The early and accurate diagnosis of acute myocardial infarction (AMI) remains a significant clinical challenge. To this end, we profiled the surface proteome of individual plasma extracellular vesicles (EVs) from AMI patients using single-vesicle sequencing, aiming to identify disease-associated alterations with diagnostic and therapeutic potential. Profiling the EV surface proteome across healthy controls (HC), coronary artery stenosis (CAS), and AMI revealed 21 differentially expressed proteins (DEPs), 11 of which were uniquely associated with AMI compared to HC. Notably, these included elevated levels of DSCAML1, CR1, ACE2, FN1, CDH15, and C5b‑9. EVs were subsequently stratified into 17 subpopulations, with clusters 1, 8, and 9 characterized by DSCAML1, ALCAM, and CR1, respectively, and showing the highest enrichment in AMI. We further demonstrated that plasma EVs from AMI patients (AMI-EVs) promote cardiomyocyte proliferation and endothelial cell activity in vitro, followed by the finding that the DSCAML1-enriched subpopulation (DSCAML1-EVs) enhances myocardial repair and angiogenesis both in vitro and in vivo, with mechanistic studies implicating the EREG/ERK pathway in these effects. In summary, DSCAML1-positive EVs show dual potential as both a diagnostic biomarker for AMI and a therapeutic target for improving post‑infarction prognosis, providing insight into the translational potential of EV‑based strategies in precision cardiology.

BACKGROUND AND AIMS:Atherosclerosis (AS), a chronic inflammatory disorder, persists as the predominant contributor to global cardiovascular morbidity and mortality. Macrophage-mediated inflammatory response plays a pivotal role in atherosclerotic lesion progression. This study investigates the functional significance and therapeutic potential of macrophage SH3 domain-binding kinase 2 (SBK2) in AS pathogenesis, with particular emphasis on its translational relevance. METHODS:Single-cell sequencing data of atherosclerotic plaques in mice fed with high-fat diet for different time periods were analysed. SBK2 expression levels were quantified in both human atherosclerotic lesions and murine arterial tissues. This study evaluated the impacts of SBK2 whole-body knockout, macrophage-specific knockout, and overexpression on murine AS progression. The molecular mechanisms were systematically investigated through integrated approaches including single-cell sequencing, co-immunoprecipitation assays, in vitro kinase activity assays, and mass spectrometry analysis. High-throughput screening of a small-molecule compound library identified potent SBK2 agonists. RESULTS:SBK2 expression was elevated in macrophages within advanced murine and human atherosclerotic plaques. Despite this upregulation, genetic ablation or macrophage-specific SBK2 deficiency exacerbated plaque formation and inflammatory responses, whereas macrophage-targeted SBK2 overexpression attenuated disease progression. This indicates that SBK2 induction represents a compensatory protective response within the atherosclerotic microenvironment. Mechanistic studies revealed that SBK2 phosphorylates NLRP3 at Ser161, triggering Tollip-dependent autophagic degradation of the inflammasome component and subsequent inflammasome inactivation. Pharmacological activation of SBK2 using rebaudioside N (RN) effectively suppressed NLRP3-mediated IL-1β/IL-18 secretion, reduced inflammatory responses, and diminished atherosclerotic burden. Notably, RN's therapeutic effects were completely abolished in SBK2-deficient models, validating its target specificity. CONCLUSIONS:Macrophage SBK2 serves as an endogenous safeguard factor that suppresses atherosclerosis by phosphorylating NLRP3 to enable its selective autophagic degradation. SBK2 is identified as the sole known protein kinase capable of mediating the selective clearance of this inflammasome. Targeting the SBK2-NLRP3 axis with RN offers a precise therapeutic strategy to mitigate inflammatory cardiovascular risk. This study identifies SBK2 as a novel therapeutic target and highlights kinase-driven inflammasome resolution as a paradigm for AS management.

