Endoscopy for acute upper gastrointestinal bleeding: a protocol for systematic review and network meta-analysis of randomized controlled trials.

Background: Previous studies have reached mixed conclusions regarding the timing of endoscopic approaches for managing individuals with acute upper gastrointestinal bleeding (AUGIB). Therefore, the authors performed a protocol for systematic review and meta-analysis to assess the efficacy of various timing endoscopic approaches in managing individuals with AUGIB. Methods: The authors will search multiple databases, including PubMed, Embase, Web of Science, China National Knowledge Infrastructure, VIP Database, Wanfang Database, WHO International Clinical Trials Registry Platform, and Chinese Clinical Trial Register. The search will cover the entire duration, starting from the establishment of these databases until July 2023. The selection criteria will focus on randomized controlled trials that assess the efficacy of endoscopy with varying timing in managing patients with AUGIB. The primary outcomes will include primary hemostasis and inpatient death. The secondary outcomes will include recurrent bleeding, need for surgical intervention, admission to the ICU, blood transfusion needs, and duration of hospitalization. Two reviewers will select the studies, extract data, and assess the risk of bias. A Bayesian approach will be used to conduct a network meta-analysis. Results: The results of this systematic review and meta-analysis will be published in peer-reviewed journals. Conclusion: This network meta-analysis provides comprehensive evidence of different timing endoscopic approaches for managing individuals with AUGIB.

Mapping Endothelial-Macrophage Interactions in Diabetic Vasculature: Role of TREM2 in Vascular Inflammation and Ischemic Response.

Vasculopathies occur 15 years earlier in individuals with diabetes mellitus (DM) as compared to those without, but the underlying mechanisms driving diabetic vasculopathy remain incompletely understood. Endothelial cells (ECs) and macrophages (MΦ) are critical players in vascular wall and their crosstalk is crucial in diabetic vasculopathy. In diabetes, EC activation enables monocyte recruitment, which transmigrate into the intima and differentiate into macrophages (MΦ). Beyond this established model of diapedesis, EC-MΦ interplay is highly intricate and heterogenous. To capture these highly context dependent EC-MΦ interactions, we leveraged single-cell (sc)RNA-seq in conjunction with spatial transcriptome (ST)-seq profiling to analyze human mesenteric arteries from non-diabetic (ND) and type 2 diabetic (T2D) donors. We provide in this study a transcriptomic map encompassing major arterial vascular cells, e.g., EC, mononuclear phagocyte (MP), and T cells, and their interactions associated with human T2D. Furthermore, we identified Triggering Receptor Expressed on Myeloid Cells 2 ( TREM2) as a top T2D-induced gene in MP, with concomitant increase of TREM2 ligands in ECs. TREM2 induction was confirmed in mouse models of T2D and monocyte/MΦ subjected to DM-mimicking stimuli. Perturbing TREM2 with either an antibody or silencing RNA in MPs led to decreased pro-inflammatory responses in MPs and ECs and increased EC migration in vitro . In a mouse model of diabetes, TREM2 expression and its interaction with ECs are increased in the ischemic, as compared to non-ischemic muscles. Importantly, neutralization of TREM2 using a neutralizing antibody enhanced ischemic recovery and flow reperfusion in the diabetic mice, suggesting a role of TREM2 in promoting diabetic PAD. Finally, we verified that both TREM2 expression and the TREM2-EC-interaction are increased in human patients with DM-PAD. Collectively, our study presents the first atlas of human diabetic vessels with a focus on EC-MP interactions. Exemplified by TREM2, our study provides valuable insights into EC-MΦ interactions, key processes contributing to diabetic vasculopathies and the potential of targeting these interactions for therapeutic development.

Inflammation modifies the platelet reactivity among thrombocytopenia patients undergoing percutaneous coronary intervention.

