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Abstract Background The triglyceride glucose (TyG) index, TyG-body mass index (TyG-BMI), and triglyceride-density lipoprotein cholesterol ratio (TG/HDL-C) are substitute indicators for insulin resistance (IR). This study aimed to compare the predictive value of these indicators for 5-year mortality in critically ill patients with chronic heart failure (CHF). Methods Critically ill patients with CHF were identified from the Multiparameter Intelligent Monitoring in Intensive Care (MIMIC) III and IV databases. The primary outcome was 5-year mortality. The relationship between the three indices and mortality risk was determined using multivariate Cox proportional hazards models, Kaplan–Meier (K‒M) analysis and restricted cubic splines analysis. A receiver operating characteristic (ROC) curve was generated to compare the ability of the three indices to predict mortality. Finally, whether the IR indices would further increase the predictive ability of the basic model including baseline variables with a significance level between survivors and non-survivors was evaluated by ROC curve. Results Altogether, 1329 patients with CHF were identified from the databases. Cox proportional hazards models indicated that the TyG index was independently associated with an elevated risk of 5-year mortality (hazard ratio [HR], 1.56; 95% confidence interval [CI] 1.29–1.9), while the TyG-BMI index and TG/HDL-C level were significantly associated with 5-year mortality, with an HR (95% CI) of 1.002 (1.000–1.003) and 1.01 (1.00–1.03), respectively. The K–M analysis revealed that the cumulative incidence of all-cause 5-year death increased with increasing quartiles of the TyG index, TyG-BMI index, or TG/HDL-C ratio. According to the ROC curve, the TyG index outperformed the TyG-BMI and TG/HDL-C ratio at predicting all-cause 5-year mortality (0.608 [0.571–0.645] vs. 0.558 [0.522–0.594] vs. 0.561 [0.524–0.598]). The effect of the TyG index on all-cause mortality was consistent across subgroups, with no significant interaction with randomized factors. Furthermore, adding the TyG index to the basic model for 5-year mortality improved its predictive ability (area under the curve, 0.762 for the basic model vs. 0.769 for the basic model + TyG index); however, the difference was not statistically significant. Conclusion As continuous variables, all three indices were significantly associated with 5-year mortality risk in critically ill patients with CHF. Although these IR indices did not improve the predictive power of the basic model in patients with CHF, the TyG index appears to be the most promising index (vs. TyG-BMI and TG/HDL-C ratio) for prevention and risk stratification in critically ill patients with CHF.

Background Increasing evidence suggests a higher propensity for acute myocardial infarction (MI) in patients with psoriasis. However, the shared mechanisms underlying this comorbidity in these patients remain unclear. This study aimed to explore the shared genetic features of psoriasis and MI and to identify potential biomarkers indicating their coexistence. Methods and Results Data sets obtained from the gene expression omnibus were examined using a weighted gene coexpression network analysis approach. Hub genes were identified using coexpression modules and validated in other data sets and through in vitro cellular experiments. Bioinformatics tools, including the Human microRNA Disease Database, StarBase, and miRNet databases, were used to construct a ceRNA network and predict potential regulatory mechanisms. By applying weighted gene coexpression network analysis, we identified 2 distinct modules that were significant for both MI and psoriasis. Inflammatory and immune pathways were highlighted by gene ontology enrichment analysis of the overlapping genes. Three pivotal genes—Src homology and collagen 1, disruptor of telomeric silencing 1‐like, and feline leukemia virus subgroup C cellular receptor family member 2—were identified as potential biomarkers. We constructed a ceRNA network that suggested the upstream regulatory roles of these genes in the coexistence of psoriasis and MI. Conclusions As potential therapeutic targets, Src homology and collagen 1, feline leukemia virus subgroup C cellular receptor family member 2, and disruptor of telomeric silencing 1‐like provide novel insights into the shared genetic features between psoriasis and MI. This study paves the way for future studies focusing on the prevention of MI in patients with psoriasis.

Abstract Background Prior research has established the correlation between insulin resistance (IR) and hypertension. While the association between triglyceride-glucose (TyG) index, a reliable surrogate marker of IR, and uncontrolled hypertension as well as arterial stiffness among individuals with hypertension remains undisclosed. Methods In this study, a total of 8513 adults diagnosed with hypertension from the National Health and Nutrition Examination Survey 1999–2018 were included. The primary outcome of the study are arterial stiffness (represented with estimated pulse wave velocity, ePWV) and uncontrolled hypertension. Logistic regression model, subgroup analysis, restricted cubic spine, and smooth curve fitting curve were conducted to evaluate the association between the IR indicators and uncontrolled hypertension and arterial stiffness in individuals with hypertension. Results Among included participants, the overall prevalence of uncontrolled hypertension was 54.3%. After adjusting for all potential covariates, compared with the first quartile of TyG index, the risk of uncontrolled hypertension increased about 28% and 49% for participants in the third quartile (OR, 1.28; 95% CI 1.06–1.52) and the fourth quartile (OR, 1.49; 95% CI 1.21–1.89) of TyG index, respectively. The higher OR of TyG index was observed in participants taking antihypertensive medication [fourth quartile versus first quartile (OR, 2.03; 95% CI 1.37–3.11)]. Meanwhile, we explored the potential association between TyG index and arterial stiffness and found that TyG index was significantly associated with increased arterial stiffness (β for ePWV, 0.04; 95% CI 0.00–0.08; P = 0.039). However, traditional IR indicator HOMA-IR showed no significant positive correlation to uncontrolled hypertension as well as arterial stiffness in US adults with hypertension. Conclusion Elevated levels of the TyG index were positive associated with prevalence of uncontrolled hypertension and arterial stiffness among US adults with hypertension.