Ulcerative colitis (UC) is a chronic, relapsing inflammatory disease of the colon. Compared with current therapeutic drugs, bioactive peptides are safer and more promising for UC prevention and treatment. Our previous studies demonstrated that the MHLWAAK peptide derived from C-phycocyanin exhibited excellent antioxidant and anti-inflammatory effects. However, its potential therapeutic effects on UC remain unexplored. In the present study, we aimed to evaluate the therapeutic potency of MHLWAAK in UC and its underlying mechanism using in vivo and in vitro experiments. The in vivo results showed that MHLWAAK effectively alleviated the inflammatory responses and intestinal tissue damage in the zebrafish model with UC induced by dextran sulfate sodium. An RNA-seq analysis revealed that MHLWAAK regulated the peroxisome proliferator-activated receptor (PPAR) pathway at the transcriptional level. The qRT-PCR results consistently indicated that lipid-related genes were upregulated after peptide administration. Additionally, in vitro studies demonstrated that MHLWAAK exerted potent anti-inflammatory effects on lipopolysaccharide-induced inflammatory responses by suppressing the expression of inflammatory genes and proteins. Additionally, western blotting revealed that PPARγ activation inhibited the NF-κB signaling pathways at the protein level after MHLWAAK administration. In summary, this study highlighted the anti-inflammatory activities of MHLWAAK in vitro and in vivo. MHLWAAK peptide development represents a novel and promising strategy for UC prevention and treatment.

Myocardial infarction (MI) remains a leading cause of morbidity and mortality worldwide, and current therapeutic strategies offer limited efficacy in promoting long-term cardiac repair. miRNAs have emerged as promising therapeutic agents owing to their capacity to modulate gene networks involved in cardiomyocyte apoptosis, mitochondrial dysfunction, and extracellular matrix (ECM) remodeling. Herein, we identified miR30d as a potential therapeutic target, exhibiting dynamic expression changes in plasma extracellular vesicles (EVs) from MI patients before and after percutaneous coronary intervention (PCI). To facilitate targeted delivery, we developed an engineered milk-derived EV-like vehicle (mELV) system in which endogenous RNAs were depleted via sonication to reduce off-target effects and improve cargo uniformity. These mELVs were further loaded with miR30d and subsequently functionalized with an ischemic myocardium targeting peptide (IMTP). Intravenous administration of miR30d-mELVsIMTP in murine MI model conferred both acute cardioprotection and sustained improvements in cardiac function, accompanied by reduced pathological remodeling. Mechanistically, miR30d directly targets Thbs2, leading to suppression of downstream MMP2 expression, attenuation of mitochondrial reactive oxygen species production, and inhibition of ECM degradation. Collectively, these findings underscore the therapeutic potential of miR30d and establish programmable RNA-depleted, IMTP-conjugated mELVs as a safe, targeted, and effective platform for miRNA delivery in post-MI gene therapy.

Cardiac fibrosis is a pivotal pathological process driving adverse cardiac remodeling and a defining feature of end-stage heart disease. Nicotine, a principal constituent of tobacco products, is now recognized as an independent risk factor for cardiovascular disease. However, its direct effects on cardiac fibroblasts (CFs) biology and the molecular mechanisms underlying nicotine-induced cardiac fibrosis remain incompletely understood. Primary CFs and a rat model of nicotine exposure were used to access the pro-fibrotic effects of nicotine. Drug affinity responsive target stability (DARTS) and cellular thermal shift assay (CETSA) were employed to identify the cellular targets of nicotine. Methylated RNA immunoprecipitation (MeRIP), RNA immunoprecipitation (RIP) and quantitative real-time PCR (qRT-PCR) were used to quantify m⁶A modification and microRNA biogenesis. miR-125b-5p overexpression or inhibition, heterogeneous nuclear ribonucleoprotein A2/B1 (HNRNPA2B1, abbreviated as A2B1 in all figures) silencing, and pharmacological inhibition with cinacalcet HCl were performed both in vitro and in vivo to evaluate the impact of this signaling axis on nicotine-induced fibrotic phenotypes. Collagen deposition, CFs proliferation, and activated transforming growth factor-β1 (TGF-β1)/Mitogen-Activated Protein Kinase (MAPK) signaling were assessed by histology, immunoblotting, and immunofluorescence. Nicotine promoted CFs proliferation and migration, myofibroblasts (MFs) transformation, and collagen accumulation. HNRNPA2B1 was identified as a potential binding target of nicotine. Mechanistically, nicotine up-regulated methyltransferase-like 14 (METTL14), thereby increasing m⁶A methylation of pri-miR-125b. HNRNPA2B1 recognized methylated pri-miR-125b, facilitated its interaction with DiGeorge Syndrome Critical Region 8 (DGCR8), and thereby accelerated miR-125b-5p maturation. Elevated miR-125b-5p suppressed p53 and activated the TGF-β1/MAPK axis, driving cardiac fibrosis. Knockdown of HNRNPA2B1 or treatment with cinacalcet HCl markedly reduced the levels of miR-125b-5p and ameliorated nicotine-induced cardiac fibrosis in vitro and in vivo. Nicotine induces excessive maturation of miR-125b-5p through an m⁶A-dependent, HNRNPA2B1-mediated mechanism, thereby promoting cardiac fibrosis. Targeting this signaling pathway—either genetically or pharmacologically with cinacalcet HCl—effectively attenuates fibrotic remodeling, providing a novel mechanistic rationale and potential therapeutic strategy management of cardiac fibrosis.

