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Hypercholesterolemia-induced LXR signaling in smooth muscle cells contributes to vascular lesion remodeling and visceral function
Vascular smooth muscle cells (VSMC) are the most abundant cell type in the artery’s media layer and regulate vascular tone and lesion remodeling during atherogenesis. Like monocyte-derived macrophages, VSMCs accumulate excess lipids and contribute to the total intimal foam cell population in human coronary plaques and mouse aortic atheroma. While there are extensive studies characterizing the contribution of lipid metabolism in macrophage immunometabolic responses in atherosclerotic plaques, the role of VSMC lipid metabolism in regulating vascular function and lesion remodeling in vivo remains poorly understood. Here, we report that the liver X receptor (LXR) signaling pathway in VSMC is continuously activated during atherogenesis. Notably, we found that LXR deficiency in SMCs under hypercholesterolemic conditions influenced lesion remodeling by altering the fate of dedifferentiated SMCs and promoting the accumulation of VSMC-derived transitional cells. This phenotypic switching was accompanied by reduced indices of plaque stability, characterized by a larger necrotic core area and reduced fibrous cap thickness. Moreover, SMC-specific LXR deficiency impaired vascular function and caused visceral myopathy characterized by maladaptive bladder remodeling and gut lipid malabsorption. Mechanistically, we found that the expression of several genes involved in cholesterol efflux and FA synthesis including Abca1 , Srebf1 , Scd1 , Scd2 , Acsl3, and Mid1ip1 was downregulated in mice lacking LXRαβ in SMCs, likely contributing to the phenotypic switching of VSMC in the atherosclerotic lesions.
Abstract P3147: Prevalence of Self-Reported Depression among Jackson State University African American Students, Data from a 2023 Cross-Sectional Survey
Background: Mental illnesses are prevalent health conditions in the United States. More than 1 in 5 US adults experience mental illness. According to the CDC, the prevalence of mental health illness and depression among US adults aged 18 and older is 12.5% and 5.0%, respectively. In 2019, 19.2% of adults had received mental health treatment in the past 12 months. Mental illnesses cost America $192.2 billion in lost earnings per year. Therefore, as research is limited, the purpose of this study is to examine mental illness, especially depression, among Jackson State University (JSU) students. Material and Methods: A cross-sectional study was designed and applied. Data were collected in 2024, targeting African American students of JSU. The survey tool was adopted from the Youth Risk Behavior Surveillance System conducted by the Centers for Disease Control and Prevention. Students were asked, “During the past 12 months, did you ever feel so sad or hopeless almost every day for two weeks or more in a row that you stopped doing some usual activities?” Descriptive and Chi-square tests were applied in this study. Results: Three hundred ninety-eight African American JSU students, 74.4% females, participated in our study. Findings showed that 185 students (46.5%) responded that they were depressed in the last 12 months. In addition, depression was significantly more prevalent among females than males (54.1% vs. 37.5%, p-value< 0.01). The odds ratio for depression was 1.96 with 95 % CI: 1.16- 3.33 among females compared to males, suggesting that females had a 1.96 higher likelihood of depression compared to males. Conclusion: The findings indicate that self-reported depression was high among JSU students, especially among African American female students. Factors associated with high depression among JSU students need to be investigated. Furthermore, mental health awareness and services must be visible on the JSU campus.
Abstract P1080: Barriers and Facilitators to Treatment Adherence: An Exploration of the Lived Experience of Patients with Heart Failure
Background: Research suggests that only ~50% of patients with HF meet recommended medication adherence; rates of overall treatment adherence, which additionally includes lifestyle changes and cardiac rehabilitation attendance, are even lower. Drivers of treatment nonadherence in this population remain poorly understood. This qualitative study aims to identify barriers and facilitators of treatment adherence among patients with HF. Methods: We recruited 19 adult patients with a diagnosis of HF from 2 clinics in Kentucky to participate in interviews. All patients had access to a phone to facilitate the interview and were free of genetic heart conditions. Treatment adherence was defined as a patient’s ability to follow the recommended treatment prescribed by their healthcare provider. A semi-structured interview guide was used to ask patients about experiences, habits, barriers, and facilitators to engaging in their HF treatment. Six patients participated in follow-up interviews to assess the study team’s interpretation of their prior responses and to ask clarifying questions to ensure saliency of the findings. Results: Over half of the participants identified physician communication as crucial to their experience, specifically: open dialog, honest explanations of treatment side effects, and willingness to listen. Many patients identified goal setting as critical to their treatment adherence, especially after initial diagnosis. By setting small, obtainable goals with their medical team, patients described feelings of increased self-confidence and reported making positive lifestyle changes. Rising cost of medication, food, and other therapies were identified as adherence barriers. Finally, 42% of patients discussed having significant fear regarding their HF diagnosis which began after a precipitating traumatic event, such as a hospitalization or heart attack, and persisted years later. However, some patients found this fear to be a motivation to make and maintain lifestyle changes. Several patients also expressed feelings of depression or isolation resulting from reduced autonomy. Conclusion: These qualitative findings suggest that patients are more likely to engage with their treatment plan when they have effective communication with their physician, set obtainable goals, and are able to afford both food and medication. Interventions to improve outcomes for patients with HF should focus on the patient-doctor relationship and connection to available financial resources.