Background and Objective: Bone tumors present significant challenges in orthopedic medicine due to variations in clinical treatment approaches for different tumor types, which includes benign, malignant, and intermediate cases. Convolutional Neural Networks (CNNs) have emerged as prominent models for tumor classification. However, their limited perception ability hinders the acquisition of global structural information, potentially affecting classification accuracy. To address this limitation, we propose an optimized deep learning algorithm for precise classification of diverse bone tumors. Materials and Methods: Our dataset comprises 786 computed tomography (CT) images of bone tumors, featuring sections from two distinct bone species, namely the tibia and femur. Sourced from The Second Affiliated Hospital of Fujian Medical University, the dataset was meticulously preprocessed with noise reduction techniques. We introduce a novel fusion model, VGG16-ViT, leveraging the advantages of the VGG-16 network and the Vision Transformer (ViT) model. Specifically, we select 27 features from the third layer of VGG-16 and input them into the Vision Transformer encoder for comprehensive training. Furthermore, we evaluate the impact of secondary migration using CT images from Xiangya Hospital for validation. Results: The proposed fusion model demonstrates notable improvements in classification performance. It effectively reduces the training time while achieving an impressive classification accuracy rate of 97.6%, marking a significant enhancement of 8% in sensitivity and specificity optimization. Furthermore, the investigation into secondary migration's effects on experimental outcomes across the three models reveals its potential to enhance system performance. Conclusion: Our novel VGG-16 and Vision Transformer joint network exhibits robust classification performance on bone tumor datasets. The integration of these models enables precise and efficient classification, accommodating the diverse characteristics of different bone tumor types. This advancement holds great significance for the early detection and prognosis of bone tumor patients in the future.

Summary: We carried out a meta-analysis on the effect of cardiac rehabilitation (CR) on cardiopulmonary function after coronary artery bypass grafting (CABG). Four databases were searched for studies comparing CR with control. A random-effects model was used to pool mean difference (MD). The meta-analysis showed an increase in peak oxygen consumption (peak VO2) (MD = 1.93 mL/kg/min, p = 0.0006), and 6-min walk distance (6MWD) (MD = 59.21 m, p

Background: Serum ferritin levels are associated with a higher risk of incident heart failure (HF). Whether serum ferritin levels, either increased or decreased, predict the risk of mortality in individuals with chronic heart failure (CHF) remains unknown.Objectives: This study aimed to clarify the potential predictive significance of serum ferritin levels in assessing the short-term mortality in critically ill patients with chronic heart failure (CHF).Methods: Critically ill patients with CHF were identified from the Multiparameter Intelligent Monitoring in Intensive Care III and IV (MIMIC III and IV) databases. Linear and logistic regression models and Cox proportional hazards models were applied to assess the associations between serum ferritin and survival.Results: A total of 1,739 and 2,322 patients with CHF identified from the MIMIC III and IV databases, respectively, fulfilled the inclusion criteria. In the MIMIC III group, compared with the reference group (serum ferritin ≥70 and

Background & Objective Selenium was one of the essential trace elements that played a pivotal role in human health. Although previous studies have investigated the relationship between selenium and non-alcoholic fatty liver disease (NAFLD) and fibrosis, these findings were still inconclusive. Our study was aimed to explore the association between blood selenium level and NAFLD and advanced liver fibrosis diagnosed by vibration controlled transient elastography (VCTE) in US adults.Methods All data were extracted from National Health and Nutrition Examination Survey database (2017–2018). Participants were divided into four groups according to quartile of blood selenium level. Liver stiffness and controlled attenuation parameter (CAP) were measured by VCTE. Multiple logistic regression models and subgroup analyses were conducted to determine the association between blood selenium level and NAFLD and advanced liver fibrosis diagnosed by a variety of methods.Results A total of 3336 participants were enrolled in main analysis. In multiple logistic regression models, the higher blood selenium level (>205.32, ≤453.62 μg/L) had a significant positive association with NAFLD (β = 1.31). Moreover, high blood selenium level had significantly inversely association to advanced liver fibrosis (β = 0.61). In subgroup analysis, the main inversely correlation between blood selenium and advanced liver fibrosis was found in males with high blood selenium level. Despite dietary selenium intake being adjusted or in different subgroups, the associations between blood selenium level and NAFLD/advanced liver fibrosis remained significant.Conclusions This study showed that blood selenium level were positively association with NAFLD among US population. Participants with lower blood selenium level showed a higher percentage of advanced liver fibrosis. Blood selenium is more likely to cause NAFLD and liver fibrosis due to imbalances in selenium homeostasis rather than dietary selenium intake.Key messagesHigh blood selenium level was association with NAFLD diagnosed by vibration controlled transient elastography.Participants with lower blood selenium level had high percentage of advanced liver fibrosis.NAFLD and liver fibrosis are caused by an imbalance of selenium homeostasis, not by dietary selenium intake.