Percutaneous coronary intervention (PCI) patients combined with thrombocytopenia (TP) are usually considered to be at low ischemic risk, receiving less proper antiplatelet therapy. However, recent studies reported a paradoxical phenomenon that PCI patients with TP were prone to experience thrombotic events, while the mechanisms and future treatment remain unclear. We aim to investigate whether inflammation modifies platelet reactivity among these patients. Consecutive 10 724 patients undergoing PCI in Fuwai Hospital were enrolled throughout 2013. High-sensitivity C-reactive protein (hsCRP) ≥2 mg/L was considered inflammatory status. TP was defined as platelet count <150×109/L. High on-treatment platelet reactivity (HTPR) was defined as adenosine diphosphate-induced platelet maximum amplitude of thromboelastogram >47mm. Among 6617 patients finally included, 879 (13.3%) presented with TP. Multivariate logistic regression demonstrated that patients with TP were associated with a lower risk of HTPR (odds ratio [OR] 0.64, 95% confidence interval [CI] 0.53-0.76) than those without TP in the overall cohort. In further analysis, among hsCRP <2 mg/L group, patients with TP exhibited a decreased risk of HTPR (OR 0.53, 95% CI 0.41-0.68); however, in hsCRP ≥2mg/L group, TP patients had a similar risk of HTPR as those without TP (OR 0.83, 95% CI 0.63-1.08). Additionally, these results remain consistent across subgroups, including patients presenting with acute coronary syndrome and chronic coronary syndrome. Inflammation modified the platelet reactivity of PCI patients with TP, providing new insights into the mechanisms of the increased thrombotic risk. Future management for this special population should pay more attention to inflammation status and timely adjustment of antiplatelet therapy in TP patients with inflammation.

What is the context? Recent studies reported a paradoxical phenomenon that percutaneous coronary intervention (PCI) patients with thrombocytopenia (TP) were prone to experience thrombotic events. The potential mechanisms underlying the increased thrombotic risk and how to manage antiplatelet therapy in PCI patients with TP remain unclear.Growing attention has been paid to immunothrombosis. Inflammation is closely associated with high-on treatment platelet reactivity (HTPR) and thrombotic risk.HTPR is an independent risk factor of thrombosis and can provide information for guiding antiplatelet therapy.What is new? This prospective cohort study enrolled 10 724 patients undergoing PCI in Fuwai Hospital (National Center for Cardiovascular Diseases, Beijing, China), with HTPR risk being the study endpoint of interest.We first reported that inflammation significantly modified the platelet reactivity of PCI patients with TP.When hsCRP level <2 mg/L, PCI patients with TP had a decreased risk of HTPR. However, when hsCRP ≥2 mg/L, TP patients had similar HTPR risk as those without TP.HsCRP levels could modify the relationship between TP and HTPR risks both in patients with acute coronary syndrome and chronic coronary syndrome.What is the impact? These results provide insights into potential mechanisms of the increased thrombotic risk in PCI patients with TP. Specifically, inflammation might be involved in the thrombotic risk of PCI patients with TP by modifying the platelet reactivity.As for future management, personalized antiplatelet therapy should be administrated to TP patients with inflammation status.

Luteolin Inhibits Lung Cancer Cell Migration by Negatively Regulating TWIST1 and MMP2 Through Upregulation of miR-106a-5p.

