Following the publication of this paper, it was drawn to the Editor's attention by a concerned reader that, in addition to a pair of data panels showing images of myocardial fibrosis in Fig. 5A on p. 897 having an overlapping section, western blots data featured in Fig. 6B for the '2 weeks' experiments on p. 898 were strikingly similar to data that had already been submitted to the journal PLoS One in a paper that was written by different authors at different research institutes. Given that the abovementioned data had already been submitted for publication before the receipt of this paper at International Journal of Molecular Medicine, the Editor has decided that it should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a reply. The Editor apologizes to the readership for any inconvenience caused. [International Journal of Molecular Medicine 35: 893‑900, 2015; DOI: 10.3892/ijmm.2015.2105].

This study aimed to investigate the relationship between ACE2 expression in peripheral blood and the prognosis of patients with adrenal adenoma and hypertension. We recruited 80 patients with adrenal adenoma and hypertension (47 males, 33 females) treated between March 2021 and September 2022. Patients were divided into high ACE2 expression (n = 26) and low ACE2 expression (n = 54) groups. General patient data, blood pressure, serum potassium, creatinine, and hormone levels (cortisol, aldosterone, catecholamines) were compared. The frequency of hypertensive episodes with palpitations was recorded. Correlations between ACE2 expression and prognosis were analyzed using Pearson correlation and Cox regression models. The ACE2 high expression group had significantly lower blood pressure, serum creatinine, and hormone levels (P < 0.001), but higher serum potassium (P < 0.001) compared to the low expression group. Over 3 months, the incidence of hypertensive episodes with palpitations was lower in the high expression group (7.69

The aim of this study was to investigate the mechanism of m6A methylation in pathological myocardial hypertrophy (PMH), focusing on whether the methyltransferase METTL3 regulates the expression and nuclear translocation of the transcription factor EB (TFEB), thereby affecting autophagic activity and exacerbating the development of myocardial hypertrophy.An in vivo PMH model was established in mice via transverse aortic constriction (TAC), and an in vitro hypertrophy model was established using H9C2 cells stimulated with angiotensin II (AngII). HE staining, Western blotting, qRT-PCR, immunofluorescence, and dual-color autophagy flux analyses were employed to detect the expression of autophagy-related proteins (LC3, Beclin-1, P62, ATG5) and apoptosis levels. Changes in TFEB and key m6A-related enzymes (METTL3, ALKBH5, heterogeneous nuclear ribonucleoprotein D [HNRNPD]) were examined, and gene overexpression or knockdown experiments were performed to clarify their roles in regulating autophagy and myocardial hypertrophy. Finally, m6A MeRIP-qPCR and RIP-qPCR were conducted to explore the effect of METTL3 on m6A modification and the stability of TFEB transcripts, verifying the interplay between METTL3 and TFEB and its impact on autophagy.In both the in vivo and in vitro hypertrophy models, autophagy was significantly impaired and apoptosis was elevated, while TFEB mRNA and protein expression and its nuclear localization were clearly reduced. At the same time, global m6A methylation was markedly increased, accompanied by upregulation of METTL3 and HNRNPD, as well as downregulation of ALKBH5. Functional assays indicated that METTL3 overexpression further inhibited autophagy-related protein expression and autophagic flux, whereas METTL3 knockdown partially restored autophagy. Mechanistic studies revealed that METTL3 modulates TFEB pre-mRNA stability by influencing the binding efficiencies of ALKBH5 and HNRNPD, resulting in decreased TFEB expression. Conversely, overexpression of TFEB could partly counteract the autophagy impairment caused by METTL3 overexpression and reciprocally regulate the expression of METTL3, ALKBH5, and HNRNPD.METTL3 mediates the inhibition of TFEB via m6A modification, thereby impairing autophagy and aggravating myocardial hypertrophy. These findings suggest that the m6A-TFEB axis may serve as a novel therapeutic target for preventing and treating myocardial hypertrophy and heart failure, offering new insights into the intervention of cardiac remodeling-related diseases.