Urban highways are barriers to social ties
Urban highways are common, especially in the United States, making cities more car-centric. They promise the annihilation of distance but obstruct pedestrian mobility, thus playing a key role in limiting social interactions locally. Although this limiting role is widely acknowledged in urban studies, the quantitative relationship between urban highways and social ties is barely tested. Here, we define a Barrier Score that relates massive, geolocated online social network data to highways in the 50 largest US cities. At the granularity of individual social ties, we show that urban highways are associated with decreased social connectivity. This barrier effect is especially strong for short distances and consistent with historical cases of highways that were built to purposefully disrupt or isolate Black neighborhoods. By combining spatial infrastructure with social tie data, our method adds a dimension to demographic studies of social segregation. Our study can inform reparative planning for an evidence-based reduction of spatial inequality, and more generally, support a better integration of the social fabric in urban planning.
Abstract P2103: Associations between the Plasma Proteome and a Polygenic Risk Score for Abdominal Aortic Aneurysm: The Atherosclerosis Risk in Communities Study (ARIC)
Introduction: Abdominal aortic aneurysm (AAA), characterized as bulging of the abdominal aorta, is life-threatening when it ruptures. While genetic susceptibility is a known risk factor for AAA, novel mechanisms associated with genetic risk have yet to be explored. This study aims to investigate the associations between the plasma proteome and genetic susceptibility for AAA, measured through a polygenic risk score (PRS). Methods: We constructed a PRS for AAA for participants in the ARIC Study, an ongoing community-based prospective cohort, based on summary statistics from a recent genome-wide association study (GWAS) for AAA (PMID: 37845353). Applying Bayesian regression with continuous shrinkage priors, we calculated the PRS for each participant using SNP dosages available from ARIC and genome-wide SNP weights from the AAA GWAS. We included 8978 European American (EA) participants as the discovery sample (52.9% female, mean age = 57.2) and 2672 African American (AA) participants as the replication (62.9% female, mean age= 56.3) sample. We measured plasma levels for 4955 proteins by SOMA scan v4 from samples collected at ARIC visit 2. We performed linear regression to evaluate the relationship between the AAA PRS and each of the 4955 plasma proteins, controlling for potential confounders. We used the following strategy to interpret PRS-protein associations in the discovery in EAs: Priority 1: 118 proteins that were previously associated with individual AAA risk variants in ARIC (PMID: 36579647); Priority 2: agnostic scan among the remaining 4837 proteins. Bonferroni correction for multiple testing was applied to the two groups of proteins separately in EAs. Uncorrected p<0.05 was applied in AAs. Results: In EA participants, 8 proteins were associated with the AAA PRS among the 118 priority proteins (p < 4.24 * 10 -4 ) and 1 protein was associated with the AAA PRS in the agnostic scan of the remaining proteins (p < 1.03 * 10 -5 ), for a total of 9 significant proteins: S100A13, TBCA, LRRN1, CRIP1, IL6R, PLA2G7, C5orf38, PCDHB10, and MMP12. Of the 9 proteins, IL6R was replicated in AA participants (p<0.05) with the consistent direction of association. Conclusion: Identifying the circulating proteomics signature for genetic susceptibility of AAA can further our understanding of AAA etiology and provide valuable insights into robust target interventions in preventing AAA.