BACKGROUND: Luteolin, a common dietary flavonoid found in plants, has been shown to have anti-cancer properties. However, its exact mechanisms of action in non-small cell lung cancer (NSCLC) are still not fully understood, particularly its role in regulating broader genomic networks and specific gene targets. In this study, we aimed to elucidate the role of microRNAs (miRNAs) in NSCLC treated with luteolin, using A549 cells as a model system. MATERIALS AND METHODS: miRNA profiling was conducted on luteolin-treated A549 cells using Exiqon microarrays, with validation of selected miRNAs by qRT-PCR. Bioinformatic analysis identified the regulatory roles of miRNAs in biological processes and pathways following luteolin treatment. Computational algorithms were employed to identify potential target genes. A549 cells were transfected with miR-106a-5p mimic and inhibitor or their corresponding controls. The expression levels of 2 genes, twist basic helix-loop-helix transcription factor 1 (TWIST1) and matrix metallopeptidase 2 (MMP2), and cell migration were assessed. RESULTS: miRNA profiling identified 341 miRNAs, with 18 exhibiting significantly altered expression (P < 0.05). Subsequent qRT-PCR analysis confirmed altered expression of 6 selected miRNAs. KEGG and GO analyses revealed significant alterations in pathways and biological processes crucial for tumor biology. TWIST1 and MMP2, which both contain conserved miR-106a-5p binding sites, exhibited an inverse correlation with the expression levels of miR-106a-5p. Dual-luciferase reporter assays confirmed TWIST1 and MMP2 as direct targets of miR-106a-5p. Luteolin treatment led to a reduction in A549 cell migration, and this reduction was further amplified by the overexpression of miR-106a-5p. CONCLUSION: Luteolin inhibits A549 cell migration by modulating the miRNA landscape, shedding light on its mechanisms and laying the foundation for miRNA-based therapeutic approaches for NSCLC.

Establishment of a human organoid-based evaluation system for assessing interspecies infection risk of animal-borne coronaviruses.

The COVID-19 pandemic presents a major threat to global public health. Several lines of evidence have shown that the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), along with two other highly pathogenic coronaviruses, SARS-CoV and Middle East Respiratory Syndrome (MERS-CoV) originated from bats. To prevent and control future coronavirus outbreaks, it is necessary to investigate the interspecies infection and pathogenicity risks of animal-related coronaviruses. Currently used infection models, including in vitro cell lines and in vivo animal models, fail to fully mimic the primary infection in human tissues. Here, we employed organoid technology as a promising new model for studying emerging pathogens and their pathogenic mechanisms. We investigated the key host-virus interaction patterns of five human coronaviruses (SARS-CoV-2 original strain, Omicron BA.1, MERS-CoV, HCoV-229E, and HCoV-OC43) in different human respiratory organoids. Five indicators, including cell tropism, invasion preference, replication activity, host response and virus-induced cell death, were developed to establish a comprehensive evaluation system to predict coronavirus interspecies infection and pathogenicity risks. Using this system, we further examined the pathogenicity and interspecies infection risks of three SARS-related coronaviruses (SARSr-CoV), including WIV1 and rRsSHC014S from bats, and MpCoV-GX from pangolins. Moreover, we found that cannabidiol, a non-psychoactive plant extract, exhibits significant inhibitory effects on various coronaviruses in human lung organoid. Cannabidiol significantly enhanced interferon-stimulated gene expression but reduced levels of inflammatory cytokines. In summary, our study established a reliable comprehensive evaluation system to analyse infection and pathogenicity patterns of zoonotic coronaviruses, which could aid in prevention and control of potentially emerging coronavirus diseases.

Renal function alters the association of lipoprotein(a) with cardiovascular outcomes in patients undergoing percutaneous coronary intervention: a prospective cohort study.

Background and hypothesis: Lipoprotein(a) [Lp(a)] and renal dysfunction are both independent risk factors for cardiovascular disease. However, it remains unclear whether renal function mediates the association between Lp(a) and cardiovascular outcomes in patients undergoing percutaneous coronary intervention (PCI). Methods: From a large prospective cohort study, 10 435 eligible patients undergoing PCI from January 2013 to December 2013 were included in our analysis. Patients were stratified into three renal function groups according to their baseline estimated glomerular filtration rate (eGFR) (<60; 60-90; ≥90 ml/min/1.73 m2). The primary endpoint was a composite of all-cause death, nonfatal MI, ischemic stroke, and unplanned revascularization [major adverse cardiac and cerebrovascular events (MACCE)]. Results: Over a median follow-up of 5.1 years, a total of 2144 MACCE events occurred. After multivariable adjustment, either eGFR <60 ml/min/1.73 m2 or elevated Lp(a) conferred a significantly higher MACCE risk. Higher Lp(a) was significantly associated with an increased risk of MACCE in patients with eGFR <60 ml/min/1.73 m2. However, this association was weakened in subjects with only mild renal impairment and diminished in those with normal renal function. A significant interaction for MACCE between renal categories and Lp(a) was observed (P = 0.026). Patients with concomitant Lp(a) ≥30 mg/dl and eGFR <60 ml/min/1.73 m2 experienced worse cardiovascular outcomes compared with those without. Conclusion: The significant association between Lp(a) and cardiovascular outcomes was mediated by renal function in patients undergoing PCI. Lp(a)-associated risk was more pronounced in patients with worse renal function, suggesting close monitoring and aggressive management are needed in this population.

