Pub Date : 2024-08-16DOI: 10.1016/j.ebiom.2024.105280
Ryan A A Bellfield, Ivan Olier, Robyn Lotto, Ian Jones, Ellen A Dawson, Guowei Li, Anil M Tuladhar, Gregory Y H Lip, Sandra Ortega-Martorell
Background: Atrial fibrillation (AF) is the most common heart arrhythmia worldwide and is linked to a higher risk of mortality and morbidity. To predict AF and AF-related complications, clinical risk scores are commonly employed, but their predictive accuracy is generally limited, given the inherent complexity and heterogeneity of patients with AF. By classifying different presentations of AF into coherent and manageable clinical phenotypes, the development of tailored prevention and treatment strategies can be facilitated. In this study, we propose an artificial intelligence (AI)-based methodology to derive meaningful clinical phenotypes of AF in the general and critical care populations.
Methods: Our approach employs generative topographic mapping, a probabilistic machine learning method, to identify micro-clusters of patients with similar characteristics. It then identifies macro-cluster regions (clinical phenotypes) in the latent space using Ward's minimum variance method. We applied it to two large cohort databases (UK-Biobank and MIMIC-IV) representing general and critical care populations.
Findings: The proposed methodology showed its ability to derive meaningful clinical phenotypes of AF. Because of its probabilistic foundations, it can enhance the robustness of patient stratification. It also produced interpretable visualisation of complex high-dimensional data, enhancing understanding of the derived phenotypes and their key characteristics. Using our methodology, we identified and characterised clinical phenotypes of AF across diverse patient populations.
Interpretation: Our methodology is robust to noise, can uncover hidden patterns and subgroups, and can elucidate more specific patient profiles, contributing to more robust patient stratification, which could facilitate the tailoring of prevention and treatment programs specific to each phenotype. It can also be applied to other datasets to derive clinically meaningful phenotypes of other conditions.
Funding: This study was funded by the DECIPHER project (LJMU QR-PSF) and the EU project TARGET (10113624).
{"title":"AI-based derivation of atrial fibrillation phenotypes in the general and critical care populations.","authors":"Ryan A A Bellfield, Ivan Olier, Robyn Lotto, Ian Jones, Ellen A Dawson, Guowei Li, Anil M Tuladhar, Gregory Y H Lip, Sandra Ortega-Martorell","doi":"10.1016/j.ebiom.2024.105280","DOIUrl":"https://doi.org/10.1016/j.ebiom.2024.105280","url":null,"abstract":"<p><strong>Background: </strong>Atrial fibrillation (AF) is the most common heart arrhythmia worldwide and is linked to a higher risk of mortality and morbidity. To predict AF and AF-related complications, clinical risk scores are commonly employed, but their predictive accuracy is generally limited, given the inherent complexity and heterogeneity of patients with AF. By classifying different presentations of AF into coherent and manageable clinical phenotypes, the development of tailored prevention and treatment strategies can be facilitated. In this study, we propose an artificial intelligence (AI)-based methodology to derive meaningful clinical phenotypes of AF in the general and critical care populations.</p><p><strong>Methods: </strong>Our approach employs generative topographic mapping, a probabilistic machine learning method, to identify micro-clusters of patients with similar characteristics. It then identifies macro-cluster regions (clinical phenotypes) in the latent space using Ward's minimum variance method. We applied it to two large cohort databases (UK-Biobank and MIMIC-IV) representing general and critical care populations.</p><p><strong>Findings: </strong>The proposed methodology showed its ability to derive meaningful clinical phenotypes of AF. Because of its probabilistic foundations, it can enhance the robustness of patient stratification. It also produced interpretable visualisation of complex high-dimensional data, enhancing understanding of the derived phenotypes and their key characteristics. Using our methodology, we identified and characterised clinical phenotypes of AF across diverse patient populations.</p><p><strong>Interpretation: </strong>Our methodology is robust to noise, can uncover hidden patterns and subgroups, and can elucidate more specific patient profiles, contributing to more robust patient stratification, which could facilitate the tailoring of prevention and treatment programs specific to each phenotype. It can also be applied to other datasets to derive clinically meaningful phenotypes of other conditions.</p><p><strong>Funding: </strong>This study was funded by the DECIPHER project (LJMU QR-PSF) and the EU project TARGET (10113624).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141995493","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-14DOI: 10.1016/j.ebiom.2024.105293
Svenja Adam, Sanne L Maas, Rosanna Huchzermeier, Leonida Rakateli, Kathrin Abschlag, Mathias Hohl, Liangliang Liao, Matthias Bartneck, Margee Teunissen, Kristiaan Wouters, Donato Santovito, Joachim Jankowski, Erik A L Biessen, Emiel P C van der Vorst
Background: Female mice are more resistant to obesogenic effects of a high-fat diet (HFD), compared to male mice. Although the underlying mechanisms are poorly understood, sex hormones seem to play an important role. Interestingly, the activity of the oestrogen receptor-α (ERα) is affected by the calcium-sensing-receptor (CaSR). Therefore, we investigated sex-differences upon diet-induced obesity and the role of adipocyte-specific CaSR herein.
Methods: Adipocyte-specific Casr deficient mice (AdipoqCre+Casrflox) and control mice (Casrflox) were injected with AAV8-PCSK9 to make them prone to develop atherosclerosis and fed an obesity-inducing diet for 12 weeks.
Findings: Female mice have lower visceral white adipose tissue (vWAT) mass compared to male mice, while this sex-difference is abolished upon adipocyte-specific Casr deficiency. Furthermore, while females showed elevated levels of inflammatory cytokines and CD3+CD8+ T cell accumulation in vWAT, compared to males, adipocyte-specific Casr deficiency abrogated this sex-phenotype and demonstrated an inhibition of inflammatory signalling pathways. The expression of Erα, as well as associated genes involved in adipocyte differentiation, was increased in female mice in a mostly adipocyte-specific Casr dependent manner. Interestingly, circulating lipid levels were reduced in female compared to male mice, which correlated with decreased atherosclerotic plaque formation. These systemic effects were abrogated upon adipocyte-specific Casr deficiency.
