European Journal of Clinical Investigation最新文献

{"title":"Mechanism and function of CEACAM1 splice isoforms.","authors":"Kenneth J Dery, Sonia M Najjar, Nicole Beauchemin, John E Shively, Jerzy W Kupiec-Weglinski","doi":"10.1111/eci.14350","DOIUrl":"10.1111/eci.14350","url":null,"abstract":"<p><strong>Background: </strong>Alternative splicing is a fundamental mechanism in the post-transcriptional regulation of genes. The multifunctional transmembrane glycoprotein receptor carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) undergoes extensive alternative splicing to allow for tunable functions in cell signalling, adhesion and modulation of immune and metabolic responses. Splice isoforms that differ in their ectodomain and short or long cytoplasmic tail (CEACAM1-S/CEACAM1-L) have distinct functional roles. The mechanisms that regulate CEACAM1 RNA splicing remain elusive.</p><p><strong>Methods: </strong>This narrative review summarizes the current knowledge of the mechanism and function of CEACAM1 splice isoforms. Historical perspectives address the biological significance of the glycosylated Ig domains, the variable exon 7, and phosphorylation events that dictate its signal transduction pathways. The use of small antisense molecules to target mis-spliced variable exon 7 is discussed.</p><p><strong>Results: </strong>The Ig variable-like N domain mediates cell adhesion and immune checkpoint inhibitory functions. Gly and Tyr residues in the transmembrane (TM) domain are essential for dimerization. Calmodulin, Calcium/Calmodulin-dependent protein kinase II delta (CamK2D), Actin and Annexin A2 are binding partners of CEACAM1-S. Homology studies of the muCEACAM1-S and huCEACAM1-S TM predict differences in their signal transduction pathways. Hypoxia-inducible factor 1-α (HIF-1-α) induces alternative splicing to produce CEACAM1-S under limited oxygen conditions. Antisense small molecules directed to exon 7 may correct faulty expression of the short and long cytoplasmic tail splicing isoforms.</p><p><strong>Conclusion: </strong>More pre-clinical and clinical studies are needed to elucidate the precise mechanisms by which CEACAM1 RNA splicing may be exploited to develop targeted interventions towards novel therapeutic strategies.</p>","PeriodicalId":12013,"journal":{"name":"European Journal of Clinical Investigation","volume":"54 Suppl 2 ","pages":"e14350"},"PeriodicalIF":4.4,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11646291/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142827960","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structural aspects of CEACAM1 interactions.","authors":"Amit K Gandhi, Yu-Hwa Huang, Zhen-Yu J Sun, Walter M Kim, Yasuyuki Kondo, Thomas Hanley, Nicole Beauchemin, Richard S Blumberg","doi":"10.1111/eci.14357","DOIUrl":"10.1111/eci.14357","url":null,"abstract":"<p><p>Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is a membrane protein that plays an important role in a variety of immune and non-immune functions. Such functions are regulated by its activity as a homophilic ligand but also through its ability to interact as a heterophilic ligand with various host proteins. These include CEACAM5, T cell immunoglobulin-mucin like protein-3 (TIM-3) and, potentially, protein death protein 1 (PD-1). Furthermore, CEACAM1 is targeted by various pathogens to allow them to invade a host and bypass an effective immune response. Clinically, CEACAM1 plays an important role in infectious diseases, autoimmunity and cancer. In this review, we describe the structural basis for CEACAM1 interactions as a homophilic and heterophilic ligand. We discuss the regulation of its monomeric, dimeric and oligomeric states in cis and trans binding as well as the consequences for eliciting downstream signalling activities. Furthermore, we explore the potential role of avidity in determining CEACAM1's activities.