Association of NPC1L1 and HMGCR gene polymorphisms with coronary artery calcification in patients with premature triple-vessel coronary disease.

BACKGROUND: Coronary artery calcification (CAC) is a highly specific marker of atherosclerosis. Niemann-Pick C1-like 1 (NPC1L1) and 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) are the therapeutic targets of ezetimibe and statins, respectively, which are important for the progression of atherosclerosis. However, CAC's genetic susceptibility with above targets is still unknown. We aimed to investigate the association of NPC1L1 and HMGCR gene polymorphisms with CAC in patients with premature triple-vessel disease (PTVD). METHODS: Four single nucleotide polymorphisms (SNPs) (rs11763759, rs4720470, rs2072183, rs2073547) of NPC1L1, and three SNPs (rs12916, rs2303151, rs4629571) of HMGCR were genotyped in 872 PTVD patients. According to the coronary angiography results, patients were divided into low-degree CAC group and high-degree CAC group. RESULTS: A total of 872 PTVD patients (mean age, 47.71 ± 6.12; male, 72.8%) were finally included for analysis. Multivariate logistic regression analysis showed no significant association between the SNPs of NPC1L1 and HMGCR genes and high-degree CAC in the total population (P > 0.05). Subgroup analysis by gender revealed that the variant genotype (TT/CT) of rs4720470 on NPC1L1 gene was associated with increased risk for high-degree CAC in male patients only (OR = 1.505, 95% CI: 1.008-2.249, P = 0.046) in dominant model, but no significant association was found in female population, other SNPs of NPC1L1 and HMGCR genes (all P > 0.05). CONCLUSIONS: We reported for the first time that the rs4720470 on NPC1L1 gene was associated with high-degree CAC in male patients with PTVD. In the future, whether therapies related to this target could reduce CAC and cardiovascular events deserves further investigation.

Baseline high-sensitivity C-reactive protein and glycosylated hemoglobinA1c predict adverse outcomes in patients with chronic coronary syndromes undergoing percutaneous coronary intervention.

Introduction: This study explored the ability of high-sensitivity C-reactive protein (hs-CRP) and glycosylated hemoglobin A1c (HbA1c) to predict adverse cardiac and cerebrovascular outcomes in patients with chronic coronary syndromes (CCS) undergoing percutaneous coronary intervention (PCI). Methods: In total, 4083 consecutive patients with CCS undergoing PCI were investigated throughout 2013 at a single center. The primary endpoint was all-cause death at the 5-year follow-up. Hs-CRP and HbA1c data were collected on admission. Results: The highest quartile of hs-CRP had a significantly increased the risk of all-cause death, with an adjusted HR of 1.747 (95 % CI 1.066-2.863), while, there was no difference in all-cause death among the groups of HbA1c after adjustment, with an adjusted HR of 1.383 (95 % CI 0.716-2.674). The highest quartiles for hs-CRP and HbA1c in the study population had a significantly increased risk of major adverse cardiac and cerebrovascular events (MACCE), with an adjusted hazard ratios (HR) of 1.263 (95 % confidence intervals [CI] 1.032-1.545) for hs-CRP and an adjusted HR of 1.417 (95 % CI 1.091-1.840) for HbA1c. Remarkably, the incidence of all-cause death and that of MACCE were significantly increased when both hs-CRP and HbA1c were elevated (HR 1.971, 95 % CI 1.079-3.601, P = 0.027 and HR 1.560, 95 % CI 1.191-2.042), P = 0.001, respectively). Addition of hs-CRP and HbA1c to conventional risk factors significantly improved prediction of the risk of all cause death (net reclassification index 0.492, P < 0.001; integrated discrimination improvement 0.007, P = 0.011) and MACCE (net reclassification index 0.160, P < 0.001; integrated discrimination improvement 0.006, P < 0.001). Conclusions: Hs-CRP and HbA1c can serve as independent predictors of MACCE in patients with CCS undergoing PCI. Furthermore, a combination of hs-CRP and HbA1c could predict all cause death and MACCE better than each component individually.

