BACKGROUND:While angiography-derived fractional flow reserve (AngioFFR)- and intravascular ultrasound (IVUS)-guided percutaneous coronary intervention (PCI) yield similar outcomes, with AngioFFR associated with lower PCI rates, the relative clinical effectiveness of AngioFFR versus IVUS-guided PCI according to angiographic lesion characteristics remains unclear. METHODS:This post hoc analysis of the FLAVOUR II trial (Comparison of Angiography-Derived Fractional Flow Reserve- and Intravascular Ultrasound-Guided Intervention Strategy for Clinical Outcomes in Patients with Coronary Artery Disease) included patients with ≥50% stenosis randomized to AngioFFR- or IVUS-guided PCI. A composite lesion risk score was derived using a marginal Cox model-based linear predictor incorporating % diameter stenosis, lesion length, true bifurcation, ostial lesion, and heavy calcification. The primary end point was target vessel failure (TVF: cardiac death, target vessel myocardial infarction, and target vessel revascularization). RESULTS:Among 1726 patients, 884 (51.2%) underwent AngioFFR-guided PCI and 842 (48.8%) underwent IVUS-guided PCI. During a median 12-month follow-up, TVF occurred in 2.4% of AngioFFR-treated vessels and 1.9% of IVUS-treated vessels (P=0.50). TVF risk increased progressively with a higher composite lesion risk score (adjusted hazard ratio, 2.76 [95% CI, 1.35-5.65]). This association was more pronounced in the AngioFFR group (adjusted hazard ratio, 3.93 [95% CI, 1.79-8.63]) than in the IVUS group (adjusted hazard ratio, 1.62 [95% CI, 0.42-6.22]). Compared with IVUS guidance, AngioFFR-guided vessels with high-risk lesions (score >0.32) had a higher TVF rate (5.1% versus 1.9%; P=0.010), whereas outcomes were comparable in those with low-risk lesions (1.5% versus 1.9%; P=0.531). AngioFFR guidance was associated with lower target vessel PCI rates in low-risk lesions (60.1% versus 76.5%; P<0.001), whereas PCI rates were uniformly high and similar between groups in high-risk lesions (96.4% versus 97.4%; P=0.675). CONCLUSIONS:A higher composite lesion risk score was associated with increased PCI rates and TVF risk after AngioFFR- or IVUS-guided treatment. AngioFFR guidance was associated with lower PCI rates in low-risk lesions, whereas IVUS guidance may yield more favorable outcomes in high-risk lesions. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT04397211.

BACKGROUND:Hyperlipidemia (HLP) exacerbates myocardial cell injury by impairing lipophagy, a crucial lipid metabolic process, thereby increasing the risk of acute myocardial infarction (AMI). This study aims to identify biomarkers associated with HLP and lipophagy that are relevant to AMI risk through a combined transcriptomic and Mendelian randomization (MR) approach. METHODS:mRNA expression data for AMI, along with genes related to HLP (HRGs) and lipophagy (LRGs), were obtained from public databases. Biomarkers were identified using differential expression analysis, weighted gene co-expression network analysis (WGCNA), MR analysis, and receiver operating characteristic (ROC) analysis, augmented by two machine learning algorithms and expression validation. These biomarkers were further used to explore the role of platelet activation-related genes (PARGs) in AMI, with enrichment analysis providing insights into their underlying mechanisms. Expression of selected biomarkers was validated in clinical samples using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). RESULTS:Three biomarkers consistently exhibited significant upregulation in AMI samples, which was confirmed by RT-qPCR. Specifically, PLAUR [Odds ratio (OR) = 1.115, 95 % confidence interval (CI): 1.006-1.237, P = 0.038] and IVNS1ABP (OR = 1.047, 95 % CI: 1.000-1.096, P = 0.048) were identified as AMI risk factors, while QKI (OR = 0.946, 95 % CI: 0.903-0.991, P = 0.020) was recognized as a protective factor. PLAUR, QKI, and IVNS1ABP demonstrated strong diagnostic performance with area under the curve (AUC) values of 0.773, 0.933, and 0.807, respectively. When combined in a nomogram, the AUC reached 0.924. These genes were primarily enriched in pathways related to cardiovascular diseases, inflammation, and cellular metabolism, and were notably linked to platelet activation, as evidenced by their strong associations with PARGs. CONCLUSION:In conclusion, the biomarkers PLAUR, QKI, and IVNS1ABP, associated with HLP and lipophagy, exhibit a potential causal relationship with AMI and significant diagnostic potential for predicting AMI risk, providing valuable insights for clinical diagnostics and AMI research.