Abstract Background The KODEX-EPD system is a novel, dielectric three-dimensional mapping system. We aim to illustrate the feasibility, safety, and outcomes of ablation using the KODEX-EPD system. Methods A total of 272 patients with supraventricular arrhythmias were enrolled and underwent catheter ablation using the KODEX-EPD system from October 2020 to July 2021. The feasibility, safety, and ablation outcomes were analyzed. Results Of the enrolled patients, 15 (5.4%) had atrial tachycardia (AT), 88 (31.4%) had atrioventricular reentrant tachycardia (AVRT), 141 (50.4%) had atrioventricular nodal reentrant tachycardia (AVNRT), 34 (12.1%) had atrial fibrillation (AF), and 9 (3.2%) had atrial flutter (AFL). All AF patients included were first-do-pulmonary vein isolation (PVI); there were 26 paroxysmal AF and 8 persistent AF. All patients achieved immediate success of ablation. The mean follow-up duration was 11.8 ± 2.4 months. One patient (1.1%) in the AVRT subgroup and two patients (1.4%) in the AVNRT subgroup experienced recurrence. When considering a three-month blanking time, the estimated freedom of AF at one-year post-ablation with and without AADs was 75.7% and 70.4%, respectively. The Kaplan–Meier analysis showed no significant difference in the overall AF recurrence (log-rank; P = 0.931) or AAD-free AF recurrence (log-rank; P = 0.841) between RFCA and cryoablation. One patient had mild pulmonary embolism. None of the patients died or had a cerebrovascular event in the periprocedural period. Conclusions This retrospective, two-center study demonstrated that catheter ablation of supraventricular arrhythmias using the KODEX-EPD system is feasible, safe, and effective. Trial registration Retrospectively registered.

Abstract MicroRNAs (miRNAs) packaged into exosomes mediate cell communication and contribute to the pathogenesis of acute type A aortic dissection (ATAAD) with acute lung injury (ALI). The expression profile of plasma exosomal miRNAs in ATAAD patients with ALI hasn’t been identified. We performed a miRNA-sequencing to analyze the differentially expressed miRNAs (DE-miRNAs) of circulating exosomes in ATAAD patients with ALI compared to patients without ALI, founding 283 specific miRNAs in two groups. We respectively selected the top 10 downregulated and upregulated DE-miRNAs for further studies. The predicted transcription factors (TFs) of these DE-miRNAs were SMAD2, SRSF1, USF1, etc. The Gene Ontology (GO) and Kyoto Encyclopedia Genes and Genomes (KEGG) analysis predicted their target genes mainly involved acute inflammatory response, cell junction, cytoskeleton, NF-κB signaling pathway, etc. Construction and analysis of the PPI network revealed that RHOA and INSR were considered hub genes with the highest connectivity degrees. Moreover, we confirmed two exosomal miRNAs (hsa-miR-485-5p and hsa-miR-206) by real-time quantitative polymerase chain reaction (RT-qPCR) in a validation cohort. Our study identified a plasma exosomal miRNAs signature related to ATAAD with ALI. Certain DE-miRNAs may contribute to the progression of this disease, which help us better understand the pathogenesis of ATAAD with ALI.

Acid sphingomyelinase (ASM) promotes atherogenesis and acute cardiovascular events. We previously demonstrated ASM inhibitor desipramine attenuated oxidized-LDL-induced macrophage apoptosis in vitro. Here, we aim to determine whether ASM-mediated apoptosis in plaque improves stability in vivo. In this study, rabbits with abdominal aorta balloon injury and a 12-week high-cholesterol diet (HCD) were used to simulate an atherosclerotic plaque model. Atherosclerotic rabbits received oral administration of saline (Control group), atorvastatin (Ator group), or desipramine (DES group). ASM activity and ceramide level were measured by ultra-performance liquid chromatography (UPLC). Plaque morphology was assessed by histochemistry and immunohistochemistry. Apoptosis was evaluated by SPECT/CT imaging of 99mTc-duramycin uptake and TUNEL. We found that increasing ASM activity and ceramide level in atherosclerotic rabbits was abated by additional atorvastatin and desipramine treatment. Meanwhile, the DES and Ator groups were similar in plaque stability, with smaller plaque size, areas of macrophages, higher smooth muscle cell content, and decreased apoptosis and matrix metalloproteinase (MMP) activities relative to the Control group. 99mTc-duramycin uptake of rabbit aorta was significantly higher in Control than in the Normal group, while it was reduced by desipramine and atorvastatin administration. Moreover, the uptake of 99mTc-duramycin positively correlated with apoptotic cell number, macrophage infiltration, and plaque instability. The present study demonstrated that desipramine exerted plaque-stabilizing effects partially by suppressing apoptosis and MMP activity in a rabbit model. And 99mTc-duramycin SPECT/CT imaging allowed noninvasively monitoring of atherosclerotic disease and evaluation of anti-atherosclerotic therapy.