Effective risk stratification is crucial for managing acute coronary syndrome (ACS). This study evaluated whether general-purpose large language models (LLMs) can reliably execute the complex clinical reasoning required for cardiovascular prognosis. We quantitatively assessed three LLMs-ChatGPT 4o, DeepSeek R1, and Grok 3-for predicting one-year major adverse cardiovascular events (MACEs), using 29 guideline-recommended features from 903 participants in the LM-ACS cohort and 64 participants in the MIMIC database. All models demonstrated significant risk overestimation and substantial output variability across ten independent runs. Although Grok 3 showed the highest initial accuracy, its average performance over all runs showed no significant difference. ROC analysis indicated that none of the LLMs outperformed traditional clinical scores, with ChatGPT 4o performing below both GRACE and TIMI score. These findings demonstrate that current LLMs are not yet suitable for standalone ACS prognosis prediction; specifically, their associative reasoning poses a fundamental challenge to reliable clinical translation.

Abstract Background Pregnancy zone protein (PZP) is a highly glycosylated macromolecular protein involved in energy metabolism, fibrinolysis, and immunomodulation. However, its association with acute coronary syndrome (ACS), particularly regarding sex differences, remains to be fully elucidated. Methods ACS patients were enrolled from the Department of Cardiology, and control subjects were recruited from the Health Examination Department. Plasma levels of PZP were quantified using a sandwich enzyme-linked immunosorbent assay (ELISA). Spearman’s correlation was used to analyze the association between PZP levels and clinical variables. The association of PZP with ACS was assessed using logistic regression models, with PZP levels analyzed as a continuous variable, and subsequently categorized into binary and quartile groupings. Potential confounding variables were selected based on the disjunctive cause criterion and were adjusted for in the logistic regression models. Results In this study, we enrolled 1170 participants, comprising 721 men and 449 women. Plasma PZP exhibited marked sexual dimorphism, with concentrations much higher in women than in men (median [IQR]: 3.46[1.87, 5.88] vs. 0.26[0.10, 0.52] µg/mL; P < 0.01). Among men, PZP levels were significantly elevated in ACS patients compared to controls (median [IQR]: 0.29[0.12, 0.55] vs. 0.15[0.06, 0.32] µg/mL; P < 0.01), whereas no difference was observed in women (median [IQR]: 3.45[1.82, 5.99] vs. 3.48[2.26, 4.89] µg/mL; P = 0.95). Correlation analyses revealed distinct sex-specific patterns: in men, PZP correlated positively with age and inversely with estimated glomerular filtration rate (eGFR), whereas in women, only a weak positive correlation with high-density lipoprotein cholesterol (HDL-C) was observed. In multivariable logistic regression, higher PZP was independently associated with ACS in men across all modeling strategies—continuous (fully adjusted OR 5.90, 95% CI 1.59–24.98; P = 0.011), dichotomized using the Youden-derived cutoff (> 0.25 µg/mL; OR 1.87, 95% CI 1.02–3.50; P = 0.045), and quartile-based (top vs. bottom quartile; OR 4.79, 95% CI 1.74–15.26; P = 0.004)—but no significant association was found in women (fully adjusted continuous OR 1.06, 95% CI 0.86–1.31; P = 0.589). Conclusions This study establishes that circulating PZP exhibits extreme sexual dimorphism and demonstrates its male-specific association with ACS through absolute quantification. Our findings highlight the necessity of sex-stratified analysis in cardiovascular biomarker research. These findings warrant prospective validation to determine whether PZP has any role in sex-stratified cardiovascular risk assessment, as well as future studies to clarify its temporal dynamics and sex-specific mechanisms.