Abstract P1167: Racism-Related Stress Related to Carotid-Femoral Pulse Wave Velocity in Cohort of Midlife Latinas
Background: Cardiovascular disease (CVD) is one of the leading causes of death among women in the U.S, with an increased risk among Latinas. One-third of Latinas report experiences of racism and discrimination in the U.S. Psychological stress has been demonstrated to worsen CVD risk factors such as blood pressure, insulin resistance, and adverse lipid profile. However, there is limited consensus surrounding the relationship between racism-related stress and subclinical CVD in the Latina population. Thus, this study examines the relationship between sociocultural stress and carotid-femoral pulse wave velocity (cfPWV), a subclinical marker of CVD, in midlife Latinas. Methods: A cross-sectional analysis was conducted using baseline data from 31 women enrolled in an ongoing longitudinal study of midlife Latinas. Participants were eligible if they self-identified as Latinas between the ages of 40 and 60 years old and were perimenopausal. Women with a history of CVD, or moderate to major depression (PH9 >10) were excluded. Racism-related stress was assessed using the Hispanic Women Social Stress Scale. Physical and anthropometric measures (e.g., weight, waist circumference, blood pressure, lipid profile) were collected during a clinical exam. Sociodemographic factors and medical history were self-reported using an interviewer-administered questionnaire. cfPWV was assessed using the Vicorder® device. Descriptive statistics and Pearson correlations were conducted (α = 0.1). Results: Participants were on average aged 47.1 ± 4.1 years, with 71% reporting having been born outside of the continental United States. At baseline, average cfPWV was 5.4 ± 0.7 m/s. Respondents had an average of 26.3 ± 25.1 on the Hispanic Social Stressor Scale (0-120) and over half (n=16) reported an experience of racism. When considering the total sample, cfPWV did not differ between women who reported at least one experience of racism (5.39 ± 0.73 m/s) compared to those who had no experience (5.75 ± 0.71 m/s). Among women who reported an experience of racism, greater severity of stress was positively correlated to cfPWV (r=0.58, p=0.02). Conclusions: In this cross-sectional analysis of midlife Latinas, the severity of racism-related stress was positively correlated to arterial stiffness. Findings support prior reports that greater exposure to racism worsens CVD risk. Additional data are necessary to further explore the impact of racism on CVD risk in this population.
S-nitrosylation-triggered secretion of mycobacterial PknG leads to phosphorylation of SODD to prevent apoptosis of infected macrophages
The tuberculosis-causing agent Mycobacterium tuberculosis (M.tb) establishes its niche inside macrophages by secretion of several virulence factors and engaging many host factors. Mycobacterial infection of macrophages results in a proinflammatory trigger–mediated secretion of TNFα. Protein kinase G (PknG), a Serine/Threonine kinase, is essential for mycobacterial survival within the macrophage. Pathogenic mycobacteria, upon infection, can trigger the secretion of proinflammatory cytokine TNFα, but whether secreted PknG plays any role in TNFα secretion at early stages of infection remains undeciphered. Moreover, at early infection stages, prevention of macrophage apoptosis is vital to successful mycobacterial pathogenesis. Our studies show that mycobacteria-secreted PknG can dampen the expression and concomitant secretion of proinflammatory TNFα. During early infection, M.tb infection–induced generation of reactive nitrogen intermediates (RNI) leads to S-nitrosylation of PknG on Cys109, thereby enabling its secretion into macrophages. Upon M.tb infection, secreted S-nitrosylated PknG phosphorylates macrophage Silencer of Death Domains (SODD) at Thr405, as identified through our phosphoproteomic studies. Thereafter, phosphorylated SODD, through an irreversible binding with the TNFR1 death domain, prevents Caspase8 activation and concomitant extrinsic apoptotic trigger. Moreover, alveolar macrophages from mice infected with PknG-knockout M.tb also exhibited SODD phosphorylation and hindered Caspase8 activation to prevent extrinsic macrophage apoptosis. Therefore, this work exhibits S-nitrosylation-mediated secretion of PknG to induce phosphorylation of macrophage SODD, which, through irreversible interaction with TNFR1, prevented extrinsic macrophage apoptosis at the early stages of infection.
