnoses, outpatient drug dispensations, and reimbursed diagnostic or therapeutic procedures over the five years preceding the OHCA. Leveraging patients with known causes, we trained two models within an expectation-maximization (EM) semi-supervised framework: (i) an observability model predicting whether a case was likely to have a known etiology, and (ii) a cause model assigning one of several medical categories (cardiac ischemic, cardiac rhythmic, cardiac other, pulmonary, neurologic, embolic, other). Models were validated using a temporal split. Results: With a posterior probability threshold of 0.5, overall accuracy reached 64.0%. Applying the algorithm to previously unknown cases enabled the reclassification of 10497 patients (55.8% of those initially unknown). After this “numerical autopsy,” the distribution of etiologies shifted from: cardiac ischemic (7.5% to 45.1%), pulmonary (2.6% to 10.0%), cardiac other (1.8% to 3.3%), neurologic (1.1% to 1.5%), other (1.0% to 1.1%), embolic (0.7% to 1.1%), and cardiac rhythmic (0.4% to 0.4%), while unknown cases decreased from 84.9% to 37.5%. Model performance was moderate yet clinically informative (AUC = 0.70, log-loss = 1.20, F1-score = 0.23), reflecting meaningful discrimination despite limited number of cases with known etiology. Conclusions: Nearly half of OHCA cases initially labeled as “unknown” can be probabilistically reclassified using routinely collected longitudinal health data. These “numerical autopsies” could inform family counseling and screening strategies, and strengthen population-level surveillance.

Abstract 08: Land Use Rezoning of a Bronx, New York Neighborhood and Cardiovascular Disease Incidence in Mid-life and Older Adult Patients

Introduction: Land use rezoning policies can spur new investment and revitalization in the area. Such revitalization efforts in low-income areas have been inconsistently linked to cardiovascular disease (CVD)-related outcomes among residents. In the Bronx, New York, a large-scale neighborhood land use rezoning effort provides an opportunity to examine CVD outcomes over time. Methods: This study compared the incidence of CVD in a retrospective cohort of initially CVD-free mid-life and older (≥ 50 years) patients of a large hospital system residing in a Bronx, New York neighborhood undergoing a land use rezoning effort (Jerome Avenue, JA, N=7413) versus residents of a comparison neighborhood (Southern Boulevard, SB, N=3757). The relative hazard of CVD was estimated using a Cox proportional hazards model, with time from the start of the rezoning (3/22/2018) to the first CVD event (heart disease, heart failure, stroke) as the outcome and followed to end of data collection window (12/31/2024); adjusted for age, sex, race/ethnicity, diabetes history, smoking status, insurance type, and neighborhood area deprivation index score. Results: The mean age of the sample was 70.6 years (SD 9.4). Approximately 68% were female and 54% used Medicaid or Medicare to pay for services. Kaplan-Meier estimates of the incidence-free probability showed a reduced risk of CVD in JA vs. SB residents. Three-year and five-year incidence-free probabilities were 93.3% and 89.2% in JA residents compared to 92.2% and 86.5% in SB residents, with an adjusted hazard ratio of 0.865 (95%CI: 0.775-0.965; p=0.010). Discussion: Mid-life and older adults living in an urban area undergoing a land use rezoning effort to increase affordable housing have a 13.5% lower risk of developing CVD than those living in a comparison neighborhood not undergoing the same rezoning efforts. These results provide further evidence that housing policies can influence cardiovascular health outcomes among residents.

The SMARCA4–TMEM47 axis plays an essential role in chikungunya virus RNA replication

Chikungunya virus (CHIKV) poses an ongoing threat to global public health. Here, we identified the cBAF complex core ATPase subunit SMARCA4 as a host factor for CHIKV. SMARCA4 acts as a chromatin remodeling factor to license expression of the four-pass transmembrane protein TMEM47. TMEM47 deficiency impairs CHIKV replication in divergent cell types and reduces viral loads and pathological effects following CHIKV infection in mice. TMEM47 interacts with both CHIKV RNA and the nonstructural protein nsP1. Ectopic expression of nsP1 causes a marked redistribution of TMEM47 to the plasma membrane, where it is required for successful assembly of viral replication spherules. We also show that the SMARCA4 inhibitors inhibit CHIKV replication in cells. These findings suggest that the SMARCA4–TMEM47 axis plays an essential role for the completion of the CHIKV life cycle and can be a potential target for anti-CHIKV therapeutics.