This study aimed to build and validate a risk prediction model for 1-year major adverse cardiovascular events (MACE) in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI), utilizing novel inflammatory biomarkers. This single-center retrospective cohort study enrolled 1,337 patients with ACS who underwent PCI between January 2021 and December 2023. Six novel inflammatory indexes (NLR, MHR, NHR, SII, SIRI, AISI) were derived from pre-PCI blood tests. After a 7:3 random split into training (n = 936) and validation (n = 401) cohorts, LASSO regression and multivariable Cox proportional hazards models identified independent predictors, and a combined biomarker-based model was constructed. Age, diabetes, Killip Class ≥ II, reduced LVEF, multivessel disease, no-reflow phenomenon, NHR, and SIRI were identified as independent predictors. The combined model achieved an AUC of 0.81 (95% CI: 0.78-0.84), which remained stable after optimism correction via bootstrapping. This performance was substantially higher than that of any single biomarker (maximum AUC: 0.71) and demonstrated significant improvements in NRI and IDI (all P < 0.001). Risk stratification demonstrated a clear gradient in MACE incidence: 6.3% (low-risk), 15.1% (intermediate-risk), and 25.3% (high-risk), P. < 0.0001, with consistent predictive performance across all evaluated clinical subgroups. The novel inflammatory biomarker-based model substantially improves risk prediction over clinical variables alone, providing a valuable framework for risk stratification and identifying patients at high residual inflammatory risk who may require closer clinical surveillance.

In this study, we identified novel pro-angiogenic peptides from Spirulina and elucidated their molecular mechanisms. Among the three fractions (A, B, and C) purified from the Spirulina protein extract by RP-HPLC, fraction B displayed the most potent pro-angiogenic activity. Through LC-MS/MS analysis, bioinformatics screening, and molecular docking, 20 candidate peptides were selected. In zebrafish models, five of these peptides, MFDCLR, MDMWGK, MNPGCR, MYDNFCK, and MPGLGR, significantly stimulated subintestinal vessel plexus (SIVP) growth and rescued intersegmental vessel (ISV) injury induced by Vatalanib (PTK787). Cellular experiments further showed that the five peptides reversed VEGFR tyrosine kinase inhibitor II (VRI)-induced impairments in proliferation, migration, and tube formation, with MDMWGK exhibiting the most pronounced pro-angiogenic effect. Moreover, the Matrigel plug assay confirmed that MDMWGK promoted extensive neovascularization in vivo. Subsequent mechanistic investigations revealed that the pro-angiogenic effect of MDMWGK was associated with activation of the VEGFA/PI3K-Akt signaling pathway, as evidenced by increased phosphorylation of PI3K and Akt. Collectively, this study provides an integrated screening strategy for discovering bioactive peptides from Spirulina and establishes a theoretical basis for developing pro-angiogenic agents.

Pathological cardiac hypertrophy is maladaptive cardiac remodeling induced by chronic adverse stimuli. In this study, the E3 ubiquitin ligase RNF128 was identified as a suppressor of pathological cardiac dysfunction with therapeutic value. Methods:The expression of Ring Finger protein 128 (RNF128) in pathological cardiac hypertrophy was characterized via public database analysis, scRNA-seq (single-cell RNA sequencing), and further validated in clinical myocardial samples and mouse disease models. The regulatory function of RNF128 in the progression of cardiac hypertrophy was verified in vivo by cardiomyocyte-specific RNF128 knockout mice and cTnT-AAV9-mediated RNF128 overexpression. Ang II (angiotensin II)-stimulated NMCMs (neonatal mouse cardiomyocytes) were used for in vitro validation. Moreover, the downstream target of RNF128 was identified through integrated analysis of scRNA-seq, interactome profiling and quantitative proteomics, followed by a panel of molecular assays. Results:Pathological cardiac hypertrophy reduced RNF128 expression in both human and murine samples. RNF128 deficiency aggravated cardiac dysfunction and pathological remodeling, while its overexpression protected cardiac function. Mechanistically, RNF128 directly interacted with SERCA2a, and catalyzed K63-linked polyubiquitination of SERCA2a at residue K476 (lysine 476), thereby impaired SERCA2a recognition by SQSTM1/p62. Consequently, RNF128 inhibited autophagy-lysosome-mediated degradation of SERCA2a. Conclusions:The findings of this study highlight RNF128 as a novel therapeutic target for heart failure, linking ubiquitination-dependent protein regulation to calcium handling in cardiomyocytes.