Interpretation: Our findings indicate that female mice show a more pronounced vWAT dysfunction compared to males upon obesity. This sex effect is abolished upon adipocyte-specific Casr deficiency. In contrast, females show diminished atherosclerotic plaque formation compared to males, an effect that was abrogated by adipocyte-specific Casr deficiency.
Funding: This work was supported by a grant from the Interdisciplinary Center for Clinical Research within the faculty of Medicine at the RWTH Aachen University, by the Corona Foundation, by the Deutsche Forschungsgemeinschaft (DFG), the BMBF and Free State of Bavaria and the DZHK.
{"title":"The calcium-sensing-receptor (CaSR) in adipocytes contributes to sex-differences in the susceptibility to high fat diet induced obesity and atherosclerosis.","authors":"Svenja Adam, Sanne L Maas, Rosanna Huchzermeier, Leonida Rakateli, Kathrin Abschlag, Mathias Hohl, Liangliang Liao, Matthias Bartneck, Margee Teunissen, Kristiaan Wouters, Donato Santovito, Joachim Jankowski, Erik A L Biessen, Emiel P C van der Vorst","doi":"10.1016/j.ebiom.2024.105293","DOIUrl":"10.1016/j.ebiom.2024.105293","url":null,"abstract":"<p><strong>Background: </strong>Female mice are more resistant to obesogenic effects of a high-fat diet (HFD), compared to male mice. Although the underlying mechanisms are poorly understood, sex hormones seem to play an important role. Interestingly, the activity of the oestrogen receptor-α (ERα) is affected by the calcium-sensing-receptor (CaSR). Therefore, we investigated sex-differences upon diet-induced obesity and the role of adipocyte-specific CaSR herein.</p><p><strong>Methods: </strong>Adipocyte-specific Casr deficient mice (AdipoqCre<sup>+</sup>Casr<sup>flox</sup>) and control mice (Casr<sup>flox</sup>) were injected with AAV8-PCSK9 to make them prone to develop atherosclerosis and fed an obesity-inducing diet for 12 weeks.</p><p><strong>Findings: </strong>Female mice have lower visceral white adipose tissue (vWAT) mass compared to male mice, while this sex-difference is abolished upon adipocyte-specific Casr deficiency. Furthermore, while females showed elevated levels of inflammatory cytokines and CD3<sup>+</sup>CD8<sup>+</sup> T cell accumulation in vWAT, compared to males, adipocyte-specific Casr deficiency abrogated this sex-phenotype and demonstrated an inhibition of inflammatory signalling pathways. The expression of Erα, as well as associated genes involved in adipocyte differentiation, was increased in female mice in a mostly adipocyte-specific Casr dependent manner. Interestingly, circulating lipid levels were reduced in female compared to male mice, which correlated with decreased atherosclerotic plaque formation. These systemic effects were abrogated upon adipocyte-specific Casr deficiency.</p><p><strong>Interpretation: </strong>Our findings indicate that female mice show a more pronounced vWAT dysfunction compared to males upon obesity. This sex effect is abolished upon adipocyte-specific Casr deficiency. In contrast, females show diminished atherosclerotic plaque formation compared to males, an effect that was abrogated by adipocyte-specific Casr deficiency.</p><p><strong>Funding: </strong>This work was supported by a grant from the Interdisciplinary Center for Clinical Research within the faculty of Medicine at the RWTH Aachen University, by the Corona Foundation, by the Deutsche Forschungsgemeinschaft (DFG), the BMBF and Free State of Bavaria and the DZHK.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11379552/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141987696","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-14DOI: 10.1016/j.ebiom.2024.105273
Jonathan Daniel Ip, Wing-Ming Chu, Wan-Mui Chan, Allen Wing-Ho Chu, Rhoda Cheuk-Ying Leung, Qi Peng, Anthony Raymond Tam, Brian Pui-Chun Chan, Jian-Piao Cai, Kwok-Yung Yuen, Kin-Hang Kok, Yi Shi, Ivan Fan-Ngai Hung, Kelvin Kai-Wang To
Background: De novo amino acid substitutions (DNS) frequently emerge among immunocompromised patients with chronic SARS-CoV-2 infection. While previous studies have reported these DNS, their significance has not been systematically studied.
Methods: We performed a review of DNS that emerged during chronic SARS-CoV-2 infection. We searched PubMed until June 2023 using the keywords "(SARS-CoV-2 or COVID-19) and (mutation or sequencing) and ((prolonged infection) or (chronic infection) or (long term))". We included patients with chronic SARS-CoV-2 infection who had SARS-CoV-2 sequencing performed for at least 3 time points over at least 60 days. We also included 4 additional SARS-CoV-2 patients with chronic infection of our hospital not reported previously. We determined recurrent DNS that has appeared in multiple patients and determined the significance of these mutations among epidemiologically-significant variants.
Findings: A total of 34 cases were analyzed, including 30 that were published previously and 4 from our hospital. Twenty two DNS appeared in ≥3 patients, with 14 (64%) belonging to lineage-defining mutations (LDMs) of epidemiologically-significant variants and 10 (45%) emerging among chronically-infected patients before the appearance of the corresponding variant. Notably, nsp9-T35I substitution (Orf1a T4175I) emerged in all three patients with BA.2.2 infection in 2022 before the appearance of Variants of Interest that carry nsp9-T35I as LDM (EG.5 and BA.2.86/JN.1). Structural analysis suggests that nsp9-T35I substitution may affect nsp9-nsp12 interaction, which could be critical for the function of the replication and transcription complex.