</p>","PeriodicalId":12013,"journal":{"name":"European Journal of Clinical Investigation","volume":" ","pages":"e14357"},"PeriodicalIF":4.4,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142647189","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Regulation of lipid storage and inflammation in the liver by CEACAM1.","authors":"Sonia M Najjar, John E Shively","doi":"10.1111/eci.14338","DOIUrl":"10.1111/eci.14338","url":null,"abstract":"<p><p>This review focuses on a special aspect of hepatic lipid storage and inflammation that occurs during nutritional excess in obesity. Mounting evidence supports that prolonged excess fatty acid (FA) uptake in the liver is strongly associated with hepatic lipid storage and inflammation and that the two processes are closely linked by a homeostatic mechanism. There is also strong evidence that bacterial lipids may enter the gut by a common mechanism with lipid absorption and that there is a set point to determine when their uptake triggers an inflammatory response in the liver. In fact, the progression from high uptake of FAs in the liver resulting in Metabolic dysfunction-associated steatotic liver disease (MASLD) to the development of the more serious Metabolic dysfunction-associated steatohepatitis (MASH) depends on the degree of inflammation and its progression from an acute to a chronic state. Thus, MASLD/MASH implicates both excess fatty acids and progressive inflammation in the aetiology of liver disease. We start the discussion by introduction of CD36, a major player in FA and lipopolysaccharide (LPS) uptake in the duodenum, liver and adipose tissue. We will then introduce CEACAM1, a major player in the regulation of hepatic de novo lipogenesis and the inflammatory response in the liver, and its dual association with CD36 in enterocytes and hepatocytes. We conclude that CEACAM1 and CD36 together regulate lipid droplet formation and inflammation in the liver.</p>","PeriodicalId":12013,"journal":{"name":"European Journal of Clinical Investigation","volume":"54 Suppl 2 ","pages":"e14338"},"PeriodicalIF":4.4,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11646288/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142827973","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The emerging role of Fusobacteria in carcinogenesis.","authors":"Raisha J Gibbs, Adam C Chambers, Darryl J Hill","doi":"10.1111/eci.14353","DOIUrl":"10.1111/eci.14353","url":null,"abstract":"<p><p>The Fusobacterium genus comprises Gram-negative, obligate anaerobic bacteria that typically reside in the periodontium of the oral cavity, gastrointestinal tract, and female genital tract. The association of Fusobacterial spp. with colorectal tumours is widely accepted, with further evidence that this pathogen may also be implicated in the development of other malignancies. Fusobacterial spp. influence malignant cell behaviours and the tumour microenvironment in various ways, which can be related to the multiple surface adhesins expressed. These adhesins include Fap2 (fibroblast-activated protein 2), CpbF (CEACAM binding protein of Fusobacteria), FadA (Fusobacterium adhesin A) and FomA (Fusobacterial outer membrane protein A). This review outlines the influence of Fusobacteria in promoting cancer initiation and progression, impacts of therapeutic outcomes and discusses potential therapeutic interventions where appropriate.</p>","PeriodicalId":12013,"journal":{"name":"European Journal of Clinical Investigation","volume":"54 Suppl 2 ","pages":"e14353"},"PeriodicalIF":4.4,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11646295/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142827975","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association between insulin-associated gene polymorphisms and new-onset diabetes mellitus in statin-treated patients.","authors":"Minju Park, Jung Sun Kim, Yoon-A Park, Da Hoon Lee, Seo-A Choi, Yoonkyung Chang, Tae-Jin Song, Hye Sun Gwak, Jeong Yee","doi":"10.1111/eci.14366","DOIUrl":"https://doi.org/10.1111/eci.14366","url":null,"abstract":"<p><strong>Background: </strong>While statins are effective at managing lipid levels, there is growing evidence for new-onset diabetes mellitus (NODM). The insulin signalling pathway (ISP) inhibited by statins is one of the potential mechanisms; however, most studies have been limited to in vitro settings. Therefore, this study aimed to identify the genetic associations within the ISP-related genes and NODM.</p><p><strong>Methods: </strong>We performed a retrospective analysis of samples collected prospectively from February 2021 to May 2021. Among ISP-related genes, we selected 11 candidate genes (IGF1, IGF2, IGF1R, INSR, IRS1, IRS2, PIK3CA, PIK3CB, PIK3R1, AKT1 and AKT2). An additional analysis was conducted comparing patients with DM prior to statin therapy and controls to determine whether the single nucleotide polymorphisms (SNPs) are specific to statin.