BackgroundAutophagy, a regulator of inflammation, has been implicated in various central nervous system pathologies. Despite this, the role and mechanisms of autophagy in lipopolysaccharide (LPS)-induced neuroinflammation are not clear. This study investigated whether autophagy can play a neuroprotective role in LPS-induced neuroinflammation.MethodsPrimary microglial cells and male C57BL/6 J mice were treated with LPS, autophagy inhibitors (3-methyladenine, 3-MA), or autophagy activators (rapamycin). Cell viability, NF-κB pathway activation, pro-inflammatory cytokine expression, M1 polarization, autophagy markers, and neuronal damage were evaluated via various techniques including CCK-8 assay, Western blot analysis, ELISA, immunohistochemistry, and histological staining.ResultsLPS (1 μg/mL) effectively inhibited cell viability, stimulated the expression of IκB-α and NF-κB, and simultaneously suppressed autophagy protein expression. The pro-inflammatory cytokines IL-1β and IL-6 showed a significant increase. Contrary to the effect of 3-MA, the rapamycin treatment inhibited the polarization of microglia cells to the M1 type in the various groups of microglia cells after LPS stimulation. This was evidenced by decreased expression of cytokines IL-1β, IL-6, and CD86, and increased expression of Arg-1, IL-10, and CD206. In vivo experiments found that mice with injections of LPS and 3-MA in the lateral ventricle showed significantly increased expression of IκB-α and NF-κB in brain tissues, elevated levels of pro-inflammatory cytokines, decreased autophagy levels, and increased necrotic neurons. There was increased aggregation of microglia cells and increased neuronophagocytosis. Conversely, mice injected with rapamycin showed enhanced neuronal cell autophagy, decreased expression of pro-inflammatory cytokines and apoptosis, and reduced neuronophagocytosis.ConclusionEnhancing autophagy can effectively mitigate LPS-induced neuroinflammation by inhibiting microglial M1 polarization and neuronophagocytosis, thereby protecting neuronal integrity. These findings suggest potential therapeutic strategies targeting autophagy in neuroinflammatory conditions.

Background:The neutrophil to high-density lipoprotein cholesterol ratio (NHR) has been proposed as a potential marker for predicting cardiovascular events. However, its prognostic role following percutaneous coronary intervention (PCI) in patients with acute ST-segment elevation myocardial infarction (STEMI) remains unclear. This study aimed to evaluate the predictive value of NHR for left ventricular remodeling (LVR) and long-term outcomes in STEMI patients post-PCI. Methods:This retrospective study included 299 STEMI patients who underwent PCI and were followed for 24 months post-procedure. Echocardiography was performed upon admission and at 6 months post-myocardial infarction (MI). LVR was defined as an increase in left ventricular diastolic volume (LVEDV) of at least 20% from baseline. Based on their VR status, patients were divided into LVR (n = 81) and non-LVR (n = 218) groups and clinical data were compared. A weighted logistic regression model was used to study the correlation between NHR and LVR. Weighted Cox proportional risk models were used to estimate hazard ratios (HRs) and 95% confidence intervals (95% CIs) for major adverse cardiovascular events (MACE). And the NHR was analyzed using receiver operating characteristic (ROC) curves to predict the occurrence of postoperative LVR and MACE in STEMI patients. Restricted cubic spline (RCS) analysis was used to explore the linear or non-linear relationship between NHR and LVR or MACE. Cox survival analysis was used to assess the relationship between NHR, LVR and survival time. Results:Among the 299 STEMI patients enrolled in the study, LVR was observed in 81 patients after 24 months of follow-up. The LVR group had significantly higher NHR levels compared to the non-LVR group (8.19 ± 1.95 vs. 6.23 ± 1.91, P < 0.001). After adjusting for potential confounders, a significant positive correlation was found between NHR and LVR. Each standard deviation increase in NHR was associated with a 43% higher risk of MACE (HR: 1.43, 95% CI: 1.25-1.64, P < 0.001). ROC curve analysis demonstrated that NHR could predict both LVR (AUC: 0.762) and MACE (AUC: 0.722). An NHR cut-off value of >8.13 was significantly linked to an increased risk of MACE (HR: 4.30, 95% CI: 2.41-7.69). Conclusions:NHR is an independent predictor of LVR and MACE after PCI in STEMI patients. Monitoring NHR may aid in identifying high-risk patients early, facilitating individualized treatment.