The heart, responsible for circulating blood throughout our body, contains four chambers. Existing analysis methods primarily focus on one single ventricle. Transthoracic echocardiography provides real-time estimations of cardiac function and enables comprehensive observations of the entire heart, especially through the apical 4-chamber view. However, no current clinical indices evaluate cardiac function considering all four chambers simultaneously. Manual estimation of the four chambers is laborious, inefficient, and complicated by anatomical complexity and variable image quality, including motion artifacts and unclear borders. There is a significant need for a high-performance segmentation tool that can assess all four chambers concurrently. To address this, we collected a clinically representative dataset of 2D apical 4-chamber view echocardiograms, with annotated 4-chamber regions serving as the basis for automatic 4-chamber synergy analysis. We then proposed a boundary-enhanced network, denoted as $BeU<^>{2}$-Net, tailored for transthoracic echocardiography 4-chamber segmentation using our private dataset. Specifically, our network employs a two-level nested encoder-decoder architecture, utilizing a segmentation-specific residual U-block with a mixture of receptive fields at each stage to capture multi-level and multi-scale features. A dedicated boundary prediction branch, incorporating edge details, is integrated to enhance boundary segmentation performance. Experiments on both private and public datasets demonstrate that our $BeU<^>{2}$-Net possesses superior boundary detection capabilities and achieves high segmentation performance for echocardiographic images.

Background Complex interconnections are evident among gut microbiota, circulating metabolites, inflammatory cytokines, and the pathogenesis of abdominal aortic aneurysms (AAA), with the causal dynamics yet to be comprehensively elucidated. The primary objective of this study was to elucidate the potential causal relationships involving gut microbiota-mediated plasma metabolites, inflammatory cytokines, and AAA.Methods We utilized data from genome-wide association studies predominantly comprising individuals of European ancestry, encompassing four major gut microbiota signatures, 233 plasma metabolite signatures (N = 136,016), 91 inflammatory cytokine signatures (N = 14,824), and AAA signatures (N = 1,458,875). Mendelian randomization (MR), employed in a two-sample format, was utilized as a tool to investigate the potential causal pathways from gut microbiota to the development of AAA. Additionally, a two-step MR approach was employed to dissect the impact of plasma metabolites and inflammatory cytokines on the relationship between gut microbiota and AAA and to ascertain the mediated fractions.Results Our findings indicate that five phylum or family-identical bacteria, 175 plasma metabolites, and seven inflammatory factors are causally associated with AAA. Among them, five bacterial species from the same phylum or family, identified from different GWAS data, were strongly associated with AAA. Of these, two exhibited negative causality and three exhibited positive causality. We found that the phylum Firmicutes and the families Oscillospiraceae might reduce the risk of AAA, whereas the families Prevotellaceae, Sutterellaceae, and Aminobacteriaceae might increase the risk of AAA. Further screening indicated that phylum Firmicutes id.1672 (GCST90017114) may confer a protective effect against AAA by reducing triglyceride levels in medium/small high-density lipoprotein (HDL).Conclusion MR analysis has delineated a causal pathway from gut microbiota, through plasma circulating metabolites and inflammatory cytokines, to the pathogenesis of AAA. The role of intestinal flora and certain biomarkers may provide a reference for the diagnosis of AAA, and contribute to the prevention, diagnosis, and treatment of AAA disease.