OBJECTIVE:To observe the effect of resveratrol (Res) on T-acute lymphoblastic leukemia (T-ALL) mice, and further explore its mechanism on Notch1 signaling pathway.METHODS:Twenty-five 6-8 weeks old female C57BL/6 mice were randomly divided into control group, T-ALL group and Res group. Res group was further divided into low-Res, middle-Res and high-Res group. The percentage of leukemia cells in peripheral blood and spleen cell suspension were detected by flow cytometry and Wright-Giemsa staining, pathological morphology of spleen and bone marrow tissues were observed by HE staining, the expression levels of Notch1, Hes-1, c-Myc, miR-19b and PTEN mRNA in spleen tissue were detected by RT-qPCR, and the protein levels of Notch1, Hes-1, c-Myc, p-PTEN and PTEN were detected by Western blot.RESULTS:Compared with control group, the leukemia cells in peripheral blood of mice in T-ALL group were markedly increased, accompanied by diffuse infiltration of leukemia cells in spleen and bone marrow tissues, the mRNA levels of Notch1, Hes-1, c-Myc, miR-19b and the protein levels of Notch1, Hes-1, c-Myc were increased (P <0.01), while the expression of PTEN mRNA and protein were significantly decreased in the spleen tissue of T-ALL mice (P <0.01). The above indicators in the H-Res group were reversed compared with T-ALL group after administration of resveratrol.CONCLUSION:Resveratrol may play a role in anti T-ALL by inhibiting Notch1 signaling pathway in mice.

Objective:Immunogenic cell death (ICD) is part of the immune system's response to coronary artery disease (CAD). In this study, we bioinformatically evaluated the diagnostic and therapeutic utility of immunogenic cell death-related genes (IRGs) and their relationship with immune infiltration features in CAD.Methods:We acquired the CAD-related datasets GSE12288, GSE71226, and GSE120521 from the Gene Expression Omnibus (GEO) database and the IRGs from the GeneCards database. After identifying the immune cell death-related differentially expressed genes (IRDEGs), we developed a risk model and detected immune subtypes in CAD. IRDEGs were identified using least absolute shrinkage and selection operator (LASSO) analysis. Using a nomogram, we confirmed that both the LASSO model and ICD signature genes had good diagnostic performance.Results:There was a high degree of coincidence and immune representativeness between two CAD groups based on characteristic genes and hub genes. Hub genes were associated with the interaction of neuroactive ligands with receptors and cell adhesion receptors. The two groups differed in terms of adipogenesis, allograft rejection, and apoptosis, as well as the ICD signature and hub gene expression levels. The two CAD-ICD subtypes differed in terms of immune infiltration.Conclusion:Quantitative real-time PCR (qRT-PCR) correlated CAD with the expression of OAS3, ITGAV, and PIBF1. The ICD signature genes are candidate biomarkers and reference standards for immune grouping in CAD and can be beneficial in precise immune-targeted therapy.

Nonischemic cardiomyopathy (NICM) is a major cause of advanced heart failure, and the morbidity and mortality associated with NICM are serious medical problems. However, the etiology of NICM is complex and the related mechanisms involved in its pathogenesis remain unclear. The microarray datasets GSE1869 and GSE9128 retrieved from the Gene Expression Omnibus database were used to identify differentially expressed genes (DEGs) between NICM and normal samples. The co-expressed genes were identified using Venn diagrams. Kyoto Encyclopedia of Genes and Genomes pathway analyses and gene ontology enrichment were used to clarify biological functions and signaling pathways. Analysis of protein-protein interaction networks using Search Tool for the Retrieval of Interacting Genes/Proteins online to define the hub genes associated with NICM pathogenesis. A total of 297 DEGs were identified from GSE1869, 261 of which were upregulated genes and 36 were downregulated genes. A total of 360 DEGs were identified from GSE9128, 243 of which were upregulated genes and 117 were downregulated genes. In the 2 datasets, the screening identified 36 co-expressed DEGs. Kyoto Encyclopedia of Genes and Genomes pathway and gene ontology analysis showed that DEGs were mainly enriched in pantothenate and CoA biosynthesis, beta-alanine metabolism, kinetochore, G-protein beta/gamma-subunit complex, and other related pathways. The PPI network analysis revealed that DUSP6, EGR1, ZEB2, and XPO1 are the 4 hub genes of interest in the 2 datasets. Bioinformatics analysis of hub genes and key signaling pathways is an effective way to elucidate the mechanisms involved in the development of NICM. The results will facilitate further studies on the pathogenesis and therapeutic targets of NICM.