Pathological cardiac hypertrophy is a major contributor to heart failure. The present study aims to elucidate the role and mechanisms of phosphoglycerate mutase 2 (PGAM2) in the pathogenesis of cardiac hypertrophy. PGAM2 expression was increased in both primary neonatal rat ventricular myocytes (NRVMs) and rat models in response to angiotensin II (Ang II). Downregulation of PGAM2 alleviated cardiac hypertrophy. Mechanistically, we found PGAM2 directly interacts with HSP90 through residues 319-323 and 622-629 in the middle and carboxy-terminal domain of HSP90 respectively. This interaction was further enhanced under Ang II stimulation. Additionally, in the presence of PGAM2, it competed with E3 ubiquitin ligase SYVN1 to interact with HSP90, effectively inhibiting the ubiquitination and degradation of HSP90. Therefore, deficiency of PGAM2 results in the downregulation of the HSP90 and its downstream mTOR and client protein IKKα signaling pathway, both of which play crucial roles in the progression of cardiac hypertrophy. In vivo, we further confirmed that PGAM2 knockdown alleviated cardiac hypertrophy through downregulation of HSP90 and mTOR/IKKα signaling pathway. Taken together, we first demonstrated that downregulation of PGAM2 alleviates cardiac hypertrophy induced by Ang II, which provides a novel target for the treatment of myocardial hypertrophy and heart failure.

Methoxetamine hydrochloride (ET-26-HCl) is a novel short-acting intravenous general anesthetic that retains the advantages of etomidate while minimizing its impact on adrenal cortical function. A single-center, randomized, open-label, placebo-controlled clinical trial was conducted using concentration-QTc (C-QTc) model analysis to evaluate the pharmacokinetics, clinical sedative effect, safety, and potential risk of QT interval prolongation of ET-26-HCl at doses of 0.8 mg/kg (the clinical dosage) and 2.8 mg/kg. In the 0.8 mg/kg group, the mean peak concentration (C max) of ET-26 was 1,510 ng/mL with upper limits of the 90% confidence interval (CI) for QTcF interval corrected by baseline and placebo (ΔΔQTcF) falling within an acceptable range, not exceeding ±10 ms (-1.543 ms to +2.788 ms). The 2.8 mg/kg group exhibited a higher C max value for ET-26, along with corresponding mean ΔΔQTcF values that remained below the ±10 ms threshold limit. Based on the established C-QTc model analysis, it is predicted that the upper limit of 90% CI for the mean ΔΔQTcF corresponding to ET-26 at twice the C max of 0.8 mg/kg is ≤ ±10 ms. The study findings in conjunction with the C-QTc model demonstrated the rapid onset and recovery properties of ET-26. Furthermore, increased exposure and dose-dependent sedative/hypnotic effects were observed, with no risk of QT prolongation for this investigational drug, thereby ensuring patient safety and minimizing potential risks in its clinical application. Clinical Trials Registration Number:ClinicalTrials.gov CTR20233230.

Aim:To evaluate the achievement of metabolic risk factor targets and influencing factors in ACS patients with diabetes during the 12 months after discharge. Methods:We retrospectively analyzed data from the Chinese Cardiovascular Association database-iHeart Project. Patients who were hospitalized with a diagnosis of ACS between 2014 and 2021 and who had at least one measurement record of LDL-C, BP, or HbA1c within 12 months after discharge were included. We further stratified patients by diabetes status and analyzed the correlation between clinical characteristics, measurement strategy, and achievement of targets. Results:Diabetes was identified in 1,027 (27.5%) of the eligible patients. The proportions of patients with diabetes achieving targets of LDL-C, BP, and HbA1c levels were 42.4%, 61.5%, and 43.7%, respectively. However, combined achievement rate was significantly lower in patients with diabetes than patients without diabetes (16.6% vs. 26.6%). Patients with diabetes who underwent the first measurement within three months or had ≥3 measurements within 12 months were positively associated with achieving combined targets. Conclusions:The achievement of multifactorial targets among patients with ACS is suboptimal, particularly among patients with concomitant diabetes. The optimal measurement strategy post-discharge is essential for improving the comprehensive management of metabolic risk factors in ACS patients.