Abstract P3128: Statins and Insulin Resistance in a Pediatric Preventive Cardiology Practice
Introduction: Statins are prescribed to lower LDL-C in children with familial hypercholesterolemia and other dyslipidemias that accelerate atherosclerosis. Associations between statin use and type 2 diabetes mellitus are reported in adults; there are scant studies in the pediatric literature. Objective: To determine if statin use is associated with higher HbA1C and HOMA-IR (homeostatic model assessment for insulin resistance) in children prescribed statins compared to non-statin users in a large pediatric preventive cardiology practice. Methods: Clinical data for patients prescribed statins were analyzed from 2003 through 2024, comparing HbA1C and HOMA-IR, and other characteristics at baseline, early follow-up (6 months) and late follow-up (3 years) post-statin initiation to statin non-users. Linear regression models were used to analyze baseline differences in HbA1C and HOMA-IR in the statin vs. non-statin groups, adjusted for age, sex, and BMI. A linear mixed effect model was used to analyze the longitudinal outcomes of HbA1C and HOMA-IR in the statin vs. non-statin groups. Results: In 757 patients with available data (406 prescribed statins), 51.5% were female with a mean age of 13.8 years at baseline. HbA1C and HOMA-IR were lower at baseline in the statin group vs. non-statin group (5.22% vs. 5.32% and 2.56 vs. 3.78 respectively, p <0.001). At 6 months post-statin initiation, HOMA-IR increased by 0.2 units more per month in the statin group than the non-statin group (p=0.03); the HbA1C rose by 0.01% more per month in the statin vs. non-statin group, approaching statistical significance (p=0.05). At 3 years post-statin initiation, the rate of change in HOMA-IR did not differ between the groups (p=0.78). However, at 3 years, the HbA1C rose by 0.0053% more per month in the statin group vs. non-statin group (p<0.001). Conclusion: In this large clinical pediatric cohort spanning over 20 years, there was a higher rate of rise of HOMA-IR early on (6 months) in those prescribed statins vs. statin non-users; after 3 years, the rate of rise of HbA1C was higher in the statin group, but HOMA-IR did not differ. Differences in HbA1C and HOMA-IR between the statin and non-statin groups, while statistically significant, were small and not likely clinically meaningful; values were more strongly driven by BMI category. Further research is needed; in the interim, clinical monitoring of HbA1C in children prescribed statins may be warranted.
Abstract P2035: All The Common Cardiovascular Diseases Are Aggravated By Climate Hazards: Current Evidence And Mechanisms
Climate change is widely recognized as a significant factor impacting cardiovascular diseases , yet a detailed and comprehensive understanding of this relationship remains underdeveloped. Aim: This study aims to provide a thorough review of the current epidemiological evidence regarding how climate change affects cardiovascular diseases. Method: Adhering to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, population-based epidemiological studies focused on climate change and cardiovascular diseases were collected from Google Scholar up to January 2023. A Bibliometric analysis was conducted to describe the basic bibliographic information of the included studies. Due to methodological reasons, a meta-analysis was not performed. Results: A total of 308 relevant studies were identified from 46,200 search records that met the specified criteria, with the USA, China, and Australia being the leading contributors in this field. These studies identified 208 unique pathways through which climate change influences the morbidity and mortality of cardiovascular diseases. Key climate factors such as heatwaves, cold spells, dust storms, air pollution, wildfires, and hurricanes were found to significantly increase the risk of cardiovascular diseases. Among these, temperature change emerged as the most extensively studied topic. Conclusion: Cardiovascular disease can be exacerbated by various climate hazards, underscoring the need for more controlled and high-quality research to further explore these hazardous effects and interventions. Moreover, further measures are needed to mitigate extreme climate changes and reduce their impact on cardiovascular health.
Structural basis of DNA replication fidelity of the Mpox virus
The Mpox virus (MPXV) is an orthopoxvirus that caused a global outbreak in 2022. The poxvirus DNA polymerase complex is responsible for the replication and integrity of the viral genome; however, the molecular mechanisms underlying DNA replication fidelity are still unclear. In this study, we determined the cryoelectron microscopy (cryo-EM) structures of the MPXV F8–A22–E4 polymerase holoenzyme in its editing state, in complex with mismatched primer–template DNA and DNA containing uracil deoxynucleotide. We showed that the MPXV polymerase has a similar replication-to-edit transition mechanism to proofread the mismatched nucleotides like the B-family DNA polymerases of other species. The unique processivity cofactor A22–E4 undergoes conformational changes in different working states and might affect the proofreading process. Moreover, we elucidated the base excision repair (BER) function of E4 as a uracil-DNA glycosylase and the coupling mechanism of genome replication and BER, characteristic of poxviruses. Our findings greatly enhance our molecular understanding of DNA replication fidelity of orthopoxviruses and will stimulate the development of broad-spectrum antiviral drugs.