Background: Hyperlipidemia (HLP) may intensify myocardial cell damage by disrupting lipophagy, a pivotal lipid metabolism pathway, thereby heightening the risk of acute myocardial infarction (AMI). This study aims to identify HLP- and lipophagy-associated biomarkers for AMI through a combined transcriptomic and Mendelian randomization (MR) approach. Methods: The mRNA expression data for AMI, along with HLP-related genes (HRGs) and lipophagy-related genes (LRGs), were sourced from public databases. Biomarkers were identified by conducting differential expression analysis, Weighted Gene Co-expression Network Analysis (WGCNA), MR analysis, and Receiver Operating Characteristic (ROC) analysis, complemented by two machine learning algorithms and expression validation. These biomarkers facilitated an investigation into the role of platelet activation-related genes (PARGs) in AMI, with enrichment analysis providing insights into their underlying mechanisms. Finally, reverse transcription-polymerase chain reaction (RT-PCR) was employed to validate biomarker expression in clinical samples. Results: Three biomarkers exhibited a consistently significant upregulation trend in AMI samples, corroborated by RT-qPCR findings. Notably, PLAUR [Odds Ratio (OR) = 1.115, 95% confidence interval (CI): 1.006-1.237, P = 0.038] and IVNS1ABP (OR = 1.047, 95% CI: 1.000-1.096, P = 0.048) emerged as AMI risk factors, while QKI (OR = 0.946, 95% CI: 0.903-0.991, P = 0.020) was identified as a protective factor. Additionally, PLAUR, QKI, and IVNS1ABP demonstrated robust diagnostic efficacy with Area Under the Curve (AUC) values of 0.773, 0.933, and 0.807, respectively; when integrated into a nomogram, the combined AUC reached 0.924. These genes were enriched in pathways linked to cardiovascular diseases, inflammatory responses, and cellular metabolic processes and appeared actively involved in platelet activation, as indicated by their strong associations with PARGs. Conclusion: In summary, the biomarkers PLAUR, QKI, and IVNS1ABP, connected to HLP and lipophagy, showed a causal relationship with AMI and marked diagnostic potential for predicting AMI risk, offering valuable support for clinical diagnostics and AMI research. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was funded by Grants from the National Natural Science Foundation of China (82360077, 82460065), 535 Talent Project of First Affiliated Hospital of Kunming Medical University (2024535Q03), Yunnan Fundamental Research Projects (202201AU070063), Union Foundation of Yunnan Provincial Science and Technology Department and Kunming Medical University (202201AY070001-082). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: IRB of the First Affiliated Hospital of Kunming Medical University gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors.

Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) restricts platelet activation via platelet collagen receptor GPVI/FcRγ-chain. In this study, screening against collagen-induced platelet aggregation was performed to identify functional CEACAM1 extracellular domain fragments. CEACAM1 fragments, including Ala-substituted peptides, were synthesized. Platelet assays were conducted on healthy donor samples for aggregation, cytotoxicity, adhesion, spreading, and secretion. Mice were used for tail bleeding and FeCl3-induced thrombosis experiments. Clot retraction was assessed using platelet-rich plasma. Extracellular segments of CEACAM1 and A1 domain-derived peptide QDTT were identified, while N, A2, and B domains showed no involvement. QDTT inhibited platelet aggregation. Ala substitution for essential amino acids (Asp139, Thr141, Tyr142, Trp144, and Trp145) in the QDTT sequence abrogated collagen-induced aggregation inhibition. QDTT also suppressed platelet secretion and "inside-out" GP IIb/IIIa activation by convulxin, along with inhibiting PI3K/Akt pathways. QDTT curtailed FeCl3-induced mesenteric thrombosis without significantly prolonging bleeding time, implying the potential of CEACAM1 A1 domain against platelet activation without raising bleeding risk, thus paving the way for novel antiplatelet drugs.

Metagenomic next-generation sequencing (mNGS) is a new high-throughput sequencing method that may have great importance in early diagnosis and clinical management of sepsis. This study aimed to detect the difference between mNGS and comprehensive routine microbiological test (CMT), and to explore the diagnostic efficacy of mNGS in septic patients. This study retrospectively analyzed 150 sepsis patients who were admitted to the intensive care units of 4 hospitals in Southwest China from October 1, 2018, to October 1, 2021, and underwent both blood mNGS and CMT. The demographic and clinical characteristics of the patients were recorded, and the distribution of pathogens was analyzed. Additionally, the diagnostic performance and concordance between mNGS and CMT were compared to evaluate the etiological diagnostic value of mNGS in sepsis patients. In this study of 150 sepsis patients, bacterial infections were identified in 126 (84.0%), viral in 15 (10.0%), and fungal in 9 (6.0%). Among the sample types, sputum was most common, representing 62% of the total cases. Bronchoalveolar lavage fluid constituted 58.7%, blood 56.0%, with other specimens including pleural fluid at 29.3%, pus at 19.3%, swabs at 9.3%, cerebrospinal fluid at 8.7%, tissue at 6.0%, and bone marrow at 5.3%. mNGS demonstrated a diagnostic accuracy of 56.0% for sepsis, with a sensitivity of 84.4%, specificity of 26.0%, a positive predictive value of 54.6%, a negative predictive value of 61.3%. Metagenomic testing enables the rapid and early identification of infectious pathogens in sepsis patients, especially fungi and viruses. The study found that mNGS has high sensitivity in diagnosing sepsis patients, particularly for fungal and viral infections. mNGS technology is beneficial for critically ill sepsis patients.