Abstract TU149: Indoor Environmental Exposures and Pediatric Heart Conditions in US

Background: Indoor environmental exposures such as mold and pesticide use are increasingly recognized as potential contributors to adverse child health outcomes, but their relationship to pediatric heart conditions remains underexplored. Methods: Data from the 2016–2019 National Survey of Children’s Health (NSCH; n = 131,367) were analyzed using survey-weighted descriptive and logistic regression models. The primary outcome was parent-reported heart condition in a child. Key exposures included household mold presence, any indoor pesticide use in the past 12 months, and housing status (renter vs. owner). Models were adjusted for child age, sex, race, ethnicity, and family poverty ratio. Independent effects of race and ethnicity were examined in fully adjusted models to assess disparities in the odds of heart conditions across population subgroups. Results: The weighted prevalence of heart conditions was 2.2%. Children in homes with mold had a higher prevalence of heart conditions (3.0%) than those without mold (2.0%) ( p = 0.0006). Similarly, households with indoor pesticide use reported more heart conditions (2.4%) than those without use (1.9%) ( p = 0.013). In unadjusted analyses, mold (OR 1.50, 95% CI 1.19–1.89) and pesticide use (OR 1.24, 95% CI 1.05–1.48) were significantly associated with heart conditions, while housing status was not. After multivariable adjustment, associations remained significant: mold (aOR 1.67, 95% CI 1.27–2.21, p &lt;0.001) and pesticide use (aOR 1.22, 95% CI 1.00–1.47, p = 0.045). Race and ethnicity showed independent effects, with non-Hispanic (aOR 1.61, p = 0.002) and Asian (aOR 0.45, p = 0.003) children differing in risk. Conclusions: Indoor environmental exposures, i.e., visible mold and indoor pesticide use, were associated with higher odds of heart conditions among U.S. children, independent of sociodemographic factors. These findings highlight the potential cardiovascular relevance of indoor environmental quality and underscore the need for targeted prevention and remediation strategies.

Abstract TH897: Fatality After Acute Myocardial Infarction in Immigrants Compared to Native Koreans: A Nationwide Population-Based Study

Background: South Korea has been trying to improve early symptom awareness of acute myocardial infarction (AMI) and stroke, focusing primarily on native Koreans. Due to potential gaps in health information, language barriers, and limited access to healthcare, immigrants might face greater difficulties in receiving prompt care for AMI and stroke. This study compared 30-day and 1-year fatality rates after AMI and stroke in immigrants versus the general Korean population. Hypothesis: We hypothesized that foreign-born immigrants in Korea have higher 30-day and 1-year fatality rates after AMI and stroke compared with native Koreans. Methods: We analyzed a cohort of foreign-born immigrants living in Korea for more than 3 months in 2022-2023, enrolled in the National Health Insurance system, who experienced incident or recurrent AMI or stroke. Cases of AMI and stroke among immigrants were identified using the operational definitions developed for national statistics. Standardized fatality rate ratios (SFR) and 95% confidence intervals (CIs) were calculated using indirect standardization, with the 2022 Korean population as the reference. Analyses were performed using the 'stdrate' procedure in SAS 9.4 software. Results: For both 2022 and 2023, the total number of immigrants diagnosed with AMI was 631 and 667, and stroke was 2,148 and 2,210, respectively. The combined mean age for both years was 60.1 ±12.2 years for AMI (women, 17.6%) and 63.0 ±12.2 years for stroke (women, 33.4%). Among immigrants, the 30-day and 1-year fatality rates for AMI were 7.85% and 11.15%, respectively, in 2022, and 10.07% and 11.85%, respectively, in 2023. The corresponding stroke fatality rates were 5.78% (30-day) and 12.60% (1-year) in 2022, and 5.47% (30-day) and 9.28% (1-year) in 2023. The fatality rate for AMI increased subsequently, with the 30-day SFR by AMI rising from 1.30 (95% CI: 0.94–1.67, p=0.0986) in 2022 to 1.61 (95% CI: 1.23–1.99, p=0.0018) in 2023. For other SFR values, no significant elevation in fatality rates was observed relative to native Koreans. Conclusions: Compared to native Koreans, immigrants suffered an increased risk of 30-day mortality after AMI. These findings call for action to understand these disparities and address the barriers to AMI care among immigrants.