BackgroundAs a cellular process, senescence functions to prevent the proliferation of damaged, old and tumor-like cells, as well as participate in embryonic development, tissue repair, etc. This study aimed to analyze the themes and topics of the scientific publications related to cellular senescence in the past three decades by machine learning.MethodsThe MeSH term “cellular senescence” was used for searching publications from 1990 to 2021 on the PubMed database, while the R platform was adopted to obtain associated data. A topic network was constructed by latent Dirichlet allocation (LDA) and the Louvain algorithm.ResultsA total of 21,910 publications were finally recruited in this article. Basic studies (15,382, 70.21%) accounted for the most proportion of publications over the past three decades. Physiology, drug effects, and genetics were the most concerned MeSH terms, while cell proliferation was the leading term since 2010. Three senolytics were indexed by MeSH terms, including quercetin, curcumin, and dasatinib, with the accumulated occurrence of 35, 26, and 22, separately. Three clusters were recognized by LDA and network analyses. Telomere length was the top studied topic in the cluster of physiological function, while cancer cell had been a hot topic in the cluster of pathological function, and protein kinase pathway was the most popular topic in the cluster of molecular mechanism. Notably, the cluster of physiological function showed a poor connection with other clusters.ConclusionCellular senescence has obtained increasing attention over the past three decades. While most of the studies focus on the pathological function and molecular mechanism, more researches should be conducted on the physiological function and the clinical translation of cellular senescence, especially the development and application of senotherapeutics.

ObjectiveThe study aimed to determine the relationship between body mass index (BMI) and the risk of acute aortic syndrome (AAS) with preoperative oxygenation impairment.MethodsA meta-analysis of published observational studies involving BMI and AAS with preoperative oxygenation impairment was conducted. A total of 230 patients with AAS were enrolled for retrospective analysis. All patients were divided into 2 groups (Non-oxygenation impairment group and Oxygenation impairment group). Logistic regression analysis was performed to assess the relation between BMI and the risk of preoperative oxygenation impairment after the onset of AAS. Dose-response relationship curve and subgroup analysis were conducted to test the reliability of BMI as an independent factor of it.ResultsFor the meta-analysis, the quantitative synthesis indicated that excessive BMI increased the risk of preoperative oxygenation impairment (OR: 1.30, 95% CI: 1.05-1.60, Pheterogeneity = 0.001). For the retrospective analysis, a significant association was observed after adjusting for a series of variables. BMI was significantly related to preoperative oxygenation impairment after the onset of AAS (OR: 1.34, 95% CI: 1.15-1.56, p

BackgroundAcute myocardial infarction (AMI), one of the most severe and fatal cardiovascular diseases, is a major cause of morbidity and mortality worldwide. Macrophages play a critical role in ventricular remodeling after AMI. The regulatory mechanisms of the AMI progression remain unclear. This study aimed to identify hub regulators of macrophage-related modules and provide translational experiments with potential therapeutic targets.Materials and methodsThe GSE59867 dataset was downloaded from the Gene Expression Omnibus (GEO) database for bioinformatics analysis. The expression patterns of 22 types of immune cells were determined using CIBERSORT. GEO2R was used to identify differentially expressed genes (DEGs) through the limma package. Then, DEGs were clustered into different modules, and relationships between modules and macrophage types were analyzed using weighted gene correlation network analysis (WGCNA). Further functional enrichment analysis was performed using significantly associated modules. The module most significantly associated with M2 macrophages (Mϕ2) was chosen for subsequent analysis. Co-expressed DEGs of AMI were identified in the GSE123342 and GSE97320 datasets and module candidate hub genes. Additionally, hub gene identification was performed in GSE62646 dataset and clinical samples.ResultsA total of 8,760 DEGs were identified and clustered into ten modules using WGCNA analysis. The blue and turquoise modules were significantly related to Mϕ2, and 482 hub genes were discerned from two hub modules that conformed to module membership values > 0.8 and gene significance values > 0.25. Subsequent analysis using a Venn diagram assessed 631 DEGs in GSE123342, 1457 DEGs in GSE97320, and module candidate hub genes for their relationship with Mϕ2 in the progression of AMI. Finally, four hub genes (CSF2RB, colony stimulating factor 2 receptor subunit beta; SIGLEC9, sialic acid-binding immunoglobulin-like lectin 9; LRRC25, leucine-rich repeat containing 25; and CSF3R, colony-stimulating factor-3 receptor) were validated to be differentially expressed and to have high diagnostic value in both GSE62646 and clinical samples.ConclusionUsing comprehensive bioinformatics analysis, we identified four novel genes that may play crucial roles in the pathophysiological mechanism of AMI. This study provides novel insights into the impact of macrophages on the progression of AMI and directions for Mϕ2-targeted molecular therapies for AMI.

Abstract Background Inflammation underlies both the pathogenesis and prognosis in patients with acute aortic dissection (AAD). This study aimed to assess the association of ICU admission of white blood cell count (WBCc) with post-discharge mortality in these patients. Methods Clinical data were extracted from the MIMIC-III V1.4 database. After adjusted to covariables, Cox regression analysis and Kaplan–Meier survival curve were performed to determine the relationship between WBCc on admission and post-discharge mortality (30-day, 90-day, 1-year and 5-year) in AAD patients. Subgroup analysis and receiver operating characteristic (ROC) curve analysis were used to test the performance of WBCc in predicting mortality in AAD patients. Results A total of 325 eligible patients were divided into 2 groups: normal-WBCc group (≤ 11 k/uL) and high-WBCc group (> 11 K/uL). In univariate Cox regression analysis, high WBCc was significant risk predictor of 30-day, 90-day, 1-year and 5-year mortality [hazard ratio (HR), 95% CI, P 2.58 1.36–4.91 0.004; 3.16 1.76–5.70 0.000; 2.74 1.57–4.79 0.000; 2.10 1.23–3.54 0.006]. After adjusting for age and other risks, high WBCc remained a significant predictor of 30-day, 90-day and 1-year mortality in AAD patients (HR, 95% CI, P 1.994 1.058–3.76 0.033; 2.118 1.175–3.819 0.013; 2.37 1.343–4.181 0.003). The area under ROC curve of WBCc for predicting 30-day, 90-day, 1-year and 5-year mortality were 0.69, 0.70, 0.66 and 0.61, respectively. The results from subgroups analysis showed that there was no interaction in most strata and patients who were younger than 69 years of age or had history of respiratory disease with an elevated WBCc had an excess risk of 30-day mortality (HR, 95% CI, P 3.18 1.41–7.14 0.005; 3.84 1.05–14.13 0.043). Conclusions Higher than normal WBCc on admission may predict post-discharge mortality in patients with AAD.

