Citations

Importance Elevated low-density lipoprotein cholesterol (LDL-C) is a modifiable risk factor for cardiovascular disease, the leading cause of premature death worldwide. Assessing the LDL-C–related burden is critical for guiding prevention and treatment strategies. Objectives To estimate the global, regional, and national burden of ischemic heart disease and ischemic stroke attributable to elevated LDL-C (relative to 35-54 mg/dL) from 1990 to 2023 and to quantify the contributions of population growth, aging, risk-deleted burden, and exposure changes to burden trends. Design, Setting, and Population This comparative risk assessment, part of the Global Burden of Disease Study 2023, estimated population-level LDL-C exposure and associated health loss in 204 countries and territories. Mean LDL-C levels were estimated using spatiotemporal gaussian process regression based on 806 studies across 161 countries. Relative risks were derived from meta-analyses of 38 randomized clinical trials. Population-attributable fractions for deaths and disability-adjusted life-years (DALYs) were estimated by age and sex for adults aged 25 years or older from 1990 to 2023, with 95% uncertainty intervals. Exposure Population-level LDL-C concentrations. Main Outcomes and Measures Population-attributable fractions, counts, and rates (all ages and age standardized per 100 000) of LDL-C–attributable deaths and DALYs from ischemic heart disease and ischemic stroke, with uncertainty intervals. Results In 2023, elevated LDL-C accounted for 3.6 million deaths (95% uncertainty interval, 2.2-5.4 million; 6.0% of global mortality) and 90.7 million DALYs (95% uncertainty interval, 58.9-123.3 million; 3.2% of DALYs). Although global all-ages rates remained stable, age-standardized death and DALY rates decreased by 45.6% and 39.5%, respectively, since 1990. In 2023, age-standardized LDL-C–attributable DALY rates were highest in Eastern Europe and lowest in high-income Asia-Pacific. One-third of the global LDL-C burden occurred in India and China. Population growth and aging drove the increasing burden, with notable regional disparities in LDL-C exposure and risk-deleted DALY rates shifting toward middle-sociodemographic settings. Conclusions and Relevance Despite declining age-standardized rates, the absolute LDL-C burden has increased since 1990 due to demographic changes and has shifted toward middle-sociodemographic countries. Measurement and surveillance gaps persist. Strengthened prevention, diagnosis, and treatment access strategies are essential to mitigate the health burden of LDL-C.

Importance Ischemic heart disease (IHD), the leading cause of death in the US, is predominantly due to modifiable risk factors. Estimates of IHD mortality attributable to risk factors provide evidence for health policy decision-making. Objective To estimate the burden of IHD death attributable to risk factors in the US from 1990-2023. Design, Setting, and Participants The Global Burden of Disease Study 2023 (GBD 2023) used vital records and a broad set of epidemiologic data to estimate IHD death rates, risk factor exposure, and relative risk curves for risk-outcome pairs for 1990-2023 for the general population. Data analysis was performed from October 2024 to December 2025. Exposure Twelve metabolic, behavioral, and environmental risk factors. Main Outcomes and Measures The primary outcomes were IHD death rates per 100 000 persons, counts, and attributable risks from 1990-2023 by age, sex, and US state. Estimates include 95% uncertainty intervals (UI). IHD death rates were estimated using ensemble modeling methods. Risk exposures were estimated using bayesian meta-regression methods. Relative risks were estimated following the Burden of Proof framework. Results In 2023, there were 473 000 IHD deaths (95% UI, 414 000-510 000) in the US, a decrease of 58.7% (95% UI, 56.8%-61.0%) in age-standardized rate since 1990. Between 2010 and 2023, there was a 19.0% decrease (95% UI, 15.0%-22.9%) for males and a 24.5% decrease (95% UI, 20.3%-29.7%) for females in IHD death rates. High systolic blood pressure (SBP), dietary risks, and high low-density lipoprotein cholesterol (LDL-C) were the leading risk factors for IHD deaths in 2023, accounting for 47.2% (95% UI, 36.4%-57.0%), 38.6% (95% UI, 17.2%-56.8%), and 28.5% (95% UI, 19.3%-39.6%) of IHD deaths, respectively. Increased exposure to several risk factors substantially increased their attributable burden for IHD deaths in 2023, with high fasting plasma glucose (FPG) increasing 38.8% (95% UI, 11.5%-81.1%) and high body mass index (BMI) increasing 54.5% (95% UI, 41.8%-66.3%) since 1990. Smoking and particulate matter pollution had the greatest decrease in attributable IHD mortality since 1990, at 33.3% (95% UI, 23.6%-41.7%) and 74.9% (95% UI, 46.7%-88.8%), respectively. Conclusion and Relevance Per the results of this systematic analysis of GBD 2023, a total of 88.7% (95% UI, 83.4%-92.5%) of IHD deaths were attributable to modifiable risk factors in the US in 2023, with high SBP, dietary risks, and high LDL-C being the greatest contributors. High BMI and high FPG showed the largest attribution increases, while exposure to other risks did not increase significantly for the population.