Abstract 023: Comparison of Office and Ambulatory Blood Pressure in Middle-Aged Adults: Findings from the DASH and DASH-Sodium Study
Background: Ambulatory blood pressure (ABP) captures BP throughout the day during a range of activities, body positions, and environments, while office blood pressure (OBP) is performed in a rested, seated position in clinic. Since ABP on average is lower than OBP, current guidelines recommend setting lower risk thresholds for ABP compared to OBP. Objective: To determine equivalent values of OBP and awake ABP in middle-aged adults with respect to subclinical cardiovascular disease (CVD). Methods: DASH and DASH-Sodium trials were feeding studies that enrolled adults age 22 and older with a systolic BP of 120 to 159 mmHg and diastolic BP of 80 to 95 mmHg without treated hypertension, diabetes, or recent CVD. In both trials, ABP and OBP were concurrently measured at two (DASH) or three (DASH-Sodium) visits. ABP was performed using a Spacelabs device for 24 hours. OBP was performed with a random-zero sphygmomanometer three times per visit over 4-5 visits, following a standardized research protocol. We measured three cardiac biomarkers: N-terminal pro-B-type natriuretic peptide (NT-proBNP), high sensitivity cardiac troponin I (hs-cTnI), and high sensitivity C-reactive protein (hs-CRP) in serum collected concurrent with ABP. We investigated equivalent values of OBP and awake ABP by using the equipercentile equating method. We calculated the risk of elevated biomarkers for OBP and awake ABP using logistic models with generalized estimating equations, and identified BP values that corresponded to the same risk of elevated biomarkers. Results: There were 587 participants (mean age 47.8±10 years, 51.9% female, and 52.9% Black) with 1,238 visits ( Table 1 ). OBP values consistently corresponded with higher values of awake ABP ( Table 2 ). Using the equipercentile equating method, OBP of 130/80 mmHg and 140/90 mmHg corresponded to awake ABP of 136/83 mmHg and 145/95 mmHg, respectively. Based on cardiac biomarkers, an OBP of 130/80 mmHg had the same risk of elevated NT-proBNP, hs-cTnI, and hs-CRP as an awake ABP of 135/83, 135/84, and 138/80 mmHg, respectively. Conclusion: Contrary to current guidelines, ABP thresholds for risk among relatively healthy, middle-aged adults, were higher than OBP. These findings challenge guidelines promoting universal equivalency values for interpreting out-of-office BP measures such as ABP, and imply that risk thresholds may vary by context, population, and the quality of the office measurement.
Abstract 064: Fairness Heterogeneity of the PREVENT Equations in US Young Adults
Background: In 2023, the AHA published Predicting Risk of cardiovascular disease EVENTs (PREVENT), a new set of race-agnostic risk prediction equations that estimate 10-year risk of cardiovascular disease (CVD) in US adults ages 30-79 years. Equations include a base model and a model adding social deprivation index (SDI). Aim: To evaluate fairness of the base and SDI-enhanced PREVENT equations across race/ethnicity and sex groups in US young adults. Methods: We included adults aged 20-39 years enrolled between 2008-2009 without a history of CVD from Kaiser Permanente Southern California. From the eligible sample of 266,378, we randomly selected 50,000 young adults for computational efficiency. Primary outcome was incident CVD (defined as myocardial infarction, fatal coronary heart disease, fatal and nonfatal stroke, and heart failure) at 10 years. We estimated 10-year CVD risk using the PREVENT base and SDI-enhanced models. To assess race-sex specific model performance, we used Brier score, Harrell’s C, and mean calibration in each group. Overall algorithmic fairness was evaluated by (1) fair calibration, which measures whether agreement between predicted and observed risk is equally accurate across groups using Hosmer-Lemeshow goodness-of-fit and pairwise Wilcoxon signed-rank tests, and (2) concordance imparity, which measures the largest deviation of discriminative abilities across racial and ethnic groups by taking the difference between maximum and minimum Harrell’s C across groups. Results: We included 50,000 young adults who were mean (SD) age 31.7 (5.4) years, 61.3% female, and 51.1% Hispanic, who had 312 incident CVD events by 10 years. Performance metrics were similar in the base and SDI-enhanced equations. Models were under-calibrated in Black and White females and Asian and Black males, indicating observed risk was higher than predicted risk. Agreement between predicted and observed risk was not equally accurate across racial and ethnic groups in males or females (biased calibrated). Discriminative abilities also varied across groups, with Harrell’s C highest in Black males and lowest in Asian females. Concordance imparity was similar in the base and SDI-enhanced models (0.097 vs. 0.095). Conclusion: The PREVENT equations may not provide consistent risk predictions for young adults across race/ethnicity and sex groups, which could lead to unequal CVD prevention efforts. Addition of SDI to the PREVENT equations did not provide improvement in fairness.
The mechanism of electrical conduction in glassy semiconductors
We argue that the dominant charge carrier in glassy semiconducting alloys is a compound particle in the form of an electron or hole bound to an intimate pair of topological lattice defects; the particle is similar to the polaron solution of the Su–Schrieffer–Heeger Hamiltonian. The spatial component of the density of states for these special polarons is determined by the length scale of spatial modulation of electronegativity caused by a separate set of standalone topological defects. The latter length scale is fixed by the cooperativity size for structural relaxation; the size is largely independent of temperature in the glass but above melting, it decreases with temperature. Thus we predict that the temperature dependence of the electrical conductivity should exhibit a jump in the slope near the glass transition; the size of the jump is predicted to increase with the fragility of the melt. The predicted values of the jump and of the conductivity itself are consistent with experiment.