Associations of Indoxyl Sulfate and p-cresyl Sulfate with Serum Uncarboxylated Matrix γ-carboxyglutamate Protein in Chronic Kidney Disease Patients.

BACKGROUND: Indoxyl sulfate (IS) and p-cresyl sulfate (PCS) are two important protein-bound uremic retention solutes. Increased serum levels of IS and PCS are associated with cardiovascular calcification. Matrix γ-carboxyglutamate protein (MGP) is a potent inhibitor of vascular calcification and inactivated uncarboxylated MGP (ucMGP) is related to vascular calcification. Nevertheless, whether serum levels of IS and PCS are associated with the serum ucMGP level in chronic kidney disease (CKD) patients with different stages is unknown. METHOD: This cross-sectional study enrolled 90 patients in different stages of chronic kidney disease. Serum levels of IS and PCS were determined. The serum concentration of ucMGP was measured with an enzyme-linked immunosorbent assay. Independent associations between serum total IS and PCS with ucMGP were evaluated. RESULTS: The mean serum level of ucMGP in participants of this study is 10.78±5.22 µg/mL. Serum levels of the two above-mentioned uremic toxins and ucMGP were elevated commensurately with deteriorating renal function. The serum level of ucMPG was associated with total IS (r = 0.456, p < 0.001) and total PCS (r =0.413, p < 0.001) levels. Multiple linear regression analysis showed that ucMGP was significantly related to levels of IS (ß = 0.442, p <0.001), but not the level of PCS concentrations after adjusting for other confounding variables. CONCLUSION: Our study showed that a higher serum IS level was independently associated with ucMGP in deteriorating CKD. Therefore, it would be worthwhile to investigate the effect of IS on ucMGP in the pathogenesis of vascular calcification in future studies.

Association between multiple inflammatory biomarkers and remnant cholesterol levels in patients with percutaneous coronary intervention: A large-scale real-world study.

BACKGROUND AND AIM: Remnant cholesterol (RC) has garnered increasing attention recently due to its association with adverse cardiovascular events. However, the relationship between RC levels and inflammation remains unclear. The goal of this study was to investigate and compare the predictive value of multiple inflammatory biomarkers for high RC in patients with percutaneous coronary intervention (PCI). METHODS AND RESULTS: Initially, a total of 10,724 consecutive individuals hospitalized for PCI at Fu Wai Hospital in 2013 were enrolled. Finally, 9983 patients receiving dual antiplatelet therapy and drug-eluting stent were selected for analysis. The inflammatory biomarkers included high-sensitivity C-reactive protein (hs-CRP), hs-CRP-to-albumin ratio (CAR), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), lymphocyte-to-hs-CRP ratio (LCR), and systemic immune-inflammation index (SII). Patients were divided into higher RC and lower RC groups based on the median RC level. Multivariate logistic regression showed that hs-CRP (OR per SD: 1.254), CAR (OR per SD: 1.245), PLR (OR per SD: 1.139), and SII (OR per SD: 1.077) were associated with high RC (≥median), while LCR (OR per SD: 0.792) was associated with low RC (

Unraveling the Adhesion Behavior of Different Cell Lines on Biomimetic PEDOT Interfaces: The Role of Surface Morphology and Antifouling Properties.