Interpretation: DNS that emerges recurrently in different chronically-infected patients may be used as a marker for potential epidemiologically-significant variants.
Funding: Theme-Based Research Scheme [T11/709/21-N] of the Research Grants Council (See acknowledgements for full list).
{"title":"The significance of recurrent de novo amino acid substitutions that emerged during chronic SARS-CoV-2 infection: an observational study.","authors":"Jonathan Daniel Ip, Wing-Ming Chu, Wan-Mui Chan, Allen Wing-Ho Chu, Rhoda Cheuk-Ying Leung, Qi Peng, Anthony Raymond Tam, Brian Pui-Chun Chan, Jian-Piao Cai, Kwok-Yung Yuen, Kin-Hang Kok, Yi Shi, Ivan Fan-Ngai Hung, Kelvin Kai-Wang To","doi":"10.1016/j.ebiom.2024.105273","DOIUrl":"10.1016/j.ebiom.2024.105273","url":null,"abstract":"<p><strong>Background: </strong>De novo amino acid substitutions (DNS) frequently emerge among immunocompromised patients with chronic SARS-CoV-2 infection. While previous studies have reported these DNS, their significance has not been systematically studied.</p><p><strong>Methods: </strong>We performed a review of DNS that emerged during chronic SARS-CoV-2 infection. We searched PubMed until June 2023 using the keywords \"(SARS-CoV-2 or COVID-19) and (mutation or sequencing) and ((prolonged infection) or (chronic infection) or (long term))\". We included patients with chronic SARS-CoV-2 infection who had SARS-CoV-2 sequencing performed for at least 3 time points over at least 60 days. We also included 4 additional SARS-CoV-2 patients with chronic infection of our hospital not reported previously. We determined recurrent DNS that has appeared in multiple patients and determined the significance of these mutations among epidemiologically-significant variants.</p><p><strong>Findings: </strong>A total of 34 cases were analyzed, including 30 that were published previously and 4 from our hospital. Twenty two DNS appeared in ≥3 patients, with 14 (64%) belonging to lineage-defining mutations (LDMs) of epidemiologically-significant variants and 10 (45%) emerging among chronically-infected patients before the appearance of the corresponding variant. Notably, nsp9-T35I substitution (Orf1a T4175I) emerged in all three patients with BA.2.2 infection in 2022 before the appearance of Variants of Interest that carry nsp9-T35I as LDM (EG.5 and BA.2.86/JN.1). Structural analysis suggests that nsp9-T35I substitution may affect nsp9-nsp12 interaction, which could be critical for the function of the replication and transcription complex.</p><p><strong>Interpretation: </strong>DNS that emerges recurrently in different chronically-infected patients may be used as a marker for potential epidemiologically-significant variants.</p><p><strong>Funding: </strong>Theme-Based Research Scheme [T11/709/21-N] of the Research Grants Council (See acknowledgements for full list).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11379563/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141987655","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-13DOI: 10.1016/j.ebiom.2024.105283
Alison N McRae, Alexander L Ticho, Yuanhang Liu, Maria Laura Ricardo-Silgado, Nothando N Mangena, Fauzi Feris Jassir, Daniel Gonzalez-Izundegui, Gerardo Calderon, Fariborz Rakhshan Rohakhtar, Vernadette Simon, Ying Li, Cadman Leggett, Daniela Hurtado, Nicholas LaRusso, Andres J Acosta
Background: Gut L-type enteroendocrine cells (EECs) are intestinal chemosensory cells that secrete satiety hormones GLP-1 and PYY in response to activation of G-protein coupled receptors (GPCRs) by luminal components of nutrient digestion and microbial fermentation. Regulator of G-protein Signaling (RGS) proteins are negative regulators of GPCR signaling. The expression profile of RGS in EECs, and their potential role in satiety hormone secretion and obesity is unknown.
Methods: Transcriptomic profiling of RGS was completed in native colonic EECs was completed using single-cell RNA sequencing (scRNA-Seq) in lean and obesity, and human jejunal EECs with data obtained from a publicly available RNAseq dataset (GSE114853). RGS validation studies were completed using whole mucosal intestinal tissue obtained during endoscopy in 61 patients (n = 42 OB, n = 19 Lean); a subset of patients' postprandial plasma was assayed for GLP-1 and PYY. Ex vivo human intestinal cultures and in vitro NCI-H716 cells overexpressing RGS9 were exposed to GLP-1 secretagogues in conjunction with a nonselective RGS-inhibitor and assayed for GLP-1 secretion.
Findings: Transcriptomic profiling of colonic and jejunal enteroendocrine cells revealed a unique RGS expression profile in EECs, and further within GLP-1+ L-type EECs. In obesity the RGS expression profile was altered in colonic EECs. Human gut RGS9 expression correlated positively with BMI and negatively with postprandial GLP-1 and PYY. RGS inhibition in human intestinal cultures increased GLP-1 release from EECs ex vivo. NCI-H716 cells overexpressing RGS9 displayed defective nutrient-stimulated GLP-1 secretion.
Interpretation: This study introduces the expression profile of RGS in human EECs, alterations in obesity, and suggests a role for RGS proteins as modulators of GLP-1 and PYY secretion from intestinal EECs.
Funding: AA is supported by the NIH(C-Sig P30DK84567, K23 DK114460), a Pilot Award from the Mayo Clinic Center for Biomedical Discovery, and a Translational Product Development Fund from The Mayo Clinic Center for Clinical and Translational Science Office of Translational Practice in partnership with the University of Minnesota Clinical and Translational Science Institute.