Abstract TU155: Health-Related Social Needs and Hypertension Awareness, Treatment, and Control among Community-Dwelling Black Men

Non-Hispanic Black men have the highest hypertension (HTN) prevalence and the lowest awareness, treatment, and control in the U.S. Health-related social needs (HRSNs) refer to social and economic conditions that affect health at the individual level. Unmet HRSNs disproportionately affect Black men and worsen care disparities. We evaluated associations between unmet HRSNs and HTN awareness, treatment, and control among community-dwelling Black men in a major Midwestern city. We conducted a cross-sectional baseline analysis of the Black Impact study, a 24-week randomized community lifestyle trial of Black men with low–to–moderate cardiovascular health in central Ohio. HTN was defined as systolic/diastolic blood pressure ≥130/80 mm Hg, current antihypertensive medication use, or self-reported diagnosis. Outcomes were awareness (self-reported diagnosis), treatment (antihypertensive medication use), and control among those treated (blood pressure &lt;130/80 mm Hg). HRSNs were assessed with the Accountable Health Communities screening tool (housing, food, transportation, utilities, safety, financial strain, employment). Each domain was handled as unmet (yes/no); total HRSNs were summed (0–7). Logistic regression estimated the odds of awareness, treatment, and control by domain and per 1-unit increase in the HRSN count. Model 1 adjusted for age; Model 2 for age and primary care physician (PCP). We analyzed 223 Black men, mean (SD) age was 54 (12) years (Table 1); 84% had a PCP and 19% had ≥1 HRSN (Table 2). Distribution across the cascade was: normotensive, 10%; unaware, 36%; aware–untreated, 8%; treated–uncontrolled, 38%; treated–controlled, 8%. In age-adjusted models, housing instability (OR 0.26, 95% CI: 0.08, 0.91), financial strain (OR 0.25, 95% CI: 0.08, 0.73), and employment need (OR 0.21, 95% CI: 0.07, 0.61) were associated with decreased odds of being treated, with only housing instability being attenuated in further adjustment. For the HRSN count, each additional unmet need was associated with a 46% and 32% decrease in the odds of being treated in model 1 and model 2, respectively (both p&lt;0.05). Associations with awareness were modest and not significant (Figure). No HRSN domain was associated with HTN control among treated participants. Screening and addressing HRSNs—especially financial strain and employment—within community and clinical programs may improve treatment uptake and advance progression along the hypertension care cascade for Black men.

Selective fluorination of Fc glycans enhances antibody-mediated effector functions

Antibody effector functions such as antibody-dependent cellular cytotoxicity (ADCC) and various complement-dependent activities are critically influenced by the structure and composition of Fc N-glycans. Terminal galactosylation is generally associated with enhanced FcγRIIIA binding and C1q recruitment, thereby improving antibody activities. Recent structural studies suggest that terminal galactose can restrict glycan flexibility and stabilize Fc conformation by interacting with CH2 domain residues, thereby reducing the entropic penalty for FcγRIIIA binding. Motivated by this structural insight, we hypothesized that fine-tuning galactose-mediated Fc glycan-Fc domain interactions via site-selective fluorination could further modulate Fc-receptor and Fc–complement interactions. To test this, we developed a chemoenzymatic glycoengineering approach to generate homogeneous antibodies bearing precisely fluorinated Fc N-glycans. Key to this strategy was the chemical synthesis of position-specific fluorinated full-length Fc glycans, which were subsequently installed onto the antibody via enzymatic Fc glycan remodeling catalyzed by a glycosynthase mutant. Using this platform, we constructed a panel of homogeneous fluorinated antibodies and evaluated their functional consequences. ELISA-based binding assays revealed that fluorination at the C2 or C6 position of terminal galactose significantly increased FcγRIIIA affinity. Corresponding enhancements in ADCC were confirmed using a cell-based reporter bioassay. Furthermore, fluorination at these positions also promoted C1q binding and elevated the antibody-dependent cellular phagocytosis potency in whole blood assays. These results collectively demonstrate that selective Fc glycan fluorination represents a unique strategy to enhance antibody effector functions, providing a paradigm for precision glycoengineering in antibody therapeutics.