Sepsis-induced cardiomyopathy (SIC) is a kind of cardiac dysfunction caused by severe sepsis, which increases the risk of heart failure and death. The molecular mechanism of its pathogenesis is still unclear. It is reported that oxidative stress is one of the main pathophysiological manifestations of SIC, suggesting that oxidative stress genes may be involved in the pathogenesis of myocardial injury in SIC. Therefore, we discussed the relationship between oxidative stress gene and the pathogenesis of SIC, in order to provide reference for clinical diagnosis or treatment of SIC. Through bioinformatics analysis, we mined the transcriptome sequencing data and expression profile chip data of SIC samples, screened out the differentially expressed long noncoding RNA (lncRNA), miRNA and mRNA, constructed a lncRNA- mRNA- miRNA ceRNA regulatory network, obtained 60 differentially expressed mRNAs (DEmRNAs) from the ceRNA network, and constructed a random forest classifier to verify its reliability as marker genes of SIC. Further exploration showed that five oxidative stress genes appeared in 60 DEmRNA gene sets, namely Ybx3, Ptpn2, Stk11, Tfdp2 and Mafk, which were also significant in identifying SIC and control samples. At the same time, all kinds of human heart tissue samples with myocardial injury can be significantly clustered and separated by the expression levels of five genes. GO/KEGG enrichment analysis showed that these five genes were mainly involved in myocardial injury through oxidative stress-related inflammatory reactions, suggested that these five oxidative stress genes are potential markers for diagnosis or treatment of SIC on the basis of further experimental verification.

Introduction: Luteolin inhibits platelet activation and thrombus formation, but the mechanisms are unclear. This study investigated the effects of luteolin on GPVI-mediated platelet activation in vitro and explored the effect of luteolin on thrombosis, coagulation, and platelet production in vivo.Methods: Washed human platelets were used for aggregation, membrane protein expression, ATP, Ca2+, and LDH release, platelet adhesion/spreading, and clot retraction experiments. Washed human platelets were used to detect collagen and convulxin-induced reactive oxygen species production and endogenous antioxidant effects. C57BL/6 male mice were used for ferric chloride-induced mesenteric thrombosis, collagen-epinephrine induced acute pulmonary embolism, tail bleeding, coagulation function, and luteolin toxicity experiments. The interaction between luteolin and GPVI was analyzed using solid phase binding assay and surface plasmon resonance (SPR).Results: Luteolin inhibited collagen- and convulxin-mediated platelet aggregation, adhesion, and release. Luteolin inhibited collagen- and convulxin-induced platelet ROS production and increased platelet endogenous antioxidant capacity. Luteolin reduced convulxin-induced activation of ITAM and MAPK signaling molecules. Molecular docking simulation showed that luteolin forms hydrogen bonds with GPVI. The solid phase binding assay showed that luteolin inhibited the interaction between collagen and GPVI. Surface plasmon resonance showed that luteolin bonded GPVI. Luteolin inhibited integrin αIIbβ3-mediated platelet activation. Luteolin inhibited mesenteric artery thrombosis and collagen- adrenergic-induced pulmonary thrombosis in mice. Luteolin decreased oxidative stress in vivo. Luteolin did not affect coagulation, hemostasis, or platelet production in mice.Discussion: Luteolin may be an effective and safe antiplatelet agent target for GPVI. A new mechanism (decreased oxidative stress) for the anti-platelet activity of luteolin has been identified.