The poly(3,4-ethylenedioxythiophene) (PEDOT) interface, renowned for its biocompatibility and intrinsic conductivity, holds substantial potential in biosensing and cellular modulation. Through strategic functionalization, PEDOT derivatives can be adaptable for multifaceted applications. Notably, integrating phosphorylcholine (PC) groups into PEDOT, mimicking the hydrophilic headgroups from cell membranes, confers exceptional antifouling properties on the coating. This study systematically investigated biomolecule interactions with distinct forms of PEDOT, incorporating variations in surface modifications and structure. Zwitterionic PEDOT-PC was electropolymerized on smooth and nanostructured surfaces using various feeding ratios in electrolytes to finely control the antifouling properties of the interface. Precise electropolymerization conditions governed the attainment of smooth and nanostructured filamentous surfaces. The study employed a quartz crystal microbalance with dissipation (QCM-D) to assess protein binding behavior. Bovine serum albumin (BSA), lysozyme (LYZ), cytochrome c (cyt c), and fibronectin (FN) were used to evaluate their binding affinities for PEDOT films. FN, a pivotal extracellular matrix component, was included for connecting to cell adhesion behavior. Furthermore, the cellular adhesion behaviors on PEDOT interfaces were evaluated. Three cell lines─MG-63 osteosarcoma, HeLa cervical cancer, and fibroblast NIH/3T3 were examined. The presence of PC moieties significantly altered the adhesive response, including the number of attached cells, their morphologies, and nucleus shrinkage. MG-63 cells exhibited the highest tolerance for PC moieties. A feeding ratio of PEDOT-PC exceeding 70% resulted in cell apoptosis. This study contributes to understanding biomolecule adsorption on PEDOT surfaces of diverse morphologies and degrees of the antifouling moiety. Meanwhile, it also sheds light on the responses of various cell types.

Prognostic significance of inflammation in patients with coronary artery disease at low residual inflammatory risk.

Patients with coronary artery disease (CAD) at low residual inflammatory risk are often overlooked in research and practice. This study examined the associations between fourteen inflammatory indicators and all-cause mortality in 5,339 CAD patients with baseline high-sensitivity C-reactive protein (hsCRP) <2 mg/L who received percutaneous coronary intervention and statin and aspirin therapy. The median follow-up time was 2.1 years. Neutrophil-derived systemic inflammatory response index (SIRI) yielded the strongest and most robust association with all-cause mortality among all indicators. Lower hsCRP remained to be associated with a lower risk of all-cause mortality. A newly developed comprehensive inflammation score (CIS) showed better predictive performance than other indicators, which was validated by an independent external cohort. In conclusion, neutrophil-derived indicators, particularly SIRI, strongly predicted all-cause mortality independent of hsCRP in CAD patients at low residual inflammatory risk. CIS may help identify individuals with inflammation burdens that cannot be explained by hsCRP alone.

Antisense yycF and BMP-2 co-delivery gelatin methacryloyl and carboxymethyl chitosan hydrogel composite for infective bone defects regeneration.

Repairing infected bone defects remains a challenge in clinical work. Intractable bacterial infections and insufficient osseointegration are major concerns for infected bone defects. To address these issues, we developed a gelatin methacryloyl (GelMA) and carboxymethyl chitosan (CMCS) composite hydrogel with BMP-2 growth factor and GO based antisense technology supported by a PLGA spring. In vitro, photo-crosslinked GelMA composite hydrogels shown excellent biocompatibility and degradability. Relying on the release of BMP-2 from the composite hydrogel provides osteogenic effects. The antisense yycF and BMP-2 were released with the degradation of GelMA and CMCS composite hydrogel. In terms of antimicrobial properties, CMCS, GO and post-transcriptional regulatory antisense yycF from the composite hydrogel synergistically kill S. aureus. In vivo, we implanted the composite hydrogel in a rat model of S. aureus infected femur defect, effectively accelerating bone healing in an infectious microenvironment. This research provides a novel biomaterial that is both antimicrobial and promotes bone regeneration, with the potential to treat infected bone defects.