Abstract TU107: Guideline-Based Pharmacotherapy Eligibility Among Older Adults with Stage I Hypertension

Background: The 2025 AHA/ACC hypertension guideline removes the age ≥ 65 years route to immediate pharmacotherapy in stage I hypertension and introduces a risk-guided approach using PREVENT ≥ 7.5%. Population-level estimates on treatment eligibility changes at this age inflection point are limited. We used nationally representative data to quantify reclassification in immediate pharmacotherapy eligibility among older adults ≥ 65 years. Methods: We included non-pregnant adults aged 40-79 from NHANES (2013-2020) with available data to compute PREVENT and pooled cohort equation (PCE) based 10-year risk. Blood pressure was the average of two final readings or a single available value. Comorbidities including diabetes, CKD, and clinical CVD were measured following standard survey definitions and lab parameters. We compared eligibility for immediate pharmacotherapy under 2017 (diabetes, CKD, ASCVD, age ≥65 years, or PCE ≥10%) versus 2025 (diabetes, CKD, clinical CVD, or PREVENT ≥7.5%) guidelines among untreated stage I hypertension overall and in older adults. Survey weights were utilized to obtain nationally representative estimates. Results: A total of 5,688 (weighted 71.4 million) adults were analyzed, where older adults comprised 33.3% (23.8 million). Untreated stage I hypertension was present in 8.61 million, among whom 2.10 million were older adults. Per 2017 guidelines, 3.88 million with untreated stage I hypertension were eligible for immediate pharmacotherapy – all older adults ≥65 years (2.10 million; 54.1%) in this group were pharmacotherapy eligible by default. Under 2025 guidelines, 1.03 million stage I older adults were reclassified with the removal of the ≥65 years criterion. Among this group, ~790,000 still qualified for immediate pharmacotherapy due to PREVENT risk ≥ 7.5%. A total of 11.4% (~240,000) stage I older adults initially eligible for immediate pharmacotherapy were reclassified as ineligible, warranting reassessment at 3-6 months per new guidelines. Conclusion: Contemporary guidelines would defer immediate antihypertensive pharmacotherapy in about 11% of older adults with stage I hypertension. Targeting the ≥65 year threshold where recommendations diverge, these findings quantify the guideline shift toward individualized care for older adults, aligning pharmacotherapy with an updated risk-based framework.

Letter by Wang and Chen Regarding Article, “Evaluation of Lipoprotein(a) as a Prognostic Marker of Extracoronary Atherosclerotic Vascular Disease Progression”

Abstract TU254: Global Impact of Tobacco Control Policies on Cardiovascular Mortality: A Lag-Adjusted Fixed-Effects Analysis of 148 Countries (2007–2022)

Background: Tobacco use remains a leading modifiable driver of cardiovascular disease (CVD) worldwide. The WHO MPOWER framework quantifies national tobacco-control strength, yet longitudinal causal associations with CVD mortality have not been comprehensively quantified across countries. Methods: A longitudinal panel of 148 countries (2007–2022) was assembled integrating: (1) Global Burden of Disease 2023 estimates of age-standardized CVD mortality attributable to tobacco (per 100 000); (2) WHO MPOWER composite scores (0–5 scale, equal-weighted across six policy components); and (3) World Bank GDP per capita (USD). We applied country- and year-fixed-effects linear regression to estimate the association between MPOWER intensity at t–3 and subsequent CVD mortality at year t , adjusting for log-transformed GDP. The three-year lag was selected a priori , consistent with cardiovascular disease latency periods. Robust (HC3) standard errors were clustered by country. Sensitivity analyses tested alternate lag structures (t–1 to t–5), exclusion of outliers (±3 SD or high Cook’s distance), and GDP-by-income-level interaction terms. Results: From 2007–2022, global tobacco-attributable CVD mortality declined from 37.3 to 32.4 per 100 000 (–13.2%), as mean MPOWER strength increased from 2.7 to 2.9. Each one-point increase in lagged MPOWER score was associated with a 1.07 ± 0.20 per 100 000 reduction in CVD mortality ( p &lt; 0.001), independent of GDP ( β = –2.10 ± 0.69; p = 0.002). Over the full MPOWER scale (0→5), this translates to ~5.4 fewer deaths per 100 000, representing a 16% decline at mean baseline mortality. A 1% increase in GDP corresponded to a 0.021 per 100 000 reduction in CVD mortality. Model fit was strong (within-country R 2 = 0.71; total R 2 = 0.97). Income-level interactions were non-significant, indicating consistent MPOWER effects across development contexts. High-policy countries (UK, Australia, Japan, Brazil) achieved steepest declines, while lower-policy countries (Nigeria, Ethiopia, Pakistan) showed limited progress. Conclusions: Stronger MPOWER implementation, sustained over multiple years, is independently associated with substantial reductions in tobacco-attributable CVD mortality worldwide, even after accounting for GDP, year effects, and lag structure. While residual confounding and ecological inference limit causal certainty, these findings provide robust, policy-relevant evidence supporting global intensification of comprehensive tobacco control.