目的 探讨癌胚抗原相关细胞黏附分子(CEACAM1)源性多肽KM17对血小板聚集、释放、黏附功能的影响.方法 采用血小板聚集仪观察多肽KM17对凝血酶、胶原、花生四烯酸(AA)、二磷酸腺苷(ADP)等激动剂诱导的血小板聚集的影响;流式细胞术观察多肽KM17对ADP激活血小板后P-选择素释放的影响;显微镜下观察多肽KM17对血小板静态黏附于胶原基质的影响.结果 多肽KM17能显著促进ADP诱导的血小板聚集且呈剂量依赖(P<0.05),而对AA、胶原及凝血酶诱导的血小板聚集差异均无统计学意义(P>0.05);此外,多肽KM17对ADP激活血小板后P-选择素释放及血小板静态黏附于胶原基质的差异也无统计学意义(P>0.05).结论 多肽KM17可明显促进ADP诱导的血小板聚集,但对ADP活化血小板后P-选择素释放及血小板静态黏附于胶原基质未见明显作用.

Introduction Percutaneous coronary intervention (PCI) guided by coronary angiography-derived fractional flow reserve (FFR) or intravascular ultrasound (IVUS) has shown improved clinical outcomes compared with angiography-only-guided PCI. In patients with intermediate stenoses, FFR resulted in fewer coronary interventions and was non-inferior to IVUS with respect to clinical outcomes. However, whether this finding can be applied to angiography-derived FFR in significant coronary artery disease (CAD) remains unclear.Method and analysis The comparison of angiography-derived FFR-guided and IVUS-guided intervention strategies for clinical outcomes in patients with coronary artery disease (FLAVOUR II) trial is a multicentre, prospective, randomised controlled trial. A total of 1872 patients with angiographically significant CAD (stenoses of at least 50% as estimated visually through angiography) in a major epicardial coronary artery will be randomised 1:1 to receive either angiography-derived FFR-guided or IVUS-guided PCI. Patients will be treated with second-generation drug-eluting stent according to the predefined criteria for revascularisation: angiography-derived FFR≤0.8 and minimal lumen area (MLA)≤3 mm2 or 3 mm270%. The primary endpoint is a composite of all-cause death, myocardial infarction and revascularisation at 12 months after randomisation. We will test the non-inferiority of the angiography-derived FFR-guided strategy compared with the IVUS-guided decision for PCI and the stent optimisation strategy.The FLAVOUR II trial will provide new insights into optimal evaluation and treatment strategies for patients with CAD.Ethics and dissemination FLAVOUR II was approved by the institutional review board at each participating site (The Second Affiliated Hospital of Zhejiang University School of Medicine Approval No: 2020LSYD410) and will be conducted in line with the Declaration of Helsinki. Informed consent would be obtained from each patient before their participation. The study results will be submitted to a scientific journal.Trial registration number NCT04397211.

BackgroundHigher CHA2DS2-VASc score is associated with an increased risk of adverse cardio-cerebrovascular events in patients with non-valvular atrial fibrillation (NVAF), regardless of oral anticoagulation (OAC) status. However, whether this association still exists in patients undergoing left atrial appendage closure (LAAC) is unknown. We evaluated the impact of CHA2DS2-VASc score on LAAC efficacy and outcomes.MethodsA total of 401 consecutive patients undergoing LAAC were included and divided into 3 groups based on CHA2DS2-VASc score (0–2, 3–4, and ≥5). Baseline characteristics, periprocedural complications, and long-term outcomes were collected and compared across all groups.ResultsThere were no significant differences in implantation success, periprocedural complications, and long-term outcomes across all score groups. Kaplan-Meier estimation showed that the cumulative ratio of freedom from all-cause mortality (P = 0.146), cardiovascular mortality (P = 0.519), and non-cardiovascular mortality (P = 0.168) did not differ significantly by CHA2DS2-VASc score group. LAAC decreased the risks of thromboembolism and major bleeding, resulting in a relative risk reduction (RRR) of 82.4% (P < 0.001) and 66.7% (P < 0.001) compared with expected risks in the overall cohort, respectively. Subgroup analysis indicated that observed risks of thromboembolism and major bleeding were significantly lower than the expected risks in score 3–4 and score ≥5 groups, respectively. The level of RRR increased with CHA2DS2-VASc score (P < 0.001 for trend) for thromboembolism but not for major bleeding (P = 0.2729 for trend).ConclusionPatients with higher CHA2DS2-VASc score did not experience worse outcomes, which may be partly attributed to more benefits provided by LAAC intervention in such patients compared to those with a low score.