背景:肠道 L 型肠内分泌细胞(EECs)是肠道化学感觉细胞,能分泌饱腹感激素 GLP-1 和 PYY,以响应营养物质消化和微生物发酵过程中腔内成分对 G 蛋白偶联受体(GPCRs)的激活。G 蛋白信号调节蛋白(RGS)是 GPCR 信号的负调节因子。RGS在肠道细胞中的表达谱及其在饱腹感激素分泌和肥胖中的潜在作用尚不清楚:方法:利用单细胞 RNA 测序(scRNA-Seq)技术完成了原生结肠 EECs 中 RGS 的转录组图谱分析,这些 RGS 蛋白来自于公开可用的 RNAseq 数据集(GSE114853)。利用在内窥镜检查中获得的 61 名患者(n = 42 名 OB,n = 19 名 Lean)的全粘膜肠组织完成了 RGS 验证研究;对患者餐后血浆的子集进行了 GLP-1 和 PYY 检测。体外人体肠道培养物和体外过表达 RGS9 的 NCI-H716 细胞暴露于 GLP-1 促泌剂和非选择性 RGS 抑制剂,并检测 GLP-1 分泌情况:结肠和空肠肠内分泌细胞的转录组分析显示,肠内分泌细胞有独特的 RGS 表达谱,而且在 GLP-1+ L 型肠内分泌细胞中表达更多。肥胖症患者结肠肠内分泌细胞中的 RGS 表达谱发生了改变。人体肠道 RGS9 表达与体重指数呈正相关,与餐后 GLP-1 和PYY 呈负相关。在人体肠道培养物中抑制 RGS 可增加体内外肠外胚层释放 GLP-1。过表达 RGS9 的 NCI-H716 细胞显示出营养素刺激的 GLP-1 分泌缺陷:这项研究介绍了 RGS 在人类肠外胚层细胞中的表达概况、肥胖症中的变化,并提出了 RGS 蛋白作为肠外胚层细胞 GLP-1 和 PYY 分泌调节剂的作用:AA得到了美国国立卫生研究院(C-Sig P30DK84567, K23 DK114460)、梅奥诊所生物医学发现中心(Mayo Clinic Center for Biomedical Discovery)和梅奥诊所临床与转化科学中心转化实践办公室(Mayo Clinic Center for Clinical and Translational Science Office of Translational Practice)与明尼苏达大学临床与转化科学研究所(University of Minnesota Clinical and Translational Science Institute)合作提供的转化产品开发基金(Translational Product Development Fund)的支持。
{"title":"Regulator of G-protein signaling expression in human intestinal enteroendocrine cells and potential role in satiety hormone secretion in health and obesity.","authors":"Alison N McRae, Alexander L Ticho, Yuanhang Liu, Maria Laura Ricardo-Silgado, Nothando N Mangena, Fauzi Feris Jassir, Daniel Gonzalez-Izundegui, Gerardo Calderon, Fariborz Rakhshan Rohakhtar, Vernadette Simon, Ying Li, Cadman Leggett, Daniela Hurtado, Nicholas LaRusso, Andres J Acosta","doi":"10.1016/j.ebiom.2024.105283","DOIUrl":"10.1016/j.ebiom.2024.105283","url":null,"abstract":"<p><strong>Background: </strong>Gut L-type enteroendocrine cells (EECs) are intestinal chemosensory cells that secrete satiety hormones GLP-1 and PYY in response to activation of G-protein coupled receptors (GPCRs) by luminal components of nutrient digestion and microbial fermentation. Regulator of G-protein Signaling (RGS) proteins are negative regulators of GPCR signaling. The expression profile of RGS in EECs, and their potential role in satiety hormone secretion and obesity is unknown.</p><p><strong>Methods: </strong>Transcriptomic profiling of RGS was completed in native colonic EECs was completed using single-cell RNA sequencing (scRNA-Seq) in lean and obesity, and human jejunal EECs with data obtained from a publicly available RNAseq dataset (GSE114853). RGS validation studies were completed using whole mucosal intestinal tissue obtained during endoscopy in 61 patients (n = 42 OB, n = 19 Lean); a subset of patients' postprandial plasma was assayed for GLP-1 and PYY. Ex vivo human intestinal cultures and in vitro NCI-H716 cells overexpressing RGS9 were exposed to GLP-1 secretagogues in conjunction with a nonselective RGS-inhibitor and assayed for GLP-1 secretion.</p><p><strong>Findings: </strong>Transcriptomic profiling of colonic and jejunal enteroendocrine cells revealed a unique RGS expression profile in EECs, and further within GLP-1+ L-type EECs. In obesity the RGS expression profile was altered in colonic EECs. Human gut RGS9 expression correlated positively with BMI and negatively with postprandial GLP-1 and PYY. RGS inhibition in human intestinal cultures increased GLP-1 release from EECs ex vivo. NCI-H716 cells overexpressing RGS9 displayed defective nutrient-stimulated GLP-1 secretion.</p><p><strong>Interpretation: </strong>This study introduces the expression profile of RGS in human EECs, alterations in obesity, and suggests a role for RGS proteins as modulators of GLP-1 and PYY secretion from intestinal EECs.</p><p><strong>Funding: </strong>AA is supported by the NIH(C-Sig P30DK84567, K23 DK114460), a Pilot Award from the Mayo Clinic Center for Biomedical Discovery, and a Translational Product Development Fund from The Mayo Clinic Center for Clinical and Translational Science Office of Translational Practice in partnership with the University of Minnesota Clinical and Translational Science Institute.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11367526/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141981905","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-13DOI: 10.1016/j.ebiom.2024.105281
Ling Xu, Dandan Yu, Min Xu, Yamin Liu, Lu-Xiu Yang, Qing-Cui Zou, Xiao-Li Feng, Ming-Hua Li, Nengyin Sheng, Yong-Gang Yao
Background: Coronavirus disease 2019 (COVID-19) is an immune-related disorder caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The complete pathogenesis of the virus remains to be determined. Unraveling the molecular mechanisms governing SARS-CoV-2 interactions with host cells is crucial for the formulation of effective prophylactic measures and the advancement of COVID-19 therapeutics.