BACKGROUND:Postprocedural anticoagulation (PPA) is frequently administered after primary percutaneous coronary intervention in ST-segment-elevation myocardial infarction, although no conclusive data support this practice.METHODS:The RIGHT trial (Comparison of Anticoagulation Prolongation vs no Anticoagulation in STEMI Patients After Primary PCI) was an investigator-initiated, multicenter, randomized, double-blind, placebo-controlled, superiority trial conducted at 53 centers in China. Patients with ST-segment-elevation myocardial infarction undergoing primary percutaneous coronary intervention were randomly assigned by center to receive low-dose PPA or matching placebo for at least 48 hours. Before trial initiation, each center selected 1 of 3 PPA regimens (40 mg of enoxaparin once daily subcutaneously; 10 Ukgh of unfractionated heparin intravenously, adjusted to maintain activated clotting time between 150 and 220 seconds; or 0.2 mgkgh of bivalirudin intravenously). The primary efficacy objective was to demonstrate superiority of PPA to reduce the primary efficacy end point of all-cause death, nonfatal myocardial infarction, nonfatal stroke, stent thrombosis (definite), or urgent revascularization (any vessel) within 30 days. The key secondary objective was to evaluate the effect of each specific anticoagulation regimen (enoxaparin, unfractionated heparin, or bivalirudin) on the primary efficacy end point. The primary safety end point was Bleeding Academic Research Consortium 3 to 5 bleeding at 30 days.RESULTS:Between January 10, 2019, and September 18, 2021, a total of 2989 patients were randomized. The primary efficacy end point occurred in 37 patients (2.5%) in both the PPA and placebo groups (hazard ratio, 1.00 [95% CI, 0.63 to 1.57]). The incidence of Bleeding Academic Research Consortium 3 to 5 bleeding did not differ between the PPA and placebo groups (8 [0.5%] vs 11 [0.7%] patients; hazard ratio, 0.74 [95% CI, 0.30 to 1.83]).CONCLUSIONS:Routine PPA after primary percutaneous coronary intervention was safe but did not reduce 30-day ischemic events.REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT03664180.

Background Diabetic cardiomyopathy results in cardiac structural and functional abnormalities. Previous studies have demonstrated that inhibiting the RhoA/ROCK signalling pathway increases the injury resistance of cardiomyocytes. The early detection of cardiac structural and functional alterations may facilitate an improved understanding of the pathophysiologic progress and guide therapy. This study aimed to identify the optimal diagnostic measures for the subtle early alterations of cardiac dysfunction in type 2 diabetes mellitus (T2DM) rats. Methods Twenty-four rat models were divided into four groups and received treatments for 4 weeks: the CON group (control rats), the DM group (T2DM rats), the DMF group (T2DM rats receiving fasudil) and the CONF group (control rats receiving fasudil) group. Left ventricular (LV) structure was quantified by histological staining and transmission electron microscopy. LV function and myocardial deformation were assessed by high-frequency echocardiography. Results Treatment with fasudil, a ROCK inhibitor, significantly protected against diabetes-induced myocardial hypertrophy, fibrosis and mitochondrial dysfunction. Impaired LV performance was found in T2DM rats, as evidenced by significant reductions in the ejection fraction (EF), fractional shortening (FS) and the mitral valve (MV) E/A ratio (which decreased 26%, 34% and 20%, respectively). Fasudil failed to improve the conventional ultrasonic parameters in T2DM rats, but the myocardial deformation measured by speckle-tracking echocardiography (STE) were significantly improved (global circumferential strain, GCS: P = 0.003; GCS rate, GCSR: P = 0.021). When receiver operating characteristic (ROC) curves were used in combination with linear regression analysis, STE parameters were found to be characterized by both optimal prediction of cardiac damage [AUC (95% CI): fractional area change, FAC: 0.927 (0.744, 0.993); GCS: 0.819 (0.610, 0.945); GCSR: 0.899 (0.707, 0.984)] and stronger correlations with cardiac fibrosis (FAC: r = -0.825; GCS: r = 0.772; GCSR: r = 0.829) than conventional parameters. Conclusion The results suggest that STE parameters are more sensitive and specific than conventional parameters in predicting the subtle cardiac functional changes that occur in the early stage, providing new insight into the management of diabetic cardiomyopathy.