Abstract Septic cardiomyopathy (SCM) is a serious complication caused by sepsis that will further exacerbate the patient's prognosis. However, immune-related genes (IRGs) and their molecular mechanism during septic cardiomyopathy are largely unknown. Therefore, our study aims to explore the immune-related hub genes (IRHGs) and immune-related miRNA-mRNA pairs with potential biological regulation in SCM by means of bioinformatics analysis and experimental validation. Method Firstly, screen differentially expressed mRNAs (DE-mRNAs) from the dataset GSE79962, and construct a PPI network of DE-mRNAs. Secondly, the hub genes of SCM were identified from the PPI network and the hub genes were overlapped with immune cell marker genes (ICMGs) to further obtain IRHGs in SCM. In addition, receiver operating characteristic (ROC) curve analysis was also performed in this process to determine the disease diagnostic capability of IRHGs. Finally, the crucial miRNA-IRHG regulatory network of IRHGs was predicted and constructed by bioinformatic methods. Real-time quantitative reverse transcription-PCR (qRT-PCR) and dataset GSE72380 were used to validate the expression of the key miRNA-IRHG axis. Result The results of immune infiltration showed that neutrophils, Th17 cells, Tfh cells, and central memory cells in SCM had more infiltration than the control group; A total of 2 IRHGs were obtained by crossing the hub gene with the ICMGs, and the IRHGs were validated by dataset and qRT-PCR. Ultimately, we obtained the IRHG in SCM: THBS1. The ROC curve results of THBS1 showed that the area under the curve (AUC) was 0.909. Finally, the miR-222-3p/THBS1 axis regulatory network was constructed. Conclusion In summary, we propose that THBS1 may be a key IRHG, and can serve as a biomarker for the diagnosis of SCM; in addition, the immune-related regulatory network miR-222-3p/THBS1 may be involved in the regulation of the pathogenesis of SCM and may serve as a promising candidate for SCM therapy.

Introduction: Patients with non-valvular atrial fibrillation (NVAF) and previous stroke are at significantly higher risk of stroke recurrence. Data on the efficacy of left atrial appendage closure (LAAC) on these patients is limited. The aim of this study was to investigate the differences of LAAC efficacy on long-term cardio- and cerebrovascular outcomes in NVAF patients with vs. without prior stroke. Methods: Three hundred and seventy consecutive NVAF patients who underwent LAAC were enrolled and divided into stroke and non-stroke groups based on history of previous stroke. Endpoints, such as thromboembolism, major bleeding, and mortality post-LAAC, were followed up among groups. Results: Patients in the stroke group had higher mean CHA2DS2-VASc and HAS-BLED scores compared to the non-stroke group (5.1 vs. 3.6 and 4.1 vs. 3.4, both P < 0.001, respectively). Over a median follow-up of 2.2 years, there were no significant differences in incidence rates of thromboembolism, device-related thrombus (DRT), major bleeding, and combined efficacy endpoints between the two groups. In both stroke and non-stroke groups, LAAC decreased the risk of thromboembolism [relative risk reduction (RRR) 87.5%, P = 0.034, and 74.6%, P = 0.004, respectively] and major bleeding (RRR 68.8%, P = 0.034, and 68.6%, P = 0.007, respectively) compared with predicted risk. The RRR in thromboembolism was greater in patients with vs. without prior stroke (OR 2.45, 95% CI: 1.20-5.12, P = 0.016). The incidence rates of all-cause mortality and non-cardiovascular death were similar between the two groups, but the risks of cardiovascular death post-LAAC both before (1.4% vs. 8.1%, respectively, P = 0.038) and after adjustment for confounding factors (P = 0.048) were significantly decreased in the stroke group. Conclusions: Patients with vs. without prior stroke did not exhibit a worse clinical prognosis after LAAC. LAAC may provide an increased benefit in cardio-cerebrovascular outcomes in patients with previous stroke compared to those without previous stroke. Further research is necessary to evaluate the efficacy of LAAC in this field.