BackgroundIn recent decades, the escalating prevalence of obesity has contributed to a significant increase in the global burden of disease, with cardiovascular diseases (CVDs) emerging as the leading cause among all diseases attributable to high body-mass index (BMI). Utilizing global burden of disease (GBD) dataset from 1990 to 2021, we conducted a comprehensive analysis of the global, regional, and national trends in deaths and disability-adjusted life years (DALYs) attributable to CVDs caused by high BMI. Age-standardized mortality rate (ASMR) and age-standardized DALY rate (ASDR) were also investigated. Furthermore, we examined the associations of gender, age, and socio-demographic index (SDI) with the burden of CVDs attributable to high BMI. Finally, we assessed the evolution of health inequalities across countries and projected the global deaths and DALYs due to high BMI-related CVDs over the next two decades.MethodsThe absolute numbers and the rates of age-standardized death, Disability-Adjusted Life Years (DALYs) per 100,000 people due to high BMI-related CVDs between 1990 and 2021 were extracted from GBD 2021. The estimated annual percentage changes (EAPCs) of high BMI-related CVDs disease burdens were calculated under the GBD's comparative risk assessment framework. Additionally, the disease burden prediction of the high BMI-related CVDs from 2022 to 2041 was performed using the bayesian age-period-cohort (BAPC) statistical model.ResultsIn 2021, high BMI-related CVDs accounted for 1.90 million deaths globally, representing an increase of 120.63% compared to 1990, with DALYs rising by 115.47% over the same period. Notably, while ASMR and ASDR among male showed no decline, female experienced 11.30% reduction in ASMRs and 6.12% reduction in ASDR. The burden was disproportionately borne by middle-aged and older populations across all age groups. Global health inequalities related to high BMI-related CVDs demonstrated a narrowing trend from 1990 to 2010, followed by a reversal into a negative correlation and continued to widen until 2021. Looking ahead, the burden of high BMI-related CVDs is projected to rise significantly due to population growth, the increasing prevalence of obesity, and aging populations.ConclusionThe results indicate that from 1990 to 2021, the burden of CVDs caused by high BMI has significantly increased. Particular attention should be directed toward middle and low-middle SDI regions. To mitigate this burden, it is imperative to implement public health strategies that emphasize education and awareness regarding the correlation between high BMI and CVDs. Policies promoting healthy dietary habits and regular physical activity are essential for reducing the future impact of high BMI-related cardiovascular morbidity and mortality. Such measures are not only urgently needed but also offer substantial long-term benefits for global health.

Macrophage-derived foam cell formation is the hallmark of atherosclerotic plaques prominently attributed to excessive lipid uptake and metabolic disorders. As a classic membrane-localized ubiquitin ligase, the role of RNF128 in atherosclerosis remains unknown. We discover that RNF128 is specifically expressed in macrophages of the lipid core based on single-cell RNA sequencing data and persistent hyperlipidemia induces the high expression of RNF128 in macrophages. RNF128 ablation in macrophages ameliorates atherosclerosis in both male and female mice under the background of ApoE and LDLR deficiency. Mechanistically, RNF128 directly binds to scavenger receptor B1 (SRB1), preventing its degradation through the lysosomal system and promoting oxidized low-density lipoprotein (oxLDL)-induced foam cell formation and inflammatory response in macrophages. In addition, RNF128 catalyzes Lys63-linked polyubiquitination on the cytoplasmic C-terminus of the SRB1 at lysine 478, which promotes the endosome SRB1 recycling to the cell membrane with the assistance of Rab11, instead of entering the lysosome for degradation.