AIM:Our previous study demonstrated that chronic intermittent hypobaric hypoxia (CIHH) improved iron metabolism disorder in obese rats through the downregulation of hepcidin. This study aimed to observe the molecular mechanism of CIHH in improving iron metabolism disorders, especially by Janus kinase/signal transducer and activation of the transcription (JAK/STAT) signaling pathway in metabolic syndrome (MS) rats.METHODS:Six-week-old male Sprague-Dawley rats were randomly divided into four groups: CON, CIHH (subjected to hypobaric hypoxia simulating 5000-m altitude for 28 days, 6 h daily), MS (induced by high fat diet and fructose water), and MS+CIHH. The serum levels of glucose, lipid metabolism, iron metabolism, interleukin-6 (IL-6), erythropoietin (Epo) and hepcidin were measured. The protein expressions of JAK2, STAT3, STAT5, bone morphogenetic protein 6 (BMP6), small mothers against decapentaplegic 1 (SMAD1) and hepcidin were examined. The mRNA expressions of erythroferrone (ERFE) and hepcidin were analyzed.RESULTS:The MS rats displayed obesity, hyperglycemia, hyperlipidemia, iron metabolism disorder, increased IL-6 and hepcidin serum levels, upregulation of JAK2/STAT3 signaling pathway, decreased Epo serum levels, downregulation of STAT5/ERFE signaling pathway in spleen, upregulation of BMP/SMAD signaling pathway in liver, and increased hepcidin mRNA and protein expression compared to CON rats. All the aforementioned abnormalities in MS rats were ameliorated in MS + CIHH rats.CONCLUSIONS:CIHH improved iron metabolism disorders, possibly by inhibiting IL-6/JAK2/STAT3 and activating Epo/STAT5/ERFE signaling pathway, thus downregulating hepcidin in MS rats.

Circular RNAs (circRNAs) have been identified as vital regulators in cardiovascular diseases, including acute myocardial infarction (AMI). In this study, the function and mechanism of circRNA heparan sulfate proteoglycan 2 (circHSPG2) in hypoxia-induced injury in AC16 cardiomyocytes were investigated. AC16 cells were stimulated with hypoxia to establish an AMI cell model in vitro. Real-time quantitative PCR and western blot assays were performed to quantify the expression levels of circHSPG2, microRNA-1184 (miR-1184), and mitogen-activated protein kinase kinase kinase 2 (MAP3K2). Counting Kit-8 (CCK-8) assay was used to measure cell viability. Flow cytometry was performed to detect cell cycle and apoptosis. Enzyme-linked immunosorbent assay (ELISA) was used to determine the expression of inflammatory factors. Dual-luciferase reporter, RNA immunoprecipitation (RIP), and RNA pull-down assays were used to analyze the relationship between miR-1184 and circHSPG2 or MAP3K2. In AMI serum, circHSPG2 and MAP3K2 mRNA were highly expressed and miR-1184 was down-regulated. Hypoxia treatment elevated HIF1α expression and repressed cell growth and glycolysis. Moreover, hypoxia promoted cell apoptosis, inflammation, and oxidative stress in AC16 cells. Hypoxia-induced circHSPG2 expression in AC16 cells. CircHSPG2 knockdown alleviated hypoxia-induced AC16 cell injury. CircHSPG2 directly targeted miR-1184, and miR-1184 targeted and suppressed MAP3K2. Inhibition of miR-1184 or overexpression of MAP3K2 abolished the alleviated effect of circHSPG2 knockdown on hypoxia-induced AC16 cell injury. Overexpression of miR-1184 relieved hypoxia-induced impairment in AC16 cells by MAP3K2. CircHSPG2 could regulate MAP3K2 expression through miR-1184. CircHSPG2 knockdown protected AC16 cells from hypoxia-induced injury by regulating the miR-1184/MAP3K2 cascade.