Methods: We analyzed human lung single-cell RNA sequencing dataset to discern the association of butyrophilin subfamily 3 member A2 (BTN3A2) expression with COVID-19. The BTN3A2 gene edited cell lines and transgenic mice were infected by live SARS-CoV-2 in a biosafety level 3 (BSL-3) laboratory. Immunoprecipitation, flow cytometry, biolayer interferometry and competition ELISA assays were performed in BTN3A2 gene edited cells. We performed quantitative real-time PCR, histological and/or immunohistochemical analyses for tissue samples from mice with or without SARS-CoV-2 infection.
Findings: The BTN3A2 mRNA level was correlated with COVID-19 severity. BTN3A2 expression was predominantly identified in epithelial cells, elevated in pathological epithelial cells from COVID-19 patients and co-occurred with ACE2 expression in the same lung cell subtypes. BTN3A2 targeted the early stage of the viral life cycle by inhibiting SARS-CoV-2 attachment through interactions with the receptor-binding domain (RBD) of the Spike protein and ACE2. BTN3A2 inhibited ACE2-mediated SARS-CoV-2 infection by reducing ACE2 in vitro and in vivo.
Interpretation: These results reveal a key role of BTN3A2 in the fight against COVID-19. Identifying potential monoclonal antibodies which mimic BTN3A2 may facilitate disruption of SARS-CoV-2 infection, providing a therapeutic avenue for COVID-19.
Funding: This study was supported by the National Natural Science Foundation of China (32070569, U1902215, and 32371017), the CAS "Light of West China" Program, and Yunnan Province (202305AH340006).
{"title":"Primate-specific BTN3A2 protects against SARS-CoV-2 infection by interacting with and reducing ACE2.","authors":"Ling Xu, Dandan Yu, Min Xu, Yamin Liu, Lu-Xiu Yang, Qing-Cui Zou, Xiao-Li Feng, Ming-Hua Li, Nengyin Sheng, Yong-Gang Yao","doi":"10.1016/j.ebiom.2024.105281","DOIUrl":"10.1016/j.ebiom.2024.105281","url":null,"abstract":"<p><strong>Background: </strong>Coronavirus disease 2019 (COVID-19) is an immune-related disorder caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The complete pathogenesis of the virus remains to be determined. Unraveling the molecular mechanisms governing SARS-CoV-2 interactions with host cells is crucial for the formulation of effective prophylactic measures and the advancement of COVID-19 therapeutics.</p><p><strong>Methods: </strong>We analyzed human lung single-cell RNA sequencing dataset to discern the association of butyrophilin subfamily 3 member A2 (BTN3A2) expression with COVID-19. The BTN3A2 gene edited cell lines and transgenic mice were infected by live SARS-CoV-2 in a biosafety level 3 (BSL-3) laboratory. Immunoprecipitation, flow cytometry, biolayer interferometry and competition ELISA assays were performed in BTN3A2 gene edited cells. We performed quantitative real-time PCR, histological and/or immunohistochemical analyses for tissue samples from mice with or without SARS-CoV-2 infection.</p><p><strong>Findings: </strong>The BTN3A2 mRNA level was correlated with COVID-19 severity. BTN3A2 expression was predominantly identified in epithelial cells, elevated in pathological epithelial cells from COVID-19 patients and co-occurred with ACE2 expression in the same lung cell subtypes. BTN3A2 targeted the early stage of the viral life cycle by inhibiting SARS-CoV-2 attachment through interactions with the receptor-binding domain (RBD) of the Spike protein and ACE2. BTN3A2 inhibited ACE2-mediated SARS-CoV-2 infection by reducing ACE2 in vitro and in vivo.</p><p><strong>Interpretation: </strong>These results reveal a key role of BTN3A2 in the fight against COVID-19. Identifying potential monoclonal antibodies which mimic BTN3A2 may facilitate disruption of SARS-CoV-2 infection, providing a therapeutic avenue for COVID-19.</p><p><strong>Funding: </strong>This study was supported by the National Natural Science Foundation of China (32070569, U1902215, and 32371017), the CAS \"Light of West China\" Program, and Yunnan Province (202305AH340006).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11367481/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141981904","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background: Short-term exposure to particulate matter air pollution has been associated with the exacerbations of COPD, but its association with COPD mortality was not fully elucidated. We aimed to assess the association between short-term particulate matter exposure and the risk of COPD mortality in China using individual-level data.
Methods: We derived 2.26 million COPD deaths from a national death registry database in Chinese mainland between 2013 and 2019. Exposures to fine particulate matter (PM2.5) and coarse particulate matter (PM2.5-10) were assessed by satellite-based models of a 1 × 1 km resolution and assigned to each individual based on residential address. The associations of PM2.5 and PM2.5-10 with COPD mortality were examined using a time-stratified case-crossover design and conditional logistic regressions with distributed lag models. We further conducted stratified analyses by age, sex, education level, and season.
Findings: Short-term exposures to both PM2.5 and PM2.5-10 were associated with increased risks of COPD mortality. These associations appeared and peaked on the concurrent day, attenuated and became nonsignificant after 5 or 7 days, respectively. The exposure-response curves were approximately linear without discernible thresholds. An interquartile range increase in PM2.5 and PM2.5-10 concentrations was associated with 4.23% (95% CI: 3.75%, 4.72%) and 2.67% (95% CI: 2.18%, 3.16%) higher risks of COPD mortality over lag 0-7 d, respectively. The associations of PM2.5 and PM2.5-10 attenuated slightly but were still significant in the mutual-adjustment models. A larger association of PM2.5-10 was observed in the warm season.