BackgroundIt has not been verified whether there is a correlation between admission hyperlactatemia and outcomes in critically ill patients with acute myocardial infarction (AMI), especially in large data studies, which we aimed to do in this study.MethodsFor this retrospective study, we extracted analysis data from a famous online intensive care unit database, the Medical Information Mart for Intensive Care (MIMIC)-IV. Included patients were divided into four groups according to the serum lactate level on admission. Hospital mortality and mortality over time were the main outcomes. To explore the relationship between admission hyperlactatemia and outcomes in critically ill patients with AMI, logistic regression, Cox regression, Kaplan-Meier curves, and subgroup analyses were used.Results2171 patients matching the selection criteria were enrolled in this study. After adjusting for potential confounding factors, hyperlactatemia on admission contributed to increased short-term mortality in critically ill patients with AMI. The adjusted odds ratio for hospital mortality were 1.62, 3.46 and 5.28 in the mild, moderate, and severe hyperlactatemia groups (95% CI: 1.20-2.18, 2.15-5.58, and 2.20-12.70, respectively). The adjusted hazard ratio for 7-day and 30-day mortality were 1.99 and 1.35 (95% CI: 1.45-2.73 and 1.09-1.67) in the mild hyperlactatemia group, 3.33 and 2.31 (95% CI: 2.22-4.99 and 1.72-3.10) in the moderate hyperlactatemia group, 4.81 and 2.91 (95% CI: 2.86-8.08 and 1.88-4.50) in the severe hyperlactatemia group. The adjusted hazard ratio for 1-year and 5-year mortality were 2.03 and 1.93 (95% CI: 1.58-2.62 and 1.52-2.47) in the moderate hyperlactatemia group, 1.92 and 1.74 (95% CI: 1.28-2.89 and 1.17-2.59) in the severe hyperlactatemia group. Subgroup analyses indicated that the positive correlation between serum lactate level on admission and short-term mortality of critically ill patients with AMI was similar in the subgroups of cardiogenic shock and acute heart failure (P for interaction > 0.05).ConclusionHyperlactatemia, especially moderate and severe hyperlactatemia, on admission is closely related to higher short-term mortality incidence in critically ill patients with AMI. The relationship between serum lactate level on admission and short-term mortality of critical AMI patients is stable in subgroups of cardiogenic shock and acute heart failure.

Objective: Oxygenation impairment is a common complication of acute aortic syndrome (AAS) patients after surgical repair. The aim of this study is to identify the relationship between body mass index (BMI) and the risk of postoperative oxygenation impairment in AAS patients.Methods: A total of 227 consecutive patients who were diagnosed as AAS and underwent surgical repair were recruited. They were divided into two groups based on the postoperative oxygenation impairment (non-oxygenation impairment group and oxygenation impairment group). Logistic regression was conducted to evaluate the association between BMI and the risk of oxygenation impairment after surgery. Dose-response curve and subgroup analysis were used to test the reliability of the results of regression analysis. A meta-analysis was then performed to further confirm these results using Pubmed, Embase, and Web of Science databases.Results: For the retrospective study, a significant association was observed after adjusting for a series of variables. BMI was significantly correlated with postoperative oxygenation impairment in patients with AAS (OR, 95% CI, P: 1.27, 1.17–1.46, 0.001). Compared with the normal weight group (18.5 kg/m2 ≤ BMI

Abstract Autophagy, a well-observed intracellular lysosomal degradation process, is particularly important to the cell viability in diabetic cardiomyopathy (DCM). Peroxidasin (PXDN) is a heme-containing peroxidase that augments oxidative stress and plays an essential role in cardiovascular diseases, while whether PXDN contributes to the pathogenesis of DCM remains unknown. Here we reported the suppression of cell viability and autophagic flux, as shown by autophagosomes accumulation and increased expression level of LC3-II and p62 in cultured H9C2 and human AC16 cells that treated with 400 μM palmitate acid (PA) for 24 h. Simultaneously, PXDN protein level increased. Moreover, cell death, autophagosomes accumulation as well as increased p62 expression were suppressed by PXDN silence. In addition, knockdown of PXDN reversed PA-induced downregulated forkhead box-1 (FoxO1) and reduced FoxO1 phosphorylation, whereas did not affect AKT phosphorylation. Not consistent with the effects of si-PXDN, double-silence of PXDN and FoxO1 significantly increased cell death, suppressed autophagic flux and declined the level of FoxO1 and PXDN, while the expression of LC3-II was unchanged under PA stimulation. Furthermore, inhibition of FoxO1 in PA-untreated cells induced cell death, inhibited autophagic flux, and inhibited FoxO1 and PXDN expression. Thus, we come to conclusion that PXDN plays a key role in PA-induced cell death by impairing autophagic flux through inhibiting FoxO1, and FoxO1 may also affect the expression of PXDN. These findings may develop better understanding of potential mechanisms regarding autophagy in insulin-resistant cardiomyocytes.