Calsyntenin-3 suppresses inflammation via inhibition of TLR N-glycosylation and membrane localization

Excessive innate immune activation drives uncontrolled inflammation and multiple inflammatory diseases. Proper N-glycosylation of membrane-associated Toll-like receptor 4 (TLR4) is essential for its trafficking to the cell membrane and subsequent innate activation, yet the mechanisms regulating this process remain poorly understood. Through a genome-wide CRISPR screening, we identify calsyntenin-3 (CLSTN3) as a potent suppressor of TLR4-triggered inflammation in macrophages. Mechanistically, CLSTN3 binds to the oligosaccharyltransferase (OST) subunit DDOST, inhibiting its interaction with the catalytic subunit STT3A and impairing OST complex assembly, which reduces N-glycosylation and membrane translocation of TLR4. Furthermore, CLSTN3 also suppresses membrane translocation and activation of other TLRs, including TLR3, TLR7 and TLR9. In addition, CLSTN3 expression is reduced in multiple inflammatory diseases and correlates negatively with the cytokine expression in sepsis. Our findings reveal CLSTN3 as a potent suppressor of inflammation by controlling membrane-associated TLR translocation via glycosylation inhibition, presenting a target for intervening inflammatory diseases.

Abstract WE508: Ultra Processed Foods (UPF) and Risk of Incident Coronary Heart Disease (CHD) REasons for Geographic and Racial Disparities in Stroke (REGARDS)

Background: Diet plays a critical role in coronary heart disease (CHD) risk, and evidence links intake of ultra-processed foods (UPFs) to increased cardiovascular risk. CHD mortality remains higher among men, and overall diet quality in the United States is poor, with men exhibiting lower Healthy Eating Index (HEI) scores than women. However, few studies have examined whether the association between UPF intake and CHD risk differs by sex. We investigated the longitudinal relationship between UPF consumption and incident CHD among both sexes, hypothesizing that UPF intake varies by sex and that higher consumption is associated with greater CHD risk. Methods: We analyzed data from participants in the REasons for Geographic and Racial Disparities in Stroke (REGARDS) cohort free from CHD with complete covariate and diet data. UPF consumption was assessed using the NOVA classification system and quantified as both a percentage of total energy and total grams. Associations between UPF intake and incident CHD, defined as fatal and non-fatal myocardial infarction, were evaluated using Cox proportional hazards models. Results: Among 15,997 participants (mean [SD] age 64 (9), 60% female), males consumed significantly more UPF, both as a percentage of total energy intake (mean ± SD 49.5% ± 11.8% vs. 47.0% ± 12.3%, p &lt; 0.0001) and as a percentage of total grams consumed (median IQR: 19.0% [12.8–27.0%] vs. 14.8% [9.7–23.1%], p &lt; 0.0001). Males also had a higher rate of CHD events across quartiles of UPF intake by energy and grams (Figure 1, Figure 2). In unadjusted models, higher UPF intake (% of total energy) was associated with significantly greater risk of incident CHD in both sexes. However, these associations were no longer statistically significant in the fully adjusted model (Table 1). Conclusions: Higher UPF intake was associated with increased CHD risk in both male and females in unadjusted models; however, these relationships attenuated to null in fully adjusted models. Although the association between UPF intake and CHD was attenuated, effect sizes remained large, suggesting a potentially meaningful relationship.