Evodia rutaecarpa has multiple pharmacological effects and is widely used in the prevention and treatment of migraine, diabetes, cardiovascular disease, cancer, and other chronic diseases; however, the pharmacological effects of its active compound evodiamine (Evo) have not been thoroughly investigated. The purpose of this study was to investigate the effects of Evo on antiplatelet activation and thrombosis. We discovered that Evo effectively inhibited collagen-induced platelet activation but had no effect on platelet aggregation caused by activators such as thrombin, ADP, and U46619. Second, we found that Evo effectively inhibited the release of platelet granules induced by collagen. Finally, evodiamine inhibits the transduction of the SFKs/Syk/Akt/PLCγ2 activation pathway in platelets. According to in vivo studies, Evo significantly prolonged the mesenteric thromboembolism induced by ferric chloride and had no discernible effect on the coagulation function of mice. In conclusion, the antiplatelet and thrombotic effects of Evo discovered in this study provide an experimental basis for the investigation of the pharmacological mechanisms of Evo and the development of antiplatelet drugs.

Background: Circulating microRNAs (miRNAs) have emerged as potential biomarkers for cardiovascular diseases. However, few studies have focused on the role of exosomal miRNAs in acute coronary syndrome (ACS). The purpose of this study was to explore weather serum exosomal microRNA-146a (exo-miR-146a) could be used as a novel diagnostic biomarker for ACS and to investigate its relationship with inflammatory response. Methods: A total of 63 ACS patients and 25 patients with normal coronary arteries (Control) were enrolled respectively. The serum exosomes were isolated and then identified by transmission electron microscopy (TEM), western blot, and nanoparticle tracking analysis (NTA). The expression levels of exo-miR-146a in serum were detected by real-time quantitative polymerase chain reaction (RT-qPCR) and the expression levels of interleukin-10 (IL-10), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha) in serum were assessed by enzyme-linked immunosorbent assay (ELISA). Spearman's correlation analysis was used to appraise the potential factors related to serum exo-miR-146a and receiver operating characteristic (ROC) curve analysis was applied for predicting the accuracy of ACS via the area under curve (AUC). Results: Exosomes isolated from serum were of typical cup-like shape, with 50-150 nm diameter, and expressed CD9, CD63, CD81, and HSP70. The expression levels of serum exo-miR-146a, IL-10, IL 6, and TNF-alpha were significantly increased in ACS patients compared with the control group, Spearman ' s correlation analysis indicated that exo-miR-146a expression was markedly positively correlated with IL 10, IL-6, and TNF-alpha. The ROC curve analyses revealed that exo-miR-146a could distinguish ACS patients from their normal controls. Conclusions: The serum exo-miR-146a may be used as a novel diagnostic biomarker for ACS patients, and it is also associated with inflammatory response.

血小板膜受体是血小板重要的组成部分,负责信息的接收和传递.血小板膜受体脱落是一种下调血小板表面受体密度的机制,跨膜受体在蛋白酶的作用下发生不可逆的蛋白水解.目前已发现黏附受体、整合素、黏附分子等多种血小板膜受体会发生脱落,每种受体具有特定的脱落位点和脱落酶.这些受体的脱落在血栓形成、血小板衰老等过程中发挥作用,未来针对血小板膜受体脱落位点和脱落酶的进一步研究可能为抗血小板治疗提供新的靶点.脱落的片段可作为反映血小板病理生理状态的生物标志物,具有重要的临床研究意义.