Klippel-Trenaunay syndrome and pregnancy: A Case-Report.

Klippel-Trenaunay Syndrome is a benign disease with a low incidence rate. Pregnant women with KTS may be at increased risk of thrombosis and coagulopathy due to normal hemodynamic changes during pregnancy. The choice of delivery route for KTS pregnant woman needs rigorous evaluation. This study reported a case of successful delivery by oxytocin combined with balloon catheter induction for the first time, providing more options for KTS pregnant woman. At the same time, this study reported a successful case of labor induced by oxytocin combined with balloon catheter for the first time, which further explored the obstetric management of pregnant women with KTS and provided them with more delivery options.

Remnant cholesterol but not LDL cholesterol is associated with 5-year bleeding following percutaneous coronary intervention.

This study was aimed to investigate the association between remnant cholesterol (RC) and low-density lipoprotein cholesterol (LDL-C) concentrations and long-term bleeding. A total of 10,724 consecutive patients who underwent percutaneous coronary intervention in 2013 were prospectively enrolled. During a median follow-up of 5.1 years, 411 bleeding events and 42 intracranial hemorrhages (ICH) were recorded. The findings revealed that lower RC concentrations were independently associated with an increased risk of long-term bleeding events (continuous RC hazard ratio [HR]: 0.47, 95% confidence interval [CI]: 0.26-0.85; Q4 vs. Q1 HR: 0.66, 95% CI: 0.45-0.98), whereas lower LDL-C concentrations did not show a similar association. Additionally, a non-linear relationship was observed between RC concentrations and the risk of ICH (P for non-linear trend = 0.014), but no such relationship was found for LDL-C concentrations. These results provided insights into the safety of LDL-C-lowering therapy and emphasized the significance of RC concentrations in lipid management.

Association Between Free Fatty Acids and Cardiometabolic Risk in Coronary Artery Disease: Results From the PROMISE Study.

CONTEXT: The association between free fatty acids (FFAs) and unfavorable clinical outcomes has been reported in the general population. However, evidence in the secondary prevention population is relatively scarce. OBJECTIVE: We aimed to examine the relationship between FFA and cardiovascular risk in patients with coronary artery disease (CAD). METHODS: This study was based on a multicenter cohort of patients with CAD enrolled from January 2015 to May 2019. The primary outcome was all-cause death. Secondary outcomes included cardiac death and major adverse cardiovascular events (MACE), a composite of death, myocardial infarction, and unplanned revascularization. RESULTS: During a follow-up of 2 years, there were 468 (3.0%) all-cause deaths, 335 (2.1%) cardiac deaths, and 1279 (8.1%) MACE. Elevated FFA levels were independently associated with increased risks of all-cause death, cardiac death, and MACE (all P < .05). Moreover, When FFA were combined with an original model derived from the Cox regression, there were significant improvements in discrimination and reclassification for prediction of all-cause death (net reclassification improvement [NRI] 0.245, P < .001; integrated discrimination improvement [IDI] 0.004, P = .004), cardiac death (NRI 0.269, P < .001; IDI 0.003, P = .006), and MACE (NRI 0.268, P < .001; IDI 0.004, P < .001). Notably, when stratified by age, we found that the association between FFA with MACE risk appeared to be stronger in patients aged ≥60 years compared with those aged <60 years. CONCLUSION: In patients with CAD, FFAs are associated with all-cause death, cardiac death, and MACE. Combined evaluation of FFAs with other traditional risk factors could help identify high-risk individuals who may require closer monitoring and aggressive treatment.

Combined effect of D-dimer, hs-CRP, and Lp(a) on 5-year clinical outcomes after percutaneous coronary intervention: A large real-world study in China.