Atherosclerosis is a systemic disease associated with inflammatory cell infiltration and activation of immune-related pathways. In our study, we aimed to uncover immune-related changes and explore novel immunological features in the development of carotid atherosclerotic plaques. First, we applied integrated bioinformatics methods, including CIBERSORT and gene set enrichment analysis (GSEA). The gene expression matrices GSE28829, GSE41571, and GSE43292 were obtained from the Gene Expression Omnibus (GEO) dataset. After a series of data pre-processing steps, the resulting combined expression matrices were analysed using the CIBERSORT, GSEA, and Cluster Profiler packages. After the comparison and analysis between the carotid atherosclerotic plaques in the early and advanced stages, we discovered that there is a higher percentage of activated memory CD4 T cells and a lower percentage of resting memory CD4 cells in advanced-stage plaques. Moreover, activation of memory CD4 T cells can promote the development of carotid atherosclerotic plaques. Additionally, FOXP3+ Treg cell maturation can also participate in the progression of carotid plaques.

Abstract Background Cardiac myxoma (CM) is the most common type of primary cardiac tumors. The prevalence of primary cardiac tumors is 0.0017–0.28% in various autopsy studies. The clinical symptoms of CM which includes embolism, intracardiac obstruction, general or constitutional manifestations and infected myxoma are largely depended on the size, growing speed, location and pedicle length of the tumor. The following case reported a missed diagnostic case of a right atrial myxoma firstly presented digestive, systemic symptoms and immunologic disorder, leading to emergent tricuspid valves obstruction situation. Case presentation We reported a critical case of a 51-year-old female with CM was firstly admitted to the gastroenterology clinical department because of poor appetite, marked fatigability and weight loss for 2 months. The physician diagnosed her as chronic gastritis and treated her with some symptomatic treatment such as ilaprazole and magnesium aluminum carbonate. After months without definitive diagnosis, this right atrial myxoma grew into right ventricle and obstructed the tricuspid valves, causing her dyspnea, sweating, dizziness, feeling of impending death when she was sleeping. Transthoracic echocardiogram revealed a 6.1 × 4.2 × 3.7 cm2 mass adjacent to tricuspid valves. The patient underwent surgical excision and pathology revealed a primary cardiac myxoma. Conclusion This case reported a critical result of missed diagnosis of right atrial myxoma and showed its systematic symptoms and immunologic disorder, highlighting the importance of systematic examinations on patients. Furthermore, it appeals early diagnosis of CM and consideration of drug targets to suppress CM development.

The senescence of vascular endothelial cells (ECs) is characterized as a hallmark of vascular aging, which leads to the initiation, progress, and advancement of cardiovascular diseases. However, the mechanism of the ECs senescence remains elusive. In this study, thoracic aortas were separated from young (8-week-old) and aged (18-month-old) mice. Decreased Ctsl expression and increased vascular remodeling were observed in senescent aorta. H2O2 was used to induce human umbilical vein endothelial cells (HUVECs) senescence, as shown by increased SA-β-gal positive cells and upregulated p21 level. CTSV significantly decreased after H2O2 treatment, while over-expression of CTSV by adenovirus reduced cellular senescence. RNA sequencing analysis was conducted subsequently, and ALDH1A2 was observed to significantly increased in H2O2 group and decreased after over-expression of CTSV. This result was further confirmed by RT-PCR and WB. Moreover, over-expression of CTSV reduced the increase of ERK1/2 and AKT phosphorylation induced by H2O2. Additionally, retinoic acid (RA), the major production of ALDH1A2, was added to CTSV over-expressed senescent HUVECs. Administration of RA activated AKT and ERK1/2, induced the expression of p21, and enhanced SA-β-gal positive cells, while not affecting the expression of CTSV and ALDH1A2. These results were further confirmed in doxorubicin (DOX)-induced senescent ECs. In conclude, we have identified that Ctsl/CTSV plays a key role in ECs senescence by regulating ALDH1A2 to activate AKT/ ERK1/2-P21 pathway. Therefore, targeting Ctsl/CTSV may be a potential therapeutic strategy in EC senescence.

Reactive oxygen species (ROS) derived from NADPH oxidases (NOX) plays an essential role in advanced glycation end products (AGEs)-induced diabetic vascular endothelial dysfunction. Peroxidasin (PXDN, VPO1) is one member of peroxidases family that catalyzes hydrogen peroxide (H2O2) to hypochlorous acid (HOCl). This present study aimed to elucidate the role of PXDN in promoting vascular endothelial dysfunction induced by AGEs in diabetes mellitus. We found that, compared to non-diabetic (db/m) mice, PXDN expression was notably increased in db/db mice with impaired endothelium-dependent relaxation. Knockdown of PXDN in vivo through tail vein injection of siRNA restored the impaired endothelium-dependent relaxation function of db/db mice which is accompanied with up-regulation of eNOS Ser1177 phosphorylation and NO production. AGEs significantly elevated expression of PXDN and 3-Cl-Tyr, but decreased phosphorylation of Akt and eNOS and NO release in HUVECs. All these effects induced by AGEs were remarkable alleviated by silencing PXDN with small interfering RNAs. In addition, HOCl treatment alone as well as HOCl added with Akt inhibitor MK2206 inhibited phosphorylation of Akt and eNOS, reducing NO production. More importantly,AGEs-induced up-regulation of PXDN and 3-Cl-Tyr with endothelial dysfunction were transformed by NOX2 silencing and H2O2 scavengers. Thus, these results support the conclusion that PXDN promotes AGEs-induced diabetic vascular endothelial dysfunction by attenuating eNOS phosphorylation at Ser1177 via NOX2/HOCl/Akt pathway.