Abstract P2053: Social Vulnerability and Likelihood of Death at Home from Cardiovascular Disease in US Counties, 2016-2020
Introduction: Areas where people disproportionately die at home from cardiovascular disease (CVD) are incompletely described. The United States (US) Centers for Disease Control and Prevention (CDC) developed the Social Vulnerability Index (SVI) using 16 US census measures clustered into four themes of vulnerability. The SVI and its themes may be utilized to score counties based on county-level social determinants of health. We conducted a county-level ecological study on the association of county SVI and its themes with CVD-related deaths occurring at home. Method: We used 2016–2020 CDC Wide-ranging Online Data for Epidemiologic Research data on county-level CVD-related (ischemic heart disease, heart failure, stroke, and hypertension) deaths in persons ≥18 years of age, and location of death (home, etc.), available for 92.4% of 3,226 US counties. The SVI and its themes (socioeconomic status [theme 1], household composition&disability [theme 2], minority status&language [theme 3], and housing type&transportation [theme 4]) are scored from 0 to 1 (low to high vulnerability) based on their national percentile ranking. We grouped county-level SVI from 2018 into quartiles (Q1 [least] to Q4 [most vulnerable]). Due to overdispersion, we used negative binomial regression to estimate the likelihood of CVD-related deaths at home in Q4 vs Q1, offset by the total county CVD-related deaths. We reported rate ratios (RR [95% Confidence Interval], p-value). Results: CVD-related home death rates increased in a stepwise manner from SVI Q1 to Q4 (Fig). For overall SVI, the likelihood of death at home was 15% higher in Q4 vs Q1 (RR 1.15 [1.12–1.18], p<0.0001). The greatest disparity was seen in theme 1, with Q4 vs Q1 having 27% higher likelihood of death at home (RR 1.27 [1.22–1.33], p<0.0001). For theme 2, there was no statistically significant difference in the likelihood of death at home in Q4 vs Q1 (RR 0.98 [0.95–1.01], p=0.36). For theme 3, Q4 vs Q1 had 6% higher likelihood of death at home (RR 1.06 [1.03–1.09], p<0.0001). For theme 4, Q4 vs Q1 had a 6% lower likelihood of death at home (RR 0.94 [0.91–0.97], p<0.001). Conclusion: In US counties, higher social vulnerability was associated with a higher likelihood of CVD-related death at home, with the strength and direction of this association varying between the themes of vulnerability. SVI and its themes may be utilized to target interventions to improve access to hospital or hospice care.
Abstract P3022: Plasma Lipidome is Associated with 10-Year Risk of Incident Diabetes in the Coronary Artery Risk Development in Young Adults (CARDIA) Study
Background: Disordered lipid metabolism is highly prevalent in diabetes. Mechanisms have been identified through which lipids can impact glucose metabolism. Previous cohort studies of lipidomics and diabetes often have been limited to narrow lipidomic coverage or have lacked sample diversity in sociodemographic characteristics. Methods: Data were from CARDIA, a population-based cohort of self-identified Black and White race adults, recruited from 4 U.S. urban centers in 1985-86 (n=5,115). On a sample subset, lipidomics data were generated from fasting plasma collected at the Yr 20 exam, using infusion-mass-spectrometry, yielding n=14 lipid classes and n=756 molecular species. For analysis, molecular species within classes that contained >1 fatty acid were grouped by total carbon length and number of double bonds (n=300 total species). Participants who had prevalent diabetes or were pregnant at Year 20 were excluded from the analysis. Associations between distinct lipid classes/species and 10-year incident diabetes [n (cases) = 1,084 (104)] were quantified with Cox proportional hazards regression, adjusting for sociodemographics, health behaviors, and clinical variables, and accounting for multiple comparisons. Results: Ten of the 14 classes were significantly associated with 10-year incident diabetes (Fig 1). Findings for species within 8 classes were consistent with class-level associations, (direction and significance); other class-species associations displayed discordance (Fig 2). For example, the ceramide class was not, but a ceramide species (22:2) was, associated with incident diabetes. Conclusions: Class- and species-level analysis revealed unique patterns of associations, motivating analysis of both. Lipidomic signatures of diabetes may elucidate metabolic pathways implicated in diabetes risk that are not captured in standard lipid panels. These findings may inform clinical evaluation of diabetes risk in early-middle-age, when preventive measures may be more effective.