To reduce cardiovascular risk in patients with established coronary heart disease, the present study investigated the combined effect of D-dimer, high-sensitivity C-reactive protein (hs-CRP), and lipoprotein(a) [Lp(a)] on long-term cardiovascular outcomes from the perspectives of thrombosis, inflammation, and lipid risk simultaneously. Consecutive 10,724 patients with percutaneous coronary intervention (PCI) were enrolled throughout 2013. Over a median follow-up of 5.1 years, each individual elevation of D-dimer, hs-CRP, and Lp(a) was associated with poor ischemic outcomes but not bleeding. Concurrent high D-dimer, hs-CRP, and Lp(a) had even greater risks of all-cause death (hazard ratio [HR] 2.714, 95% confidence interval [CI] 1.742-4.231) and cardiac death (HR 4.152, 95% CI 2.207-7.812) and had incremental value beyond the traditional risk factors model. Concurrent high D-dimer, hs-CRP, and Lp(a) levels had a synergistic effect on adverse 5-year ischemic outcomes, highlighting that the potential utility of simultaneous assessment of multiple cardiovascular risk biomarkers may help to identify high-risk patients after PCI.

Inhibition of DNMT1 methyltransferase activity via glucose-regulated O-GlcNAcylation alters the epigenome.

The DNA methyltransferase activity of DNMT1 is vital for genomic maintenance of DNA methylation. We report here that DNMT1 function is regulated by O-GlcNAcylation, a protein modification that is sensitive to glucose levels, and that elevated O-GlcNAcylation of DNMT1 from high glucose environment leads to alterations to the epigenome. Using mass spectrometry and complementary alanine mutation experiments, we identified S878 as the major residue that is O-GlcNAcylated on human DNMT1. Functional studies in human and mouse cells further revealed that O-GlcNAcylation of DNMT1-S878 results in an inhibition of methyltransferase activity, resulting in a general loss of DNA methylation that preferentially occurs at partially methylated domains (PMDs). This loss of methylation corresponds with an increase in DNA damage and apoptosis. These results establish O-GlcNAcylation of DNMT1 as a mechanism through which the epigenome is regulated by glucose metabolism and implicates a role for glycosylation of DNMT1 in metabolic diseases characterized by hyperglycemia.

Inverse Association of Lipoprotein(a) on Long-Term Bleeding Risk in Patients with Coronary Heart Disease: Insight from a Multicenter Cohort in Asia.

BACKGROUND: Lipoprotein(a), or Lp(a), has been recognized as a strong risk factor for atherosclerotic cardiovascular disease. However, the relationship between Lp(a) and bleeding remains indistinct, especially in the secondary prevention population of coronary artery disease (CAD). This investigation aimed to evaluate the association of Lp(a) with long-term bleeding among patients with CAD. METHODS: Based on a prospective multicenter cohort of patients with CAD consecutively enrolled from January 2015 to May 2019 in China, the current analysis included 16,150 participants. Thus, according to Lp(a) quintiles, all subjects were divided into five groups. The primary endpoint was bleeding at 2-year follow-up, and the secondary endpoint was major bleeding at 2-year follow-up. RESULTS: A total of 2,747 (17.0%) bleeding and 525 (3.3%) major bleeding were recorded during a median follow-up of 2.0 years. Kaplan-Meier survival analysis showed the highest bleeding incidence in Lp(a) quintile 1, compared with patients in Lp(a) quintiles 2 to 5 (p < 0.001), while the incidence of major bleeding seemed similar between the two groups. Moreover, restricted cubic spline analysis suggested that there was an L-shaped association between Lp(a) and 2-year bleeding after adjustment for potential confounding factors, whereas there was no significant association between Lp(a) and 2-year major bleeding. CONCLUSION: There was an inverse and L-shaped association of Lp(a) with bleeding at 2-year follow-up in patients with CAD. More attention and effort should be made to increase the clinician awareness of Lp(a)'s role, as a novel marker for bleeding risk to better guide shared-decision making in clinical practice.