Background: This study aimed to investigate role of erythropoietin in atherosclerosis and explore whether un-derlying mechanism is associated with PI3K/AKT/mTOR pathway.Methods: High-fat-diet-induced atherosclerosis model was established in apolipoprotein E knockout mice (C57BL/6 genetic background). Mice were randomly divided into the control group and the EPO group. Hematoxylin-eosin was performed for the determination of atherosclerotic lesions. The expression levels of related proteins were detected by western blot analysis.Results: Erythropoietin significantly enhanced the incidence of hemorrhage in atherosclerotic plaques compared with the control group. The proteins' expression signaling pathways (including PI3K, AKT, and mTOR) and angiogenesis-related proteins (VEGF, COX-2, and HIF-1 alpha) were proved to be up-regulated by erythropoietin. Additionally, erythropoietin significantly enhanced the incidence of hemorrhage in the atherosclerotic plaques compared with the control group. The vitro experiments were conducted in macrophages at 21% O2 or 1% O2. The data showed that expression ofp-PI3K, p-AKT, p-mTOR, VEGF, COX-2, and HIF-1 alpha related proteins increased in 1% O2 group than 21% O2 group. Moreover, compared with control group, protein expression including p- PI3K, p-AKT, p-mTOR, VEGF, COX-2, and HIF-1 alpha was markedly increased in EPO group, decreased in inhibitors group, and similar results were observed in EPO+ inhibitors group. Conclusion: The present study demonstrated that erythropoietin might promote angiogenesis in atherosclerotic vulnerable by activating PI3K/AKT/mTOR signaling pathway in atherosclerotic, providing a novel therapeutic target for atherosclerotic targeted therapy.

目的 探究血清簇集蛋白(Clusterin)、组织激肽释放酶1(KLK1)与老年急性心力衰竭(AHF)病情关系及对患者预后的评估价值.方法 选取2019 年7 月—2021 年10 月河北医科大学第二医院心血管内四科收治老年AHF患者80 例为研究对象(AHF组),另选取同期在医院行健康体检者 80 例为健康对照组.根据心功能将AHF患者分为轻度亚组(n =37)和重度亚组(n =43),依据患者是否发生终点事件分为终点事件亚组(n =36)和非终点事件亚组(n =44).比较各组间的基本资料及血清Clusterin、KLK1 水平;Spearman相关性分析AHF患者血清Clusterin、KLK1 水平与病情程度之间的关系;Logistic 回归分析 AHF 患者发生终点事件的影响因素;受试者工作特征曲线(ROC)分析血清Clusterin、KLK1 对AHF患者预后的评估价值.结果 AHF组SCr、TnI、CK-MB、NT-proBNP、LVEDD、BNP、Clusterin水平显著高于健康对照组(t/P =8.439/<0.001、31.607/<0.001、5.212/<0.001、15.676/<0.001、11.106/<0.001、17.847/<0.001、12.792/<0.001),LVEF、KLK1 水平显著低于健康对照组(t/P =3.900/<0.001、8.963/<0.001);终点事件亚组 TnI、CK-MB、NT-proBNP、BNP、Clusterin 水平均显著高于非终点事件亚组(t/P = 8.389/<0.001、3.517/0.001、10.993/<0.001、5.626/<0.001、7.303/<0.001),LVEF、KLK1 水平显著低于非终点事件亚组(t/P =2.749/0.007、6.225/<0.001);与轻度亚组患者比较,重度亚组患者血清Clusterin水平显著升高,KLK1水平显著降低(t/P =8.236/<0.001、12.703/<0.001);Spearman相关性分析结果显示,AHF患者血清Clusterin水平与病情程度呈显著正相关(r =0.613,P<0.01),而血清KLK1 水平与病情程度呈显著负相关(r =-0.680,P<0.01);Logistic回归分析结果显示,BNP高、Clusterin高、KLK1 低是影响AHF患者发展为不良终点事件的危险因素[OR(95%CI)=1.401(1.132～1.735)、1.545(1.219～1.959)、1.624(1.246～2.116)];ROC曲线结果显示,血清 Clusterin、KLK1 及二者联合评估AHF患者预后的曲线下面积(AUC)分别为0.879、0.834、0.964,二者联合评估AHF患者预后的AUC大于单项预测(Z/P =2.001/0.045、2.712/0.007).结论 血清Clusterin、KLK1 对老年AHF病情及预后具有良好的评估价值.