Abstract TH872: Elevated Lipoprotein(a) and Incident Aortic Stenosis Independent of Low-Density Lipoprotein Cholesterol in a Multisystem United States Cohort

Background: Lipoprotein(a) [Lp(a)] has been implicated in the pathogenesis of calcific aortic valve disease through pro-inflammatory and pro-calcific mechanisms. However, large-scale population data assessing its impact on incident aortic stenosis (AS), particularly independent of low-density lipoprotein cholesterol (LDL-C), remains limited. Clarifying this relationship is increasingly relevant as Lp(a)-lowering therapies emerge. Methods: We used the TriNetX U.S. Collaborative Network (2015–2025; 71 health systems) to identify adults aged 18–75 with measured Lp(a). Patients were divided into two cohorts based on Lp(a) level: elevated (≥50 mg/dL or ≥125 nmol/L) and non-elevated (≤49 mg/dL or ≤124 nmol/L). Individuals with prior aortic valve disease or procedures (aortic stenosis, bicuspid or congenital valve, rheumatic disease, endocarditis, prosthetic valve, or prior AVR/TAVR) were excluded. We used 1:1 greedy nearest-neighbor propensity-score matching to balance baseline characteristics by age, sex, race, and ethnicity. Matched analyses evaluated the risk of incident non-rheumatic aortic stenosis (ICD-10 I35.0). Aortic stenosis with insufficiency (I35.2) served as a secondary outcome. A sensitivity analysis restricted to individuals with LDL-C ≤70 mg/dL examined residual risk beyond LDL-C. Results: Among 84,138 matched patients (42,069 per group), incident AS occurred in 0.9% of those with elevated Lp(a) versus 0.7% with non-elevated Lp(a) (risk ratio [RR] 1.33, 95% CI [1.14–1.55]; p &lt; 0.001). Aortic stenosis with insufficiency showed a similar but non-significant association (RR 1.35, 95% CI [0.97–1.87]; p = 0.07). In the LDL-restricted cohort (n = 30,098; 15,049 per group), the association with incident AS remained statistically significant (1.5% vs 1.2%; RR 1.28, 95% CI [1.05–1.55]; p = 0.014), indicating residual risk independent of LDL-C. Conclusions: Elevated Lp(a) was independently associated with a higher risk of incident AS, and this relationship persisted even among individuals with optimal LDL-C levels. These findings support Lp(a) as an independent risk pathway in calcific aortic valve disease and emphasize the potential clinical impact of emerging Lp(a)-lowering therapies.

Abstract TU233: Achieving Goal Low Density Lipoprotein Cholesterol in Pediatric Patients Treated with Lipid-Lowering Therapy

Background: Randomized clinical trials show short- and medium-term safety and good LDL-C lowering of lipid lowering therapy (LLT) in pediatric patients, with 40-60% of patients reaching their LDL-C goals. However, there is a paucity of data on effectiveness of LLT in real-world pediatric practice. We aimed to describe the proportion of pediatric patients treated with LLT at our center who reached LDL-C goal (&lt;130 mg/dL or &lt;100 mg/dL in high-risk patients), and to identify patient characteristics associated with reaching goal LDL-C levels. Methods: This single center retrospective study reviews patients on LLT cared for in a pediatric preventive cardiology program between 2010 and 2024. The percentage of patients who reach goal LDL-C at least once within one year of statin initiation was described. The cumulative time weighted LDL was estimated using the area under the LDL-C vs. age trajectory, expressed as “mg/dL years”. We also compared baseline patient characteristics (including usual vs. high-risk) for patients who reached goal LDL-C versus those who did not. Results: Of 1,307 patients evaluated for dyslipidemia during this timeframe, 719 were prescribed a statin and 628 had a baseline LDL-C; 322 patients on statin therapy that had a follow-up LDL-C within one year of statin initiation were included. Mean age of patients was 14.2 years (SD 3.86 years) and 47% were female. Patients were primarily treated with atorvastatin (70%) and simvastatin (25%). Overall, 69% of patients reached goal LDL-C levels within one year of statin initiation. Of those who were evaluated and reached goal, 66% were usual risk and 3% were high risk. Baseline characteristics significantly associated with reaching goal LDL-C included higher SBP, older age, lower LDL-C at baseline, lower total cholesterol at baseline, lower HbA1C at baseline, lower first-year cumulative time weighted LDL and lower first-year mean time weighted LDL-C. Conclusions: A majority of patients were able to reach goal LDL-C within one year of starting LLT, however, 31% did not reach goal. Attention to younger patients with high LDL-C may be necessary to help patients with hypercholesterolemia reach their goals. Lower LDL-C at baseline was associated with reaching goal, which suggests that for patients with higher LDL-C either higher doses or multiple drug therapy might be indicated.