</p><p><strong>Results: </strong>A total of 602 patients were analysed, including 71 (11.8%) with statin-induced NODM. After adjustment, IGF1R rs2715439, INSR rs1799817, INSR rs2059807 and PIK3R1 rs3730089 were found to be independently associated with NODM. In an additional analysis, all SNPs that demonstrated an association with statin-induced NODM lost their significance in patients with DM prior to statin therapy.</p><p><strong>Conclusion: </strong>This study revealed the ISP-related genetic effects, specifically involving genes such as INSR, IGF1R and PIK3R1, in the development of statin-induced NODM. Our findings suggest a potential mechanism of statin-induced NODM related to ISP-related genetic variants.</p>","PeriodicalId":12013,"journal":{"name":"European Journal of Clinical Investigation","volume":" ","pages":"e14366"},"PeriodicalIF":4.4,"publicationDate":"2024-11-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142754913","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Circulating Fetuin-A concentrations in rheumatic diseases: a systematic review and meta-analysis.","authors":"Biagio Di Lorenzo, Stefano Zoroddu, Arduino A Mangoni, Panagiotis Paliogiannis, Gian Luca Erre, Ciriaco Carru, Angelo Zinellu","doi":"10.1111/eci.14365","DOIUrl":"https://doi.org/10.1111/eci.14365","url":null,"abstract":"<p><strong>Background: </strong>Rheumatic diseases (RDs) include a broad group of disabling conditions with different phenotypes, from autoimmune to autoinflammatory, degenerative, metabolic or mixed manifestations. With the continuous efforts to identify therapeutic targets for new biologic drugs to treat overt clinical manifestations, research is also focusing on the discovery of new biomarkers to diagnose and manage early disease stages. In this context, we conducted a systematic review and meta-analysis of Fetuin-A (FtA), a glycoprotein synthesized by the liver that participates in several biological processes and has been proposed as a biomarker for several disorders, including rheumatoid arthritis.</p><p><strong>Methods: </strong>A systematic search in PubMed, Scopus and Web of Science, from inception to the 24th of August 2024, led to the identification of 13 manuscripts from 219 records; six additional studies were identified through reference hand-search, for a total of 19 studies.</p><p><strong>Results: </strong>There was a significant decrease in FtA concentrations in RD patients (standardized mean difference, SMD = -.91; 95% CI -1.43 to -.39, p = .001), with no substantial contribution from any individual study nor publication bias. The effect size was significantly associated with erythrocyte sedimentation rate, various lipid fractions, geographical area of study conduction, study design and specific type of RD.</p><p><strong>Conclusion: </strong>In conclusion, our study identified significant reductions in FtA concentrations in RD patients versus healthy controls. These alterations were significantly associated with specific study and patient characteristics. Further research is required to identify the exact pathophysiological mechanisms underlying these alterations and the possible utility of measuring FtA for the diagnosis and management of RDs.</p>","PeriodicalId":12013,"journal":{"name":"European Journal of Clinical Investigation","volume":" ","pages":"e14365"},"PeriodicalIF":4.4,"publicationDate":"2024-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142738825","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genome-wide methylation profiling of maternal cell-free DNA using methylated DNA sequencing (MeD-seq) indicates a placental and immune-cell signature.","authors":"Marjolein M van Vliet, Ruben G Boers, Joachim B Boers, Olivier J M Schäffers, Lotte E van der Meeren, Régine P M Steegers-Theunissen, Joost Gribnau, Sam Schoenmakers","doi":"10.1111/eci.14363","DOIUrl":"https://doi.org/10.1111/eci.14363","url":null,"abstract":"<p><strong>Background: </strong>Placental-originated cell-free DNA (cfDNA) provides unique opportunities to study (epi)genetic placental programming remotely, but studies investigating the cfDNA methylome are scarce and usually technologically challenging. Methylated DNA sequencing (MeD-seq) is well compatible with low cfDNA concentrations and has a high genome-wide coverage. We therefore aim to investigate the feasibility of genome-wide methylation profiling of first trimester maternal cfDNA using MeD-seq, by identifying placental-specific methylation marks in cfDNA.