Logic-based machine learning predicts how escitalopram attenuates cardiomyocyte hypertrophy
Cardiomyocyte hypertrophy is a key clinical predictor of heart failure. High-throughput and AI-driven screens have the potential to identify drugs and downstream pathways that modulate cardiomyocyte hypertrophy. Here, we developed LogiRx, a logic-based mechanistic machine learning method that predicts drug-induced pathways. We applied LogiRx to discover how drugs discovered in a previous compound screen attenuate cardiomyocyte hypertrophy. We experimentally validated LogiRx predictions in neonatal cardiomyocytes, adult mice, and two patient databases. Using LogiRx, we predicted antihypertrophic pathways for seven drugs currently used to treat noncardiac disease. We experimentally validated that escitalopram (Lexapro) and mifepristone inhibit hypertrophy of cultured cardiomyocytes in two contexts. The LogiRx model predicted that escitalopram prevents hypertrophy through an “off-target” serotonin receptor/PI3Kγ pathway, mechanistically validated using additional investigational drugs. Further, escitalopram reduced cardiomyocyte hypertrophy in a mouse model of hypertrophy and fibrosis. Finally, mining of both FDA and University of Virginia databases showed that patients with depression on escitalopram have a lower incidence of cardiac hypertrophy than those prescribed other serotonin reuptake inhibitors that do not target the serotonin receptor. Mechanistic machine learning by LogiRx discovers drug pathways that perturb cell states, which may enable repurposing of escitalopram and other drugs to limit cardiac remodeling through off-target pathways.
Abstract MP69: Nursing facility use and frailty index as indicators of reserve and resilience in adults with hospitalization for a cardiovascular event: The REasons for Geographic And Racial Differences in Stroke (REGARDS) study
Introduction: Reserve and resilience refer to the degree of robustness prior to, and the subsequent ability to recover from a health stressor. Frailty and nursing facility use (NFU) may characterize varying levels of physical reserve and resilience among individuals hospitalized for a cardiovascular event. Objective: To characterize older US adults who had a CVD hospitalization using novel indicators of reserve and resilience: nursing facility use and a frailty index. Methods: We analyzed data from 1,605 Black and White REasons for Geographic And Racial Differences in Stroke (REGARDS) study participants with Medicare fee-for-service coverage who were age ≥65.5 years and had no NFU before an adjudicated myocardial infarction, heart failure, or stroke hospitalization in 2004-2019. Participants were grouped into mutually exclusive categories based on Medicare claims for NFU and vital status (i.e., alive without NFU, alive with NFU, and death) within 182 days and 183-365 days following discharge. We calculated a claims-based frailty index (index ranges from 0 to 1, with higher values indicating greater deficit accumulation) within 182 days before admission, and within 182 days and 183-365 days following discharge. Results: The mean age at admission was 77.4 years, 43.6% were female, and 30.4% were Black. Most participants were alive without NFU for 365 days post-discharge (64.9%), followed by those who died within 182 days following discharge (11.6%), and those who were alive with NFU within 182 days and alive without NFU in the 183-365 days following discharge (10.3%). Participants who were alive without NFU for 365 days post-discharge had the lowest frailty index in each assessment period (Figure) and were younger (mean age 76.5 years) versus the other groups (range 77.3-80.4 years). There were no substantial differences in subgroups defined by NFU and vital status post-discharge in analyses stratified by sex or race. Conclusion: NFU and frailty index identify older adults with varying levels of apparent reserve and resilience before and after a cardiovascular hospitalization.