This review identifies the menopausal transition as a critical yet underrecognized determinant of asthma heterogeneity in midlife women. It synthesizes evidence that fluctuating sex hormones may shape distinct asthma phenotypes and endotypes, influencing clinical manifestations, disease modifiers, and therapeutic responses. By framing menopause-associated asthma as a biologically distinct, hormone-driven condition, the article highlights key research priorities for precision medicine approaches tailored to women’s respiratory health.

Abstract In asthma, pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNFα) drive excessive mitochondrial fission in ASM cells through activating dynamin-related protein 1 (DRP1). Recently, we demonstrated that aryl hydrocarbon receptor (AhR) is expressed in human ASM and is upregulated during inflammation and asthma. This study explores the role of AhR in regulating mitochondrial fission in human ASM cells under pro-inflammatory and asthmatic conditions. Primary human nonasthmatic and asthmatic ASM cells were treated with 6-formylindolo[3,2-b]carbazole (FICZ: AhR agonist), with or without TNFα. Mitochondrial morphology was assessed using MitoTracker staining. DRP1 expression was evaluated in whole-cell and mitochondrial fractions. Loss- and gain-of-function studies (AhR inhibition, knockdown, and overexpression) were performed. AhR binding on the DRP1 promoter and promoter activity were assessed by ChIP-qPCR and luciferase reporter. The effects of AhR activation on oxygen consumption rate (OCR) were analyzed using seahorse XF-Pro. AhR activation significantly inhibited TNFα- and asthma-induced mitochondrial fission in ASM cells via inhibiting DRP1 in both inactive and active forms. In contrast, AhR inhibition or knockdown aggravated mitochondrial fission, while AhR overexpression failed to prevent TNFα-induced fission without ligand activation. Mechanistically, AhR bound the DRP1 promoter and suppressed its promoter activity, consistent with a genomic mode of action, while failing to alter ERK1/2 phosphorylation. Additionally, AhR activation also reduced TNFα- and asthma-induced increase in OCR. Collectively, this study shows that AhR activation prevents mitochondrial fission by inhibiting DRP1 in ASM during inflammation and highlights AhR as a promising therapeutic target for asthma and other airway diseases associated with mitochondrial dysfunction.

ABSTRACT Background and Purpose Neuroimaging of acute ischemic stroke (AIS) may provide clues to the underlying mechanism based on stroke location. Patients who experience stroke despite therapeutic anticoagulation provide a clinical challenge, and the subsequent preventive regimen may depend on the underlying stroke mechanism. We conducted a retrospective analysis of patients presenting with stroke despite anticoagulation (AC+) and compared their imaging findings to those of patients with stroke while not on anticoagulation (AC−). Methods Retrospectively, patients hospitalized with AIS were categorized as AC+ and AC− based on their prehospital anticoagulation use. A total of 119 patients met the inclusion criteria for AC+ strokes, which were compared to a random sample of 135 AC− patients during the same time frame. Imaging was dichotomized into embolic (ES) and nonembolic stroke (NES) groups. Descriptive analyses were used to compare imaging appearance between the two groups. Secondary analyses using multivariate logistic regression were used to identify risk factors for strokes in the AC+ group. Results ES were proportionally higher among the AC+ group compared to the AC− cohort. Atrial fibrillation was an independent predictor for breakthrough stroke among the entire cohort (adjusted OR 69.8 [21.1–291.8], p < 0.001), as well as a predictor for ES among those with AC+ stroke (adjusted OR 55.29 [14.4–286.2], p < 0.001). Conclusions AC+ patients have a higher proportion of embolic appearing strokes, suggesting incomplete response to anticoagulation rather than competing mechanisms as the cause of stroke in these patients. Further investigation into stroke mechanisms and management in this unique population is needed.