Interpretation: This individual-level, nationwide, case-crossover study suggests that short-term exposure to PM2.5 and PM2.5-10 might act as one of the environmental risk factors for COPD mortality.
Funding: This study is supported by the National Key Research and Development Program of China (2023YFC3708304 and 2022YFC3702701), the National Natural Science Foundation of China (82304090 and 82030103), the 3-year Action Plan for Strengthening the Construction of the Public Health System in Shanghai (GWVI-11.2-YQ31), and the Science and Technology Commission of Shanghai Municipality (21TQ015).
{"title":"Ambient particulate matter and chronic obstructive pulmonary disease mortality: a nationwide, individual-level, case-crossover study in China.","authors":"Shuo Jiang, Xunliang Tong, Kexin Yu, Peng Yin, Su Shi, Xia Meng, Renjie Chen, Maigeng Zhou, Haidong Kan, Yue Niu, Yanming Li","doi":"10.1016/j.ebiom.2024.105270","DOIUrl":"10.1016/j.ebiom.2024.105270","url":null,"abstract":"<p><strong>Background: </strong>Short-term exposure to particulate matter air pollution has been associated with the exacerbations of COPD, but its association with COPD mortality was not fully elucidated. We aimed to assess the association between short-term particulate matter exposure and the risk of COPD mortality in China using individual-level data.</p><p><strong>Methods: </strong>We derived 2.26 million COPD deaths from a national death registry database in Chinese mainland between 2013 and 2019. Exposures to fine particulate matter (PM<sub>2.5</sub>) and coarse particulate matter (PM<sub>2.5-10</sub>) were assessed by satellite-based models of a 1 × 1 km resolution and assigned to each individual based on residential address. The associations of PM<sub>2.5</sub> and PM<sub>2.5-10</sub> with COPD mortality were examined using a time-stratified case-crossover design and conditional logistic regressions with distributed lag models. We further conducted stratified analyses by age, sex, education level, and season.</p><p><strong>Findings: </strong>Short-term exposures to both PM<sub>2.5</sub> and PM<sub>2.5-10</sub> were associated with increased risks of COPD mortality. These associations appeared and peaked on the concurrent day, attenuated and became nonsignificant after 5 or 7 days, respectively. The exposure-response curves were approximately linear without discernible thresholds. An interquartile range increase in PM<sub>2.5</sub> and PM<sub>2.5-10</sub> concentrations was associated with 4.23% (95% CI: 3.75%, 4.72%) and 2.67% (95% CI: 2.18%, 3.16%) higher risks of COPD mortality over lag 0-7 d, respectively. The associations of PM<sub>2.5</sub> and PM<sub>2.5-10</sub> attenuated slightly but were still significant in the mutual-adjustment models. A larger association of PM<sub>2.5-10</sub> was observed in the warm season.</p><p><strong>Interpretation: </strong>This individual-level, nationwide, case-crossover study suggests that short-term exposure to PM<sub>2.5</sub> and PM<sub>2.5-10</sub> might act as one of the environmental risk factors for COPD mortality.</p><p><strong>Funding: </strong>This study is supported by the National Key Research and Development Program of China (2023YFC3708304 and 2022YFC3702701), the National Natural Science Foundation of China (82304090 and 82030103), the 3-year Action Plan for Strengthening the Construction of the Public Health System in Shanghai (GWVI-11.2-YQ31), and the Science and Technology Commission of Shanghai Municipality (21TQ015).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11367568/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141975347","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-12DOI: 10.1016/j.ebiom.2024.105278
Núria Vázquez-Bellón, Neus Martínez-Bosch, Pablo García de Frutos, Pilar Navarro
Pancreatic ductal adenocarcinoma (PDAC) represents the most prevalent type of pancreatic cancer and ranks among the most aggressive tumours, with a 5-year survival rate of less than 11%. Projections indicate that by 2030, it will become the second leading cause of cancer-related deaths. PDAC presents distinctive hallmarks contributing to its dismal prognosis: (i) late diagnosis, (ii) heterogenous and complex mutational landscape, (iii) high metastatic potential, (iv) dense fibrotic stroma, (v) immunosuppressive microenvironment, and (vi) high resistance to therapy. Mounting evidence has shown a role for TAM (Tyro3, AXL, MerTK) family of tyrosine kinase receptors in PDAC initiation and progression. This review aims to describe the impact of TAM receptors on the defining hallmarks of PDAC and discuss potential future directions using these proteins as novel biomarkers for early diagnosis and targets for precision therapy in PDAC, an urgent unmet clinical need.