Abstract P2165: Association of neighborhood environment chracteristics and suboptimal cardiovascular health based on Life’s Essential 8 among young adults in Puerto Rico
Background: Cardiovascular health (CVH) among young adults in Puerto Rico (PR) is below optimal levels, underscoring the vulnerability of this understudied population. Understanding the influence of neighborhood environment on CVH is crucial for designing public health interventions that promote and sustain CVH. We assessed the association between neighborhood environment characteristics and CVH among young adults living in PR. Methods: This study analyzed data from 2,179 adults aged 18–29 years (mean age: 22.6 y; 60.8% women) participating in the PR-OUTLOOK study. CVH was measured using the AHA's Life’s Essential 8 metric score (range 0-100), with suboptimal CVH defined as a score below 80. The neighborhood environment was evaluated using the Mujahid Neighborhood Health Questionnaire, which assesses neighborhood violence, safety, aesthetic quality, walkability, access to healthy foods, social cohesion, and interaction with neighbors. Responses were recorded on a 5-point Likert scale (1=strongly disagree to 5=strongly agree), except for the violence and neighbor interaction scales, which ranged from 1=often to 4=never. Separate logistic regression models examined the association between each neighborhood environment characteristic and suboptimal CVH, adjusting for age, sex at birth, education, and subjective social status. Results: Mean scores (±SD) for neighborhood environment characteristics were as follows: violence (3.7±0.5), safety (3.4±1.1), aesthetic quality (2.8±0.5), walkability (3.1±0.8), availability of healthy foods (2.4±1.0), social cohesion (3.3±0.7), and activities with neighbors (1.3±0.8). Approximately 72.5% of participants had suboptimal CVH. In adjusted models, young adults who perceived their neighborhoods as having higher aesthetic quality (OR = 0.70, 95% CI: 0.57–0.85), greater walkability (OR = 0.84, 95% CI: 0.75–0.94), and better availability of healthy foods (OR = 0.89, 95% CI: 0.81–0.98) had lower odds of suboptimal CVH compared to their counterparts. Conclusions: Young adults in PR residing in neighborhoods with better aesthetics, walkability, and access to healthy foods have lower odds of suboptimal CVH. Further research is necessary to explore the long-term effects of these neighborhood characteristics on CVH, which could inform the design of targeted interventions to improve cardiovascular outcomes in this population.
On the shape of air bubbles trapped in ice
Water usually contains dissolved gases, and because freezing is a purifying process these gases must be expelled for ice to form. Bubbles appear at the freezing front and are then trapped in ice, making pores. These pores come in a range of sizes from microns to millimeters and their shapes are peculiar; never spherical but elongated, and usually fore-aft asymmetric. We show that these remarkable shapes result of a delicate balance between freezing, capillarity, and mass diffusion. A nonlinear ordinary differential equation suffices to describe the bubbles, which features two nondimensional numbers representing the supersaturation and the freezing rate, and two additional parameters representing simultaneous freezing and nucleation treated as the initial condition. Our experiments provide us with a large variety of pictures of bubble shapes. We show that all of these bubbles have their rounded tip well described by an asymptotic regime of the differential equation and that most bubbles can have their full shape quantitatively matched by a full solution. This method enables the measurement of the freezing conditions of ice samples, and the design of freeze-cast porous materials. Furthermore, the equation exhibits a bifurcation that explains why some bubbles grow indefinitely and make long cylindrical “ice worms,” well known to glaciologists.
Abstract 050: Diet quality, pathway-specific polygenic risk scores, and risk of type 2 diabetes among US men and women
Background: Healthy diets are associated with lower risk of type 2 diabetes (T2D) risk, but it is unclear if individuals with different genetic risks benefit from specific dietary strategies. Hypothesis: The associations between healthy dietary patterns and lower T2D risk may be modified by global and pathway-specific polygenic risk scores (PRS). Methods: We conducted prospective analyses in 40,609 participants from the Nurses’ Health Studies and Health Professionals Follow-Up Study, who were free of baseline diabetes, cardiovascular disease, and cancer, with up to 36 years of follow-up. Diet was assessed every 4 years via a food frequency questionnaire. We examined 6 recommendation-based and 2 mechanistic-based dietary patterns. A global PRS and 12 pathway-specific PRS denoting distinct T2D mechanisms were calculated. Cox regression was used to examine diet, PRS, and their interactions with T2D risk. Results: We identified a total of 4,760 T2D cases during the follow-up. Higher global PRS and 11 pathway-specific PRS, except the one related to bilirubin metabolism, significantly predicted higher T2D risk. In multivariable-adjusted analyses, all dietary indices indicating a lower dietary quality were associated with higher T2D risk (hazard ratios comparing extreme quintiles 1.06-2.21, P-trend <0.05/8). We found additive interactions between the Global PRS and the alternate Healthy Eating Index, healthy plant-based diet index, and proinflammatory and hyper-insulinemic diets, in relation to T2D risk (relative excess risk due to interaction 0.09 to 0.32, P-interaction ≤0.004; Figure ). PRS for beta-cell dysfunction and fat deposition-mediated insulin resistance also showed interactions with proinflammatory and hyper-insulinemic diets ( P-interaction ≤0.004; Figure ). Conclusions Healthy dietary patterns are associated with lower T2D risk across a wide genetic risk spectrum. Diets targeting inflammation and insulinemia may be particularly beneficial for those genetically predisposed to beta-cell dysfunction and fat deposition-mediated insulin resistance.