Importance Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are associated with increased risk of diabetic retinopathy (DR) and nonarteritic anterior ischemic optic neuropathy (NAION). The risk of sight-threatening complications associated with GLP-1 RAs is underexamined. Objective To investigate whether the use of GLP-1 RAs in patients with T2D is associated with the development of DR, NAION, or DR complications. Design, Setting, and Participants This retrospective cohort study of adults (aged ≥18 years) with T2D and a recent hemoglobin A 1c level of 6.5% or higher was conducted between January 1, 2015, and September 30, 2022, using the TriNetX database. The cohort was divided into 2 groups, adjusted for baseline characteristics through propensity score matching (PSM), based on whether the individuals received prescriptions for a GLP-1 RA. The statistical analysis was conducted on October 10, 2024. Exposures At least 2 prescriptions of a GLP-1 RA given 6 months apart. Main Outcomes and Measures Cox proportional hazard regression models were used to evaluate the primary outcome: association between GLP-1 RAs and the risk of incident DR, NAION, or sight-threatening complications over a 2-year follow-up period. Results After PSM, 185 066 individuals (mean [SD] age, 59.0 [12.5] years; 93 389 females [50.5%]) were prescribed GLP-1 receptor agonists. Use of GLP-1 RAs was associated with an increased incidence of DR (hazard ratio [HR], 1.07; 95% CI, 1.03-1.11), while no statistically significant difference was observed in the risk of NAION (HR, 1.26; 95% CI, 0.94-1.70). In a subgroup analysis of 32 695 patients with preexisting DR, GLP-1 RAs were not associated with progression to proliferative DR (HR, 1.06; 95% CI, 0.97-1.15) or diabetic macular edema (HR, 0.98; 95% CI, 0.95-1.01) but were associated with a lower occurrence of vitreous hemorrhages (HR, 0.74; 95% CI, 0.68-0.80), neovascular glaucoma (HR, 0.78; 95% CI, 0.68-0.88), or blindness (HR, 0.77; 95% CI, 0.73-0.82). Conclusions and Relevance In this cohort study of individuals with T2D, GLP-1 RA use was associated with a modestly increased risk of incident DR; however, fewer patients experienced sight-threatening DR complications, including blindness, even among those with preexisting DR. These findings suggest that all patients with T2D treated with GLP-1 RAs, regardless of preexisting DR, should be regularly screened and monitored for potential complications of T2D.

Introduction: Throughout the lifetime of an asthmatic, the lung undergoes changes in the composition of its extracellular matrix (ECM) and becomes more fibrotic, a characteristic feature of airway remodeling. Due to this, lung functionality decreases as the lung becomes less elastic and airway resistance increases. The ECM proteins constantly network with their respective mechanosensory receptors and regulatory proteins on the cell membrane. These signaling interactions allow for continuous interactions and feedback between the ECM and airway smooth muscle cells (ASM). ASM cells are one of the major structural cells that regular airway remodeling and are the primary target for treating asthma. In this study, we investigated the specific alterations that occur in the ECM of ASM cells treated with TGF-β1. Methods: Human primary airway smooth muscle (ASM) cells were grown to confluency in DMEM/F-12 with 10% FBS and 1% AbAm in standard conditions. Cells were serum deprived for 48 hours prior to experiments. Cells were treated with TGF-β1 (2 ng/mL) in serum free media. Cells were harvested after 48 hours and 200 µg of protein lysate was prepared. Data-independent acquisition (DIA) mass spectrometry was performed at IDeA National Resource for Quantitative Proteomics. Fold changes for ECM class proteins were collected from DIA results. Pathway analysis was then done using Qiagen ingenuity pathway analysis. Furthermore, expression patterns of select proteins were confirmed via western blotting. Results: The effects of TGF-β1 on specific types of collagens, integrins, laminins, and additional ECM proteins were analyzed. Western blotting confirmed similar changes in expression as measured by DIA. TGF-β1 exposure upregulated LAMA4, LAMB2, and LAMC1 which is likely to increase the prevalence of Laminins 221 and 421. TGF-β1 augmented integrin signaling by upregulating ITGA7, ITGA11, ITGA1, ITGB1 and downregulating ITGA2 and ITGB8. TGF-β1 increased expression of TSP1, TSP2, TSP3, TNS-C, FB, Elastin and Versican while downregulating TNS-X. Several interactions between ECM proteins and their sensors and receptors were highlighted for their enrichment. Conclusion: The DIA analysis shows an upregulation of proteins involved in airway remodeling by TGF-β1 in ASM cells. These findings substantiate our previous results as well as provide insights into a more targeted approach in studying ECM-Cell interactions. NIH R01HL171245 (Venkatachalem), R01HL146705 (Venkatachalem), R01HL142061 (Pabelick, Prakash). and IDeA National Resource for Quantitative Proteomics (R24GM137786). This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