Atrial tachycardia originating from the right atrial appendage has a higher probability of failure of catheter ablation. Here we report a case of a 13-year-old boy with incessant tachycardia, complicated by heart enlargement, and heart failure. Electrophysiological examination showed that atrial tachycardia (AT) originated from the apex of the right atrial appendage, and endocardial catheter ablation was ineffective. After thoracoscopic approach, the right atrial appendage was successfully ablated with bipolar radiofrequency ablation forceps, atrial tachycardia was terminated and sinus rhythm was restored. Within 3 months since the patient was discharged from the hospital, no arrhythmia occurred and the heart structure returned to normal. Thus, thoracoscopic clamp radiofrequency ablation may be a reasonable choice for young patients with atrial tachycardia originated from the right atrial appendage when transendocardial ablation is not effective.

Background: Magnesium, the fourth most abundant mineral nutrient in our body, plays a critical role in regulating ion channels and energy generation, intracardiac conduction, and myocardial contraction. In this study, we assessed the association of admission serum magnesium level with all-cause in-hospital mortality in critically ill patients with acute myocardial infarction (AMI).Methods: Clinical data were extracted from the eICU Collaborative Research Database (eICU-CRD). Only the data for the first intensive care unit (ICU) admission of each patient were used, and baseline data were extracted within 24 h after ICU admission. Logistic regression, Cox regression, and subgroup analyses were conducted to determine the relationship between admission serum magnesium level and 30-day in-hospital mortality in ICU patients with AMI.Results: A total of 9,005 eligible patients were included. In the logistic regression analysis, serum magnesium at 2.2 to ≤2.4 and >2.4 mg/dl levels were both significant predictors of all-cause in-hospital mortality in AMI patients. Moreover, serum magnesium of 2.2 to ≤2.4 mg/dl showed higher risk of in-hospital mortality than magnesium of >2.4 mg/dl (adjusted odds ratio, 1.63 vs. 1.39). The Cox regression analysis yielded similar results (adjusted hazard ratio, 1.36 vs. 1.25).Conclusions: High-normal serum magnesium and hypermagnesemia may be useful and easier predictors for 30-day in-hospital mortality in critically ill patients with AMI.

Background Coronary artery disease (CAD) is a common disease with high cost and mortality. Here, we studied the differentially expressed genes (DEGs) between epicardial adipose tissue (EAT) and subcutaneous adipose tissue (SAT) from patients with CAD to explore the possible pathways and mechanisms through which EAT participates in the CAD pathological process. Methods Microarray data for EAT and SAT were obtained from the Gene Expression Omnibus database, including three separate expression datasets: GSE24425, GSE64554 and GSE120774. The DEGs between EAT samples and SAT control samples were screened out using the limma package in the R language. Next, we conducted bioinformatic analysis of gene ontology terms and Kyoto Encyclopedia of Genes and Genomes pathways to discover the enriched gene sets and pathways associated with DEGs. Simultaneously, gene set enrichment analysis was carried out to discover enriched gene functions and pathways from all expression data rather than DEGs. The PPI network was constructed to reveal the possible protein interactions consistent with CAD. Mcode and Cytohubba in Cytoscape revealed the possible key CAD genes. In the next step, the corresponding predicted microRNAs (miRNAs) were analysed using miRNA Data Integration Portal. RT-PCR was used to validate the bioinformatic results. Results The three datasets had a total of 89 DEGs (FC log2 > 1 and P value < 0.05). By comparing EAT and SAT, ten common key genes (HOXA5, HOXB5, HOXC6, HOXC8, HOXB7, COL1A1, CCND1, CCL2, HP and TWIST1) were identified. In enrichment analysis, pro-inflammatory and immunological genes and pathways were up-regulated. This could help elucidate the molecular expression mechanism underlying the involvement of EAT in CAD development. Several miRNAs were predicted to regulate these DEGs. In particular, hsa-miR-196a-5p and hsa-miR-196b-5p may be more reliably associated with CAD. Finally, RT-PCR validated the significant difference of OXA5, HOXC6, HOXC8, HOXB7, COL1A1, CCL2 between EAT and SAT (P value < 0.05). Conclusions Between EAT and SAT in CAD patients, a total of 89 DEGs, and 10 key genes, including HOXA5, HOXB5, HOXC6, HOXC8, HOXB7, COL1A1, CCND1, CCL2, HP and TWIST1, and miRNAs hsa-miR-196a-5p and hsa-miR-196b-5p were predicted to play essential roles in CAD pathogenesis. Pro-inflammatory and immunological pathways could act as key EAT regulators by participating in the CAD pathological process.