</p><p><strong>Methods: </strong>We collected cfDNA from nonpregnant controls (female n = 6, male n = 12) and pregnant women (n = 10), first trimester placentas (n = 10), and paired preconceptional and first trimester buffy coats (total n = 20). Differentially methylated regions (DMRs) were identified between pregnant and nonpregnant women. We investigated placental-specific markers in maternal cfDNA, including RASSF1 promoter and Y-chromosomal methylation, and studied overlap with placental and buffy coat DNA methylation.</p><p><strong>Results: </strong>We identified 436 DMRs between cfDNA from pregnant and nonpregnant women, which were validated using male cfDNA. RASSF1 promoter methylation was higher in maternal cfDNA (fold change 2.87, unpaired t-test p < .0001). Differential methylation of Y-chromosomal sequences could determine fetal sex. DMRs in maternal cfDNA showed large overlap with DNA methylation of these regions in placentas and buffy coats. Sixteen DMRs in maternal cfDNA were specifically found only in placentas. These novel potential placental-specific DMRs were more prominent than RASSF1.</p><p><strong>Conclusions: </strong>MeD-seq can detect (novel) genome-wide placental DNA methylation marks and determine fetal sex in maternal cfDNA. Our results indicate a placental and immune-cell contribution to the pregnancy-specific cfDNA methylation signature. This study supports future research into maternal cfDNA methylation.</p>","PeriodicalId":12013,"journal":{"name":"European Journal of Clinical Investigation","volume":" ","pages":"e14363"},"PeriodicalIF":4.4,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142727166","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ceramide and phosphatidylcholine lipids-based risk score predicts major cardiovascular outcomes in patients with heart failure.","authors":"Angelika Witoslawska, Jennifer M T A Meessen, Mika Hilvo, Antti Jylhä, Faiez Zannad, Marianna Cerrato, Patrick Rossignol, Deborah Novelli, Kevin Duarte, Giovanni Targher, Roberto Latini, Nicolas Girerd, Reijo Laaksonen","doi":"10.1111/eci.14359","DOIUrl":"https://doi.org/10.1111/eci.14359","url":null,"abstract":"<p><strong>Background: </strong>Ceramide and phosphatidylcholine lipids-based risk score (CERT2) has shown a strong prognostic value in predicting cardiovascular (CV) events in patients with ischemic heart disease. This study aimed to investigate the prognostic value of CERT2 risk score in patients with heart failure (HF).</p><p><strong>Methods: </strong>The current study combines data for 4234 subjects from the COMMANDER-HF trial and 1227 subjects from the GISSI-HF trial, which enrolled patients with a history of HF. The CERT2 risk score was calculated for all the participants as previously described. The primary outcome was CV death, but all-cause death and major adverse CV events (three-point MACE) were analysed as well.</p><p><strong>Results: </strong>After adjustment for established CV risk factors and potential confounders, patients with the highest CERT2 risk category remained at almost three-fold higher risk of CV death (COMMANDER-HF: HR 2.80, 95% CI 2.18-3.60, GISSI-HF: 2.84, 95% CI 1.70-4.74), all-cause death (COMMANDER-HF: HR 2.97, 95% CI 2.36-3.75, GISSI-HF: 2.83, 95% CI 1.83-4.38) and MACE (COMMANDER-HF: HR 2.73, 95% CI 2.20-3.38, GISSI-HF: 2.67, 95% CI 1.67-4.26) compared to those with the lowest CERT2 risk category.</p><p><strong>Conclusions: </strong>The CERT2 risk score is strongly associated with an increased risk of CV death, all-cause death and MACE in patients with HF.</p>","PeriodicalId":12013,"journal":{"name":"European Journal of Clinical Investigation","volume":" ","pages":"e14359"},"PeriodicalIF":4.4,"publicationDate":"2024-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142692738","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"[²²⁵Ac]Ac-PSMA for the treatment of metastatic castration-resistant prostate cancer: A systematic review and meta-analysis.","authors":"Maria Luisa Garo, Petra Petranović Ovčariček, Stefano Fanti, Luca Giovanella","doi":"10.1111/eci.14358","DOIUrl":"https://doi.org/10.1111/eci.14358","url":null,"abstract":"<p><strong>Background: </strong>Approximately 10%-20% of prostate cancers progress to metastatic and castration-resistant forms (mCRPC). Radioligand (RLT) therapy with [¹⁷⁷Lu]Lu-prostate-specific membrane antigen (PSMA) is an approved treatment for metastasized mCRPC. Moreover, Actinium-225 (²²⁵Ac), an alpha-emitter isotope, has also been used to label PSMA and, recently, to treat mCRPC patients with encouraging results. However, robust clinical data on [²²⁵Ac]Ac-PSMA therapy and its comparison with [¹⁷⁷Lu]Lu-PSMA are still limited. Our aim was to evaluate the role of [²²⁵Ac]Ac-PSMA in treating mCRPC and compare it with conventional [¹⁷⁷Lu]Lu-PSMA therapy.