Objective: Levosimendan has been demonstrated to reduce the incidence of cardiogenic shock and facilitate weaning from cardiopulmonary bypass. However, the beneficial effects of levosimendan treatment on hospital outcomes in patients receiving venoarterial extracorporeal membrane oxygenation (VA-ECMO) are uncertain. We performed a systematic review and meta-analysis to evaluate the short-term effects of levosimendan use for patients undergoing VA-ECMO. Methods: We searched PubMed, Embase, and the Cochrane Library for English articles published from inception to July 15, 2021. Observational studies comparing levosimendan versus non- levosimendan for VA-ECMO were considered eligible for the current study. Results: Nine observational studies with 1058 patients were included. In-hospital mortality was 46.3% in the levosimendan group as compared with 50.7% in the control group. Levosimendan significantly reduced in-hospital mortality in patients undergoing VA-ECMO compared with the control group (RR, 0.80; 95% CI, 0.67-0.95; p = 0.013). The incidence of weaning from VA-ECMO was 79.3% in the levosimendan group as compared with 63.4% in the control group. Levosimendan significantly increase the incidence of weaning from VA-ECMO in patients as compared with the control group (RR, 1.20; 95% CI, 1.07-1.34; p = 0.002). In the one-way sensitivity analysis for estimating the effect of each study on mortality or weaning from VA-ECMO, omission of each study did not make a significant difference. Conclusions: Our study indicates that levosimendan use significantly reduced in-hospital mortality and increase the incidence of weaning in patients undergoing VA-ECMO.

Background Delirium is a common symptom of heart failure (HF) and is associated with increased mortality, prolonged hospital stays, and heightened medical costs. The impact of delirium on the prognosis of HF patients is currently controversial. Therefore, we conducted a meta-analysis to evaluate the prognostic significance of delirium in HF.Methods Relevant articles were systematically searched in PubMed, Cochrane Library, Web of Science, and Embase based on the PRISMA guidelines. Studies that reported mortality and hospitalization-related outcomes in HF patients with or without delirium using raw or adjusted hazard ratio (HR) and odds ratio (OD) were included. Meta-analysis was then performed to evaluate the effect of delirium in HF patients. Outcomes of interest were all-cause mortality and events of the hospitalization.Results Of the 1,501 studies identified, 7 eligible studies involving 12,830,390 HF patients (6,322,846 males and 6,507,544 females) were included in the meta-analysis. There were 91,640 patients with delirium (0.71%) and 12,738,750 patients without delirium (99.28%). HF patients with delirium had higher OR for in-hospital mortality (1.95, 95% CI = 1.30-2.91, P = 0.135), higher pooled HR for 90-day mortality (2.64, 95% CI = 1.06-1.56, P = 0.215), higher pooled HR for 1-year mortality (2.08, 95% CI = 1.34-3.22, P = 0.004), and higher pooled HR for 30-day readmission rate (4.15, 95% CI = 2.85-6.04, P = 0.831) than those without delirium.Conclusion Current evidence suggests that combined delirium increases the risk of HF-related mortality and hospitalization-related outcomes in patients with HF. However, more research is needed to assess the impact of delirium on the prognosis of HF patients.

Background Nicorandil was reported to improve microvascular dysfunction and reduce reperfusion injury when administered before primary percutaneous coronary intervention. In this multicenter, prospective, randomized, double‐blind clinical trial (CHANGE [Effects of Nicorandil Administration on Infarct Size in Patients With ST‐Segment–Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention]), we investigated the effects of nicorandil administration on infarct size in patients with ST‐segment–elevation myocardial infarction treated with primary percutaneous coronary intervention. Methods and Results A total of 238 patients with ST‐segment–elevation myocardial infarction were randomized to receive intravenous nicorandil (n=120) or placebo (n=118) before reperfusion. Patients in the nicorandil group received a 6‐mg intravenous bolus of nicorandil followed by continuous infusion at a rate of 6 mg/h. Patients in the placebo group received the same dose of placebo. The predefined primary end point was infarct size on cardiac magnetic resonance (CMR) imaging performed at 5 to 7 days and 6 months after reperfusion. CMR imaging was performed in 201 patients (84%). Infarct size on CMR imaging at 5 to 7 days after reperfusion was significantly smaller in the nicorandil group compared with the placebo (control) group (26.5±17.1 g versus 32.4±19.3 g; P=0.022), and the effect remained significant on long‐term CMR imaging at 6 months after reperfusion (19.5±14.4 g versus 25.7±15.4 g; P=0.008). The incidence of no‐reflow/slow‐flow phenomenon during primary percutaneous coronary intervention was much lower in the nicorandil group (9.2% [11/120] versus 26.3% [31/118]; P=0.001), and thus, complete ST‐segment resolution was more frequently observed in the nicorandil group (90.8% [109/120] versus 78.0% [92/118]; P=0.006). Left ventricular ejection fraction on CMR imaging was significantly higher in the nicorandil group than in the placebo group at both 5 to 7 days (47.0±10.2% versus 43.3±10.0%; P=0.011) and 6 months (50.1±9.7% versus 46.4±8.5%; P=0.009) after reperfusion. Conclusions In the present trial, administration of nicorandil before primary percutaneous coronary intervention led to improved myocardial perfusion grade, increased left ventricular ejection fraction, and reduced myocardial infarct size in patients with ST‐segment–elevation myocardial infarction. Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT03445728.