{"title":"Hallmarks of pancreatic cancer: spotlight on TAM receptors.","authors":"Núria Vázquez-Bellón, Neus Martínez-Bosch, Pablo García de Frutos, Pilar Navarro","doi":"10.1016/j.ebiom.2024.105278","DOIUrl":"10.1016/j.ebiom.2024.105278","url":null,"abstract":"<p><p>Pancreatic ductal adenocarcinoma (PDAC) represents the most prevalent type of pancreatic cancer and ranks among the most aggressive tumours, with a 5-year survival rate of less than 11%. Projections indicate that by 2030, it will become the second leading cause of cancer-related deaths. PDAC presents distinctive hallmarks contributing to its dismal prognosis: (i) late diagnosis, (ii) heterogenous and complex mutational landscape, (iii) high metastatic potential, (iv) dense fibrotic stroma, (v) immunosuppressive microenvironment, and (vi) high resistance to therapy. Mounting evidence has shown a role for TAM (Tyro3, AXL, MerTK) family of tyrosine kinase receptors in PDAC initiation and progression. This review aims to describe the impact of TAM receptors on the defining hallmarks of PDAC and discuss potential future directions using these proteins as novel biomarkers for early diagnosis and targets for precision therapy in PDAC, an urgent unmet clinical need.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11367522/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141975376","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-12DOI: 10.1016/j.ebiom.2024.105275
Xuan Ying Poh, I Russel Lee, Chee Wah Tan, Jean-Marc Chavatte, Siew Wai Fong, Yun Shan Goh, Angeline Rouers, Nathan Wong, Anthony Torres-Ruesta, Shirley Y Y Mah, Aileen Y Y Yeoh, Mihir Gandhi, Nabilah Rahman, Yi Qing Chin, J Jonathan Lim, Terence J K Yoong, Suma Rao, Po Ying Chia, Sean W X Ong, Tau Hong Lee, Sapna P Sadarangani, Ray J H Lin, Daniel R X Lim, Wanni Chia, Laurent Renia, Ee Chee Ren, Raymond T P Lin, David C Lye, Lin-Fa Wang, Lisa F P Ng, Barnaby E Young
Background: Understanding how SARS-CoV-2 breakthrough infections impacts the breadth of immune responses against existing and pre-emergent SARS-CoV-2 strains is needed to develop an evidence-based long-term immunisation strategy.
Methods: We performed a randomised, controlled trial to assess the immunogenicity of homologous (BNT162b2) versus heterologous (mRNA-1273) booster vaccination in 100 BNT162b2-vaccinated infection-naïve individuals enrolled from October 2021. Post hoc analysis was performed to assess the impact of SARS-CoV-2 infection on humoral and cellular immune responses against wild-type SARS-CoV-2 and/or Omicron subvariants.
Findings: 93 participants completed the study at day 360. 71% (66/93) of participants reported first SARS-CoV-2 Omicron infection by the end of the study with similar proportions of infections between homologous and heterologous booster groups (72.3% [34/47] vs 69.6% [32/46]; p = 0.82). Mean wildtype SARS-CoV-2 anti-S-RBD antibody level was significantly higher in heterologous booster group compared with homologous group at day 180 (14,588 IU/mL; 95% CI, 10,186-20,893 vs 7447 IU/mL; 4646-11,912; p = 0.025). Participants who experienced breakthrough infections during the Omicron BA.1/2 wave had significantly higher anti-S-RBD antibody levels against wildtype SARS-CoV-2 and antibody neutralisation against BA.1 and pre-emergent BA.5 compared with infection-naïve participants. Regardless of hybrid immunity status, wildtype SARS-CoV-2 anti-S-RBD antibody level declined significantly after six months post-booster or post-SARS-CoV-2 infection.
Interpretation: Booster vaccination with mRNA-1273 was associated with significantly higher antibody levels compared with BNT162b2. Antibody responses are narrower and decline faster among uninfected, vaccinated individuals. Boosters may be more effective if administered shortly before infection outbreaks and at least six months after last infection or booster.
{"title":"First SARS-CoV-2 Omicron infection as an effective immune booster among mRNA vaccinated individuals: final results from the first phase of the PRIBIVAC randomised clinical trial.","authors":"Xuan Ying Poh, I Russel Lee, Chee Wah Tan, Jean-Marc Chavatte, Siew Wai Fong, Yun Shan Goh, Angeline Rouers, Nathan Wong, Anthony Torres-Ruesta, Shirley Y Y Mah, Aileen Y Y Yeoh, Mihir Gandhi, Nabilah Rahman, Yi Qing Chin, J Jonathan Lim, Terence J K Yoong, Suma Rao, Po Ying Chia, Sean W X Ong, Tau Hong Lee, Sapna P Sadarangani, Ray J H Lin, Daniel R X Lim, Wanni Chia, Laurent Renia, Ee Chee Ren, Raymond T P Lin, David C Lye, Lin-Fa Wang, Lisa F P Ng, Barnaby E Young","doi":"10.1016/j.ebiom.2024.105275","DOIUrl":"10.1016/j.ebiom.2024.105275","url":null,"abstract":"<p><strong>Background: </strong>Understanding how SARS-CoV-2 breakthrough infections impacts the breadth of immune responses against existing and pre-emergent SARS-CoV-2 strains is needed to develop an evidence-based long-term immunisation strategy.</p><p><strong>Methods: </strong>We performed a randomised, controlled trial to assess the immunogenicity of homologous (BNT162b2) versus heterologous (mRNA-1273) booster vaccination in 100 BNT162b2-vaccinated infection-naïve individuals enrolled from October 2021. Post hoc analysis was performed to assess the impact of SARS-CoV-2 infection on humoral and cellular immune responses against wild-type SARS-CoV-2 and/or Omicron subvariants.</p><p><strong>Findings: </strong>93 participants completed the study at day 360. 71% (66/93) of participants reported first SARS-CoV-2 Omicron infection by the end of the study with similar proportions of infections between homologous and heterologous booster groups (72.3% [34/47] vs 69.6% [32/46]; p = 0.82). Mean wildtype SARS-CoV-2 anti-S-RBD antibody level was significantly higher in heterologous booster group compared with homologous group at day 180 (14,588 IU/mL; 95% CI, 10,186-20,893 vs 7447 IU/mL; 4646-11,912; p = 0.025). Participants who experienced breakthrough infections during the Omicron BA.1/2 wave had significantly higher anti-S-RBD antibody levels against wildtype SARS-CoV-2 and antibody neutralisation against BA.1 and pre-emergent BA.5 compared with infection-naïve participants. Regardless of hybrid immunity status, wildtype SARS-CoV-2 anti-S-RBD antibody level declined significantly after six months post-booster or post-SARS-CoV-2 infection.</p><p><strong>Interpretation: </strong>Booster vaccination with mRNA-1273 was associated with significantly higher antibody levels compared with BNT162b2. Antibody responses are narrower and decline faster among uninfected, vaccinated individuals. Boosters may be more effective if administered shortly before infection outbreaks and at least six months after last infection or booster.</p><p><strong>Funding: </strong>Singapore NMRC, USFDA, MRC.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11367514/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141975375","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-08DOI: 10.1016/j.ebiom.2024.105264
Anne-Catherine Pouleur, Nassiba Menghoum, Julien Cumps, Alice Marino, Maria Badii, Sibille Lejeune, Julie Thompson Legault, Gabrielle Boucher, Damien Gruson, Clotilde Roy, Sylvain Battault, Louiza Mahrouche, Valérie Pedneault-Gagnon, Daniel Charpentier, Alexandra Furtos, Julie Hussin, David Rhainds, Jean-Claude Tardif, Luc Bertrand, Christine Des Rosiers, Sandrine Horman, Christophe Beauloye
Background: The metabolic environment plays a crucial role in the development of heart failure (HF). Our prior research demonstrated that myo-inositol, a metabolite transported by the sodium-myo-inositol co-transporter 1 (SMIT-1), can induce oxidative stress and may be detrimental to heart function. However, plasmatic myo-inositol concentration has not been comprehensively assessed in large cohorts of patients with heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF).