</p><p><strong>Methods: </strong>A systematic search was performed in PubMed, Web of Science, Scopus and the Cochrane Register of Controlled Trials from June 2023 to January 2024. This work was conducted in accordance with PRISMA guidelines.</p><p><strong>Results: </strong>After screening and study selection according to PRISMA guidelines, 11 studies were included, 9 of which focused on [²²⁵Ac]Ac-PSMA only and two on tandem therapy ([²²⁵Ac]Ac-PSMA/[¹⁷⁷Lu]Lu-PSMA). Overall, the pooled proportion of PSA decline in patients was .85 (95% CI: .79-.91, p < .001); patients pretreated with [¹⁷⁷Lu]Lu-PSMA achieved a pooled proportion of PSA decline of .90 (95% CI: .82-.97, p < .001). In patients treated with tandem therapy, PSA decline was observed in approximately 90% of them, while PSA response rates above 50% ranged from 53.3% to 65%. Xerostomia was the most frequently reported side effect, along with anaemia, thrombocytopenia and nephrotoxicity.</p><p><strong>Conclusions: </strong>Overall, the main results of our study showed that [²²⁵Ac]Ac-PSMA-617 had a significant therapeutic effect on mCRPC with an acceptable toxicity level. The latter, however, appears greater than with [¹⁷⁷Lu]Lu-PSMA-617. In future studies, an adequate analysis of the incidence of side effects associated with [²²⁵Ac]Ac-PSMA should be performed to evaluate the role of cumulative toxicity of earlier treatments and the higher frailty of heavily pretreated patients.</p>","PeriodicalId":12013,"journal":{"name":"European Journal of Clinical Investigation","volume":" ","pages":"e14358"},"PeriodicalIF":4.4,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142647187","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Machine learning for stroke in heart failure with reduced ejection fraction but without atrial fibrillation: A post-hoc analysis of the WARCEF trial.","authors":"Hironori Ishiguchi, Yang Chen, Bi Huang, Ying Gue, Elon Correa, Shunichi Homma, John L P Thompson, Min Qian, Gregory Y H Lip, Azmil H Abdul-Rahim","doi":"10.1111/eci.14360","DOIUrl":"https://doi.org/10.1111/eci.14360","url":null,"abstract":"<p><strong>Background: </strong>The prediction of ischaemic stroke in patients with heart failure with reduced ejection fraction (HFrEF) but without atrial fibrillation (AF) remains challenging. Our aim was to evaluate the performance of machine learning (ML) in identifying the development of ischaemic stroke in this population.</p><p><strong>Methods: </strong>We performed a post-hoc analysis of the WARCEF trial, only including patients without a history of AF. We evaluated the performance of 9 ML models for identifying incident stroke using metrics including area under the curve (AUC) and decision curve analysis. The importance of each feature used in the model was ranked by SAPley Additive exPlanations (SHAP) values.</p><p><strong>Results: </strong>We included 2213 patients with HFrEF but without AF (mean age 58 ± 11 years; 80% male). Of these, 74 (3.3%) had an ischaemic stroke in sinus rhythm during a mean follow-up of 3.3 ± 1.8 years. Out of the 29 patient-demographics variables, 12 were selected for the ML training. Almost all ML models demonstrated high AUC values, outperforming the CHA₂DS₂-VASc score (AUC: 0.643, 95% confidence interval [CI]: 0.512-0.767). The Support Vector Machine (SVM) and XGBoost models achieved the highest AUCs, with 0.874 (95% CI: 0.769-0.959) and 0.873 (95% CI: 0.783-0.953), respectively. The SVM and LightGBM consistently provided significant net clinical benefits. Key features consistently identified across these models were creatinine clearance (CrCl), blood urea nitrogen (BUN) and warfarin use.</p><p><strong>Conclusions: </strong>Machine-learning models can be useful in identifying incident ischaemic strokes in patients with HFrEF but without AF. CrCl, BUN and warfarin use were the key features.</p>","PeriodicalId":12013,"journal":{"name":"European Journal of Clinical Investigation","volume":" ","pages":"e14360"},"PeriodicalIF":4.4,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142647188","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}