Endothelial cell dysfunction is the main contributing factor of diabetic foot ulcer (DFU). Circulating exosomes have been found to play an important role in many processes, such as cell senescence and angiogenesis. However, the underlying roles and mechanism of circulating exosomes in the onset and progression of DFU remain unclear. In this study, we isolated exosomes from the plasma of patients with DFU (DFU-Exos) and non-diabetic foot wounds (NDF-Exos). DFU-Exos promoted cell senescence and inhibited tube formation in Human Umbilical Vein Endothelial Cells (HUVECs), unlike NDF-Exos. Several datasets suggest that miR-181b-5p expression might be enriched in exosomes from DFU; this was verified using quantitative real-time PCR (qRT-PCR). We also found that miR-181b-5p, which was taken up by HUVECs, promoted cell senescence and inhibited tube formation. Dual luciferase reporter assay, qRT-PCR, Western blotting, and immunofluorescence staining confirmed that miR-181b-5p could negatively regulate nuclear factor erythroid 2-related factor 2 (NRF2) expression by binding to its 3′ UTR, thus further suppressing heme oxygenase-1 (HO-1) expression. In addition, NRF2 and HO-1 inhibitors could also rescue the effects of senescence and tube formation exerted by miR-181b-5p inhibitor. In vivo experiments showed that exosomes isolated from HUVECs which inhibited miR-181b-5p expression promoted angiogenesis to further restore the capacity of wound healing. In conclusion, this study indicated that circulating exosomal miR-181b-5p promoted cell senescence and inhibited angiogenesis to impair wound healing in DFU by regulating the NRF2/HO-1 pathway.

Background: The risk/benefit tradeoff of dual antiplatelet therapy after percutaneous coronary intervention may vary in East Asian patients as compared with their non-East Asian counterparts. Methods: The double-blind, placebo-controlled, randomized TWILIGHT trial (Ticagrelor With Aspirin or Alone in High-Risk Patients After Coronary Intervention) enrolled patients undergoing high-risk percutaneous coronary intervention. After 3 months of treatment with ticagrelor plus aspirin, event-free and adherent patients remained on ticagrelor and were randomly assigned to receive aspirin or placebo for 1 year. The primary end point was Bleeding Academic Research Consortium type 2, 3, or 5 bleeding; the key secondary end point was the first occurrence of death from any cause, nonfatal myocardial infarction, or nonfatal stroke. Results: Of 9006 enrolled and 7119 randomized patients in TWILIGHT, 1169 patients (13.0%) were enrolled at 27 Chinese sites in this prespecified substudy, of whom 1028 (14.4%) patients were randomized after 3 months. The incidence of the primary end point was 6.2% in the ticagrelor+aspirin group versus 3.5% in the ticagrelor+placebo group between randomization and 1 year (hazard ratio, 0.56 [95% CI, 0.31–0.99]; P =0.048). The key secondary end point occurred in 3.4% of patients in the ticagrelor+aspirin group versus 2.4% in the ticagrelor+placebo group (hazard ratio, 0.70 [95% CI, 0.33–1.46]; P =0.34). There was no interaction between the region of randomization (China versus the rest of the world) and randomized treatment assignment in terms of the primary or key secondary end points. Conclusions: Ticagrelor monotherapy significantly reduced clinically relevant bleeding without increasing ischemic events as compared with ticagrelor plus aspirin in Chinese patients undergoing high-risk percutaneous coronary intervention. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02270242.

To investigate the association between brachial‐ankle pulse wave velocity (baPWV) and cardiovascular and cerebrovascular disease (CVD) in different age groups.