Vascular peroxidase 1 (VPO1) is a member of the peroxidase family which aggravates oxidative stress by producing hypochlorous acid (HOCl). Our previous study demonstrated that VPO1 plays a critical role in endothelial dysfunction through dimethylarginine dimethylaminohydrolase2 (DDAH2)/asymmetric Dimethylarginine (ADMA) pathway. Hereby we describe the regulatory role of VPO1 on endothelial nitric oxide synthase (eNOS) expression and activity in human umbilical vein endothelial cells (HUVECs). In HUVECs AngiotensinII (100 nM) treatment reduced Nitric Oxide (NO) production, decreased eNOS expression and activity, which were reversed by VPO1 siRNA. Knockdown of VPO1 also attenuated ADMA production and eNOS uncoupling while enhancing phosphorylated ser1177 eNOS expression level. Furthermore, HOCl stimulation was shown to directly induce ADMA production and eNOS uncoupling, decrease phosphorylated ser1177 eNOS expression. It also significantly suppressed eNOS expression and activity together with NO production. Therefore, VPO1 plays a vital role in regulating eNOS expression and activity via hydrogen peroxide (H2O2)-VPO1-HOCl pathway. Keywords: Vascular peroxidase 1, Endothelial nitric oxide synthase, Nitric oxide, Asymmetricdimethylarginine, Angiotensin II, Oxidative stress

Cardiac fibrosis is the most important mechanism contributing to cardiac remodeling after myocardial infarction (MI). VPO1 is a heme enzyme that uses hydrogen peroxide (H2O2) to produce hypochlorous acid (HOCl). Our previous study has demonstrated that VPO1 regulates myocardial ischemic reperfusion and renal fibrosis. We investigated the role of VPO1 in cardiac fibrosis after MI. The results showed that VPO1 expression was robustly upregulated in the failing human heart with ischemic cardiomyopathy and in a murine model of MI accompanied by severe cardiac fibrosis. Most importantly, knockdown of VPO1 by tail vein injection of VPO1 siRNA significantly reduced cardiac fibrosis and improved cardiac function and survival rate. In VPO1 knockdown mouse model and cardiac fibroblasts cultured with TGF-β1, VPO1 contributes to cardiac fibroblasts differentiation, migration, collagen I synthesis and proliferation. Mechanistically, the fibrotic effects following MI of VPO1 manifested partially through HOCl formation to activate Smad2/3 and ERK1/2. Thus, we conclude that VPO1 is a crucial regulator of cardiac fibrosis after MI by mediating HOCl/Smad2/3 and ERK1/2 signaling pathways, implying a promising therapeutic target in ischemic cardiomyopathy. Keywords: Cardiac fibrosis, Myocardial infarction, Vascular peroxidase1, Cardiac remodeling, Cardiac fibroblasts

Background Hydrogen peroxide (H2O2) is a critical molecular signal in the development of abdominal aortic aneurysm (AAA) formation. Vascular peroxidase 1 (VPO1) catalyzes the production of hypochlorous acid (HOCl) from H2O2 and significantly enhances oxidative stress. The switch from a contractile phenotype to a synthetic one in vascular smooth muscle cells (VSMCs) is driven by reactive oxygen species and is recognized as an early and important event in AAA formation. This study aims to determine if VPO1 plays a critical role in the development of AAA by regulating VSMC phenotypic switch. Methods and Results VPO1 is upregulated in human and elastase‐induced mouse aneurysmal tissues compared with healthy control tissues. Additionally, KLF4, a nuclear transcriptional factor, is upregulated in aneurysmatic tissues along with a concomitant downregulation of differentiated smooth muscle cell markers and an increase of synthetic phenotypic markers, indicating VSMC phenotypic switch in these diseased tissues. In cultured VSMCs from rat abdominal aorta, H2O2 treatment significantly increases VPO1 expression and HOCl levels as well as VSMC phenotypic switch. In support of these findings, depletion of VPO1 significantly attenuates the effects of H2O2 and HOCl treatment. Furthermore, HOCl treatment promotes VSMC phenotypic switch and ERK1/2 phosphorylation. Pretreatment with U0126 (a specific inhibitor of ERK1/2) significantly attenuates HOCl‐induced VSMC phenotypic switch. Conclusions Our results demonstrate that VPO1 modulates VSMC phenotypic switch through the H2O2/VPO1/HOCl/ERK1/2 signaling pathway and plays a key role in the development of AAA. Our findings also implicate VPO1 as a novel signaling node that mediates VSMC phenotypic switch and plays a key role in the development of AAA. Clinical Trial Registration URL: www.chictr.org.cn. Unique identifier: ChiCTR1800016922.

Innate immune recognition is classically mediated by the interaction of host pattern-recognition receptors and pathogen-associated molecular patterns; this triggers a series of downstream signaling events that facilitate killing and elimination of invading pathogens. In this report, we provide the first evidence that peroxidasin (PXDN; also known as vascular peroxidase-1) directly binds to gram-negative bacteria and mediates bactericidal activity, thus, contributing to lung host defense. PXDN contains five leucine-rich repeats and four immunoglobulin domains, which allows for its interaction with lipopolysaccharide, a membrane component of gram-negative bacteria. Bactericidal activity of PXDN is mediated via its capacity to generate hypohalous acids. Deficiency of PXDN results in a failure to eradicate Pseudomonas aeruginosa and increased mortality in a murine model of Pseudomonas lung infection. These observations indicate that PXDN mediates previously unrecognized host defense functions against gram-negative bacterial pathogens.