Atrial fibrillation (AF) is associated with increased risks of arterial thromboembolic events, stroke, and mortality. Current treatments are limited by high bleeding risk, poor adherence, and strict renal function requirements. Thus, there is an unmet need for novel anticoagulants with improved safety profiles. SHR-2004, a humanized monoclonal antibody targeting factor XI (FXI), has potential efficacy in preventing arteriovenous thromboembolism. To evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of SHR-2004 in patients with AF. This open-label phase 1b study enrolled patients aged ≥40 and <80 years, who were either diagnosed with or had a history of atrial fibrillation or atrial flutter and had a CHA2DS2-VASc risk score ≥1 (male) or ≥2 (female). Patients received 6 doses of SHR-2004 subcutaneously (180 mg, once every 2 weeks), for nearly 3 months. The primary endpoints were safety and tolerability. PK and PD parameters, including activated partial thromboplastin time (aPTT) and FXI activity were assessed. Between April 10, 2024 and May 6, 2024, 10 patients were enrolled, with a median age of 68.0 years (IQR, 55.0-70.0), and 9 (90.0%) being male. The median CHA2DS2-VASc risk score was 2.5 (IQR, 2.0-3.0). SHR-2004 was well tolerated at the tested dose. Treatment-emergent adverse events (AEs) occurred in 8 (80.0%) patients, and treatment-related AEs were reported in 6 (60.0%). All AEs were mild or moderate. Only 1 patient experienced a serious AE (atrial fibrillation leading to hospitalization), which was considered by the investigator to be moderate and likely not to be treatment-related. Notably, no major or clinically relevant non-major bleeding events were reported. Two patients (20.0%) experienced minor bleeding events, both of which were positive urinary occult blood. The PK and PD profiles of SHR-2004 are shown in Figures 1 and 2. The SHR-2004 exposure had a rapid increase and achieved the steady state by Day 57, with drug accumulation reaching nearly a 2.0-fold trough ratio. Administration of SHR-2004 led to a rapid and nearly complete inhibition of FXI activity by Day 3. Reductions in FXI activity were associated with a rapid and sustained prolongation of aPTT with approximately a 2.3-fold prolongation reached on Day 3, which was stably maintained up to Day 85. On Day 106, FXI activity inhibition was 91%, and aPTT prolongation was 1.8-fold. By Day 136, FXI activity and aPTT had returned to baseline levels. Multiple subcutaneous doses of SHR-2004 were safe and well tolerated in patients with AF, particularly regarding the low risk of bleeding. The safety, PK, and PD data from this trial support further exploration of SHR-2004 in patients with AF.1. Pharmacokinetic profile of SHR-2004 2. Pharmacodynamics profile of SHR-2004

BACKGROUND AND AIMS:The optimal antiplatelet agent regimen in patients with ST-segment elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (PPCI) with bivalirudin anticoagulation is uncertain. This analysis sought to evaluate the safety and efficacy of ticagrelor compared with clopidogrel in patients with STEMI treated with PPCI with radial artery access and bivalirudin anticoagulation. METHODS:This post-hoc analysis compared bivalirudin plus ticagrelor with bivalirudin plus clopidogrel in 3009 BRIGHT-4 patients that were treated with PPCI. The primary endpoint was all-cause death or Bleeding Academic Research Consortium (BARC) types 3-5 bleeding occurring within 30 days. RESULTS:The 30-day all-cause death or BARC types 3-5 bleeding occurred in 2.0 % of patients treated with ticagrelor vs. 3.9 % of patients treated with clopidogrel (HR 0.51, 95 % CI 0.29 to 0.89; P = 0.02), driven by a reduction in all-cause death with ticagrelor (1.9 % vs. 3.7 %; P = 0.02) with no difference in BARC types 3-5 bleeding (0.1 % vs. 0.3 %; P = 0.34), although BARC type 2 bleeding was increased with ticagrelor (2.7 % vs. 1.2 %; P = 0.02). There was no significant difference between two groups in risk of stent thrombosis and composite of all-cause death, recurrent myocardial infarction, ischemia-driven target vessel revascularization, or stroke. CONCLUSIONS:Among patients with STEMI treated with PPCI, the risk of the composite of all-cause mortality and BARC types 3-5 bleeding at 30 days was lower with ticagrelor than with clopidogrel on a background of bivalirudin, without an increase in stent thrombosis and major bleedings.