Methods: Plasmatic myo-inositol levels were measured using mass spectrometry and correlated with clinical characteristics in no HF subjects and patients with HFrEF and HFpEF from Belgian (male, no HF, 53%; HFrEF, 84% and HFpEF, 40%) and Canadian cohorts (male, no HF, 51%; HFrEF, 92% and HFpEF, 62%).
Findings: Myo-inositol levels were significantly elevated in patients with HF, with a more pronounced increase observed in the HFpEF population of both cohorts. After adjusting for age, sex, body mass index, hypertension, diabetes, and atrial fibrillation, we observed that both HFpEF status and impaired kidney function were associated with elevated plasma myo-inositol. Unlike HFrEF, abnormally high myo-inositol (≥69.8 μM) was linked to unfavourable clinical outcomes (hazard ratio, 1.62; 95% confidence interval, [1.05-2.5]) in patients with HFpEF. These elevated levels were correlated with NTproBNP, troponin, and cardiac fibrosis in this subset of patients.
Interpretation: Myo-inositol is a metabolite elevated in patients with HF and strongly correlated to kidney failure. In patients with HFpEF, high myo-inositol levels predict poor clinical outcomes and are linked to markers of cardiac adverse remodelling. This suggests that myo-inositol and its transporter SMIT1 may have a role in the pathophysiology of HFpEF.
Funding: BECAME-HF was supported by Collaborative Bilateral Research Program Québec - Wallonie-Brussels Federation.
{"title":"Plasma myo-inositol elevation in heart failure: clinical implications and prognostic significance. Results from the BElgian and CAnadian MEtabolomics in HFpEF (BECAME-HF) research project.","authors":"Anne-Catherine Pouleur, Nassiba Menghoum, Julien Cumps, Alice Marino, Maria Badii, Sibille Lejeune, Julie Thompson Legault, Gabrielle Boucher, Damien Gruson, Clotilde Roy, Sylvain Battault, Louiza Mahrouche, Valérie Pedneault-Gagnon, Daniel Charpentier, Alexandra Furtos, Julie Hussin, David Rhainds, Jean-Claude Tardif, Luc Bertrand, Christine Des Rosiers, Sandrine Horman, Christophe Beauloye","doi":"10.1016/j.ebiom.2024.105264","DOIUrl":"10.1016/j.ebiom.2024.105264","url":null,"abstract":"<p><strong>Background: </strong>The metabolic environment plays a crucial role in the development of heart failure (HF). Our prior research demonstrated that myo-inositol, a metabolite transported by the sodium-myo-inositol co-transporter 1 (SMIT-1), can induce oxidative stress and may be detrimental to heart function. However, plasmatic myo-inositol concentration has not been comprehensively assessed in large cohorts of patients with heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF).</p><p><strong>Methods: </strong>Plasmatic myo-inositol levels were measured using mass spectrometry and correlated with clinical characteristics in no HF subjects and patients with HFrEF and HFpEF from Belgian (male, no HF, 53%; HFrEF, 84% and HFpEF, 40%) and Canadian cohorts (male, no HF, 51%; HFrEF, 92% and HFpEF, 62%).</p><p><strong>Findings: </strong>Myo-inositol levels were significantly elevated in patients with HF, with a more pronounced increase observed in the HFpEF population of both cohorts. After adjusting for age, sex, body mass index, hypertension, diabetes, and atrial fibrillation, we observed that both HFpEF status and impaired kidney function were associated with elevated plasma myo-inositol. Unlike HFrEF, abnormally high myo-inositol (≥69.8 μM) was linked to unfavourable clinical outcomes (hazard ratio, 1.62; 95% confidence interval, [1.05-2.5]) in patients with HFpEF. These elevated levels were correlated with NTproBNP, troponin, and cardiac fibrosis in this subset of patients.</p><p><strong>Interpretation: </strong>Myo-inositol is a metabolite elevated in patients with HF and strongly correlated to kidney failure. In patients with HFpEF, high myo-inositol levels predict poor clinical outcomes and are linked to markers of cardiac adverse remodelling. This suggests that myo-inositol and its transporter SMIT1 may have a role in the pathophysiology of HFpEF.</p><p><strong>Funding: </strong>BECAME-HF was supported by Collaborative Bilateral Research Program Québec - Wallonie-Brussels Federation.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11363489/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141912225","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}