Abstract Purpose: Left atrial appendage closure (LAAC) may present an alternative to anticoagulation in patients with non-valvular atrial fibrillation (NVAF). However, evidence regarding benefit of LAAC in patients with prior major bleeding is limited. We evaluate whether a previous bleeding factor influences the safety and effectiveness of LAAC. Methods: A total of 377 consecutive patients scheduled for LAAC were categorized into a bleeding group (n=137) and non-bleeding group (n=240). The implantation success and prevalence of severe peri-procedural complications, and efficacy/ safety endpoints during follow-up were investigated. Results: The bleeding group had more patients ≥75 years old (P=0.044), higher CHA2DS2-VASc (P=0.029) and HAS-BLED scores (P=0.001) than the non-bleeding group. Implantation success and severe peri-procedural complications were similar. During an average 2 years’ follow-up, major bleeding events (P=0.917), all-cause death (P=0.313), co-primary efficacy events (P=0.063), and the cumulative survival ratio (P=0.828) were comparable. However, the incidence of thromboembolism was lower in the bleeding group (P=0.031). The observed thromboembolism rate was reduced by 86.1% (P<0.005) and 43.9% (P<0.05) and the observed bleeding rate was decreased by 39.0% (P<0.05) and 34.8% (P<0.05) in the bleeding and non-bleeding groups, respectively. The extent of relative risk reduction in thromboembolism was significantly higher in the bleeding group (86.1% vs. 43.9%, P<0.01). Conclusion: LAAC may provide a safe and effective alternative to long-term antithrombotic therapy in NVAF patients with or without prior bleeding. The efficacy of LAAC in reducing thromboembolism instead of major bleeding seems to be higher in patients with versus without prior bleeding.

目的:比较经食道超声心动图(TEE)和心脏CT血管造影(CCTA)用于左心耳封堵术后随访检测器械相关残余分流(PDL)、器械相关血栓的效果.方法:纳入了昆明医科大学第一附属医院2017年7月至2019年8月成功接受左心耳封堵术的非瓣膜性心房颤动(房颤)患者,患者术后45 d、术后6个月同时进行CCTA和TEE检查,分析对比封堵器PDL、器械相关血栓形成及不良事件等.结果:49例患者成功行左心耳封堵术(WatchmanTM封堵器35例,LambreTM封堵器14例),平均年龄(68.3±9.4)岁,CHA2DS2-VASc评分为(3.24±1.28)分,HASBLED评分为(2.61±1.37)分.术后45 d,49例患者完成TEE和CCTA随访,术后6个月,39例患者完成TEE和CCTA随访.术后45 d随访时,CCTA的PDL检出率明显较TEE高(87.7％vs.67.3％,P=0.006),另外两种检测手段均在同一例患者中检出器械相关血栓.术后6个月随访时,CCTA的PDL检出率仍高于TEE(84.6％vs.20.5％,P<0.001).45 d随访时检出的1例器械相关血栓患者,在6个月随访时TEE和CCTA均显示仍存在器械相关血栓,TEE显示血栓大小从23 mm×8 mm缩小到14 mm×3.4 mm.该组病例中有1例患者诊断心原性脑梗死,无死亡事件发生.结论:左心耳封堵术后45 d似乎不能完全封堵左心耳,CCTA比TEE监测到更多的PDL,可作为左心耳封堵术后随访的辅助手段.

A novel severe acute respiratory syndrome human coronavirus (SARS HCoV) was identified from respiratory illness patients (named SARS-CoV-2 by ICTV) in December 2019 and has recently emerged as a serious threat to world public health. However, no approved drugs have been found to effectively inhibit the virus. Since it has been reported that HIV protease inhibitors can be used as anti-SARS drugs by targeting SARS-CoV-1 3CLpro, we chose six approved anti-HIV drugs and investigated their binding interactions with 3CLpro to evaluate their potential to become clinical drugs for the new coronavirus pneumonia (COVID-19) caused by SARS-CoV-2 infection. The molecular docking results indicate that the 3CLpro of SARS-CoV-2 has a higher binding affinity for all the studied inhibitors than does SARS-CoV-1. Two docking complexes (indinavir and darunavir) with high docking scores were further subjected to MM-PBSA binding free energy calculations to detail the molecular interactions between these two protease inhibitors and SARS HCoV 3CLpro. Our results show that, among the inhibitors tested, darunavir has the highest binding affinity with SARS-CoV-2 and SARS-CoV-1 3CLpro, indicating that it may have the potential to be used as an anti-COVID-19 clinical drug. The mechanism behind the increased binding affinity of HIV protease inhibitors toward SARS-CoV-2 3CLpro (as compared to SARS-CoV-1) was investigated by MD simulations. Our study provides insight into the possible role of structural flexibility during interactions between SARS HCoV 3CLpro and inhibitors and sheds light on structure-based design of anti-COVID-19 drugs targeting SARS-CoV-2 3CLpro.