Background Although micro‐ and nanoplastics are an emerging risk factor for the development of cardiovascular diseases, the association of marine microplastic levels (MMLs) with the burden of cardiometabolic diseases at a population level remains unexplored. We investigated the relationship between the mean microplastic concentration in ocean water within 200 nautical miles of the US coastline and the prevalence of type 2 diabetes, coronary artery disease, and stroke in nearby counties. Methods Microplastic concentration data within 200 nautical miles of the US coastline were geospatially analyzed to calculate mean MMLs. The coastal counties were stratified into 4 categories based on MMLs in the adjacent ocean water body: low, medium, high, or very high. The Behavioral Risk Factor Surveillance System 2019 to 2020 survey data were used to identify the prevalence of type 2 diabetes, coronary artery disease, and stroke in these counties. Univariate and population‐weighted multivariate quasi‐Poisson regression, adjusted for county‐level confounding variables, was used to evaluate the unadjusted and adjusted associations between disease prevalence and MMLs. Results The mean age of the population was 43±6 years. After adjusting for age, sex, physician access, and socioenvironmental vulnerabilities at the county level, counties with very high MMLs exhibited an 18%, 7%, and 9% higher adjusted prevalence of type 2 diabetes, coronary artery disease, and stroke, respectively, compared with those with low levels. Conclusion Marine microplastic levels were significantly associated with the prevalence of cardiometabolic diseases in coastal counties. Comprehensive studies at an individual level are needed to further investigate the health impacts of microplastic pollution.

ABSTRACTBackgroundMicroplastics are emerging as environmental pollutants with potential neurotoxic effects, yet their association with neurological disabilities remains largely unexplored.MethodsIn this cross‐sectional study comprising 218 coastal counties in the United States, we compared the self‐reported prevalence of cognitive disability, mobility disability, self‐care disability, and independent living disability in counties with very high and low marine microplastic levels (MMLs). Unadjusted and adjusted prevalence ratios (PRs) were computed using population‐weighted quasi‐Poisson regression across three different models to examine the relationship between disability prevalence and MMLs.ResultsCounties exposed to very high marine microplastic levels had a higher mean prevalence of self‐reported cognitive disability (15.2% vs. 13.9%), mobility disability (14.1% vs. 12.3%), self‐care disability (4.2% vs. 3.6%), and independent living disability (8.5% vs. 7.7%) compared to those exposed to low levels (p < 0.001). Regression analyses revealed significantly elevated adjusted prevalence ratios (PRs) for cognitive (PR: 1.09 [95% CI: 1.06–1.12], p < 0.001), mobility (PR: 1.06 [1.03–1.10], p < 0.001), self‐care (PR: 1.16 [1.11–1.20], p < 0.001), and independent living disability (PR: 1.08 [1.05–1.12], p < 0.001) in counties with very high microplastic exposure compared to those with low exposure.ConclusionsThis study highlights a significant association between marine microplastic pollution and the self‐reported prevalence of cognitive, mobility, self‐care, and independent living disabilities at the county level. While merely associative, these findings emphasize the urgent need for further investigation into the individual‐level health impacts of microplastic exposure and underscore the importance of environmental interventions to mitigate potential risks.

Abstract OBJECTIVES To estimate gender disparities among first and last authorships in cardiothoracic randomized controlled trials (RCTs) and association of gender with publications in high-impact journals. METHODS PubMed/MEDLINE database was searched from 1 January 2014 to 31 December 2020 using R statistical software via the ‘easyPubMed’ package to retrieve pertinent data. The ‘gender’ package was utilized to determine gender using the United States Social Security Administration Baby Name Data. The percentage of female first and last authors were computed along with determining the uniqueness of the names. The association of gender and publication in high-impact peer-reviewed journals was delineated. Jonckheere’s trend was computed. RESULTS The database search retrieved a total of 4820 RCTs, of which gender was encoded for the first author in 3247 (67%) RCTs, among which 911 (28%) studies had women as first authors, with a similar trend across 7 years (P = 0.23). Gender was encoded for the last author of 3204 (66%) RCTs, of which 622 (19%) studies had women as last authors, with a similar trend across 7 years (P = 0.45). A total of 627 studies were published in high-impact-factor journals, among which 79 (16%) studies had female first authors and 67 (13%) studies had female last authors. CONCLUSIONS There is an obvious gender disparity of first and last authors in cardiothoracic surgery-related RCTs, with a similar trend across 7 years. However, the post-hoc analysis did demonstrate a positive trend with an increase in the number of female first authors, demonstrating progress.