To explore the myocardial protective effect of Neuregulin-4 (NRG-4) gene expression on spontaneous hypertension (SHR) rats and its mechanism through mediating the activation of the ErbB signaling pathway, this study was conducted. For this purpose, forty 24-week-old male SPF SHR rats were selected as the experimental group, and 10 age and sex-matched Wistar Kyoto (WKY) rats were selected as the control group. Cardiac tissues were collected for hematoxylin-eosin (HE) staining, terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) staining, Masson staining, and immunohistochemical staining. Following tail vein injection of recombinant lentiviral vectors, the experimental groups were constructed as the control group (SHR rats without any treatment), Empty vector group (Empty Vector transfection), shRNA negative control (NC) group (LV-shRNA-NRG-4 NC transfection to silence the expression of NRG-4), shRNA group (LV-shRNA-NRG-4 transfection), pcDNA3.1(-) NC group (pcDNA3.1(-)-NRG-4 empty vector transfection) and pcDNA3.1(-) group (pcDNA3.1(-)-NRG-4 transfection to overexpress NRG-4). Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot were used to detect the expression levels In addition, methyl thiazolyl tetrazolium salt (MTT) assay and flow cytometry were performed to detect the proliferation and apoptosis of cardiomyocytes, respectively. Results showed that in the SHR group, the cardiomyocytes showed hypertrophy, disordered arrangement, hyperchromatic nucleus, irregular shape, obvious rupture of myocardial fibers, and obvious proliferation of fibrous stroma; obvious myocardial fibrosis, and there were more blue collagen fibers around cardiomyocytes and myocardial arterioles; cardiomyocytes were swollen, muscle fibers arranged disorderly, collagen around the coronary artery and myocardial interstitium increased significantly with a cross-linking appearance; besides, compared with WKY group, the apoptosis index of cardiomyocytes in SHR group was significantly increased (P<0.05). The expression of NRG-4 protein was decreased in the SHR group compared with the WKY group (P<0.05). In vitro, there was no difference in the mRNA expression of NRG-4, ErbB2 and ErbB4, MMP2, TGFβ1 and α-SMA, as well as Caspase3, Bax and Bcl-2 among the control group, Empty vector group, shRNA NC group and pcDNA3.1(-) NC group (P>0.05). While shRNA group showed decreased expressions of NRG-4, ErbB2, ErbB4, MMP2, TGFβ1, α-SMA and Bcl-2, while increased Caspase3 and Bax expressions, as well as promoted cell proliferation and cell apoptosis when compared with the shRNA NC group (P<0.05); while compared with pcDNA3.1(-) NC group, pcDNA3.1(-) group had highly increased expressions of NRG-4, ErbB2, ErbB4, MMP2, TGFβ1, α-SMA and Bcl-2, while decreased Caspase3 and Bax expressions, inhibited cell proliferation and cell apoptosis (all P<0.05). It is concluded Upregulation of NRG-4 gene expression can promote the activation of the ErbB signaling pathway, thus inhibiting the proliferation and apoptosis of cardiomyocytes in SHR rats, reversing myocardial fibrosis, and playing its cardioprotective role.

BACKGROUND:Atherosclerosis (AS) remains prevalent despite hyperlipidemia-lowering therapies. Although multiple functions of miR-199b-5p have been implicated in cancers, its role in endothelial apoptosis and AS remains unclear. This study aimed to examine the role of miR-199b-5p in mitochondrial dynamics and endothelial apoptosis.METHODS:Human umbilical vein endothelial cells (HUVECs) treated with oxidized low-density lipoprotein (ox-LDL) were subjected to other treatments, followed by a series analysis. We found that ox-LDL-treated HUVECs were associated with miR-199b-5p downregulation, increased reactive oxygen species level, reduced adenosine triphosphate (ATP) production, mitochondrial fission, and apoptosis, whereas enhanced miR-199b-5p expression or applied mitochondrial division inhibitor 1 (Mdivi-1) markedly reversed these changes.RESULTS:Mechanistically, A-kinase anchoring protein 1 (AKAP1) was confirmed as a downstream target of miR-199b-5p by dual-luciferase activity reporter assay. AKAP1 overexpression reversed the anti-apoptotic effects of miR-199b-5p through the enhanced interaction of AKAP1 and dynamin protein 1 (DRP1) in ox-LDL-treated HUVECs. Moreover, miR-199b-5p downregulation, AKAP1 upregulation, and excessive mitochondrial fission were verified in human coronary AS endothelial tissues.CONCLUSION:The miR-199b-5p-dependent regulation of AKAP1/DRP1 is required to inhibit hyperlipidemia- induced mitochondrial fission and endothelial injury and may be a promising therapeutic target for AS.