Milène Freneau, Raphael Blanchet, Maxence Bodet, Sandro Benichi, Mary-Adel Mrad, Surya Prakash Rao Batta, Marc Rio, Stéphanie Bonnaud, Pierre Lindenbaum, Fabien Laporte, Stéphane Cuénot, Thibaud Quillard, Mike Maillasson, Sandrine Morel, Brenda Kwak, Philippe Bijlenga, Jean-François Deleuze, Christian Dina, Stéphanie Chatel, Emmanuelle Bourcereau, Solène Jouan, Arturo Consoli, Cyril Dargazanli, Julien Ognard, Hubert Desal, Anne-Clémence Vion, Romain Bourcier, Gervaise Loirand, Richard Redon
Aims Intracranial aneurysm (IA) is a common cerebrovascular abnormality characterized by localized dilation and wall thinning in cerebral arteries, which can rupture and lead to fatal subarachnoid hemorrhage. Although genetic factors can contribute to IA, the genetic predisposition of IA is largely unknown. This study aims to identify rare functional variants associated with IA in families with multiple affected subjects and explore their impact on IA pathophysiology. Methods and results By combining whole exome sequencing and identity-by-descent analyses, we have identified two rare missense variants in the CTSO gene associated to IA in two large families with multiple affected subjects. We found that the cysteine-type papain-like cathepsin O (CTSO) encoded by CTSO is expressed in the circle of Willis of mice and in the wall of human IA domes. Stretching of vascular smooth muscle cells (VSMC) induced CTSO secretion. CTSO controls VSMC migration and adhesion to the extracellular matrix, and directly interacts with fibronectin (FN). CTSO depletion, or expression of the two CTSO variants, which are poorly secreted, increased the amount of FN. Moreover, CTSO depletion augmented VSMC stiffness, which was reduced by the addition of exogenous CTSO. Conclusion Collectively, our findings identify CTSO as a potential new player in arterial remodeling, regulating FN deposition and VSMC function, supporting the causal role of rare coding CTSO variants in familial forms of IA.
{"title":"Identification of rare missense variants reducing cathepsin O secretion in families with intracranial aneurysm","authors":"Milène Freneau, Raphael Blanchet, Maxence Bodet, Sandro Benichi, Mary-Adel Mrad, Surya Prakash Rao Batta, Marc Rio, Stéphanie Bonnaud, Pierre Lindenbaum, Fabien Laporte, Stéphane Cuénot, Thibaud Quillard, Mike Maillasson, Sandrine Morel, Brenda Kwak, Philippe Bijlenga, Jean-François Deleuze, Christian Dina, Stéphanie Chatel, Emmanuelle Bourcereau, Solène Jouan, Arturo Consoli, Cyril Dargazanli, Julien Ognard, Hubert Desal, Anne-Clémence Vion, Romain Bourcier, Gervaise Loirand, Richard Redon","doi":"10.1093/cvr/cvaf279","DOIUrl":"https://doi.org/10.1093/cvr/cvaf279","url":null,"abstract":"Aims Intracranial aneurysm (IA) is a common cerebrovascular abnormality characterized by localized dilation and wall thinning in cerebral arteries, which can rupture and lead to fatal subarachnoid hemorrhage. Although genetic factors can contribute to IA, the genetic predisposition of IA is largely unknown. This study aims to identify rare functional variants associated with IA in families with multiple affected subjects and explore their impact on IA pathophysiology. Methods and results By combining whole exome sequencing and identity-by-descent analyses, we have identified two rare missense variants in the CTSO gene associated to IA in two large families with multiple affected subjects. We found that the cysteine-type papain-like cathepsin O (CTSO) encoded by CTSO is expressed in the circle of Willis of mice and in the wall of human IA domes. Stretching of vascular smooth muscle cells (VSMC) induced CTSO secretion. CTSO controls VSMC migration and adhesion to the extracellular matrix, and directly interacts with fibronectin (FN). CTSO depletion, or expression of the two CTSO variants, which are poorly secreted, increased the amount of FN. Moreover, CTSO depletion augmented VSMC stiffness, which was reduced by the addition of exogenous CTSO. Conclusion Collectively, our findings identify CTSO as a potential new player in arterial remodeling, regulating FN deposition and VSMC function, supporting the causal role of rare coding CTSO variants in familial forms of IA.","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"43 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145920328","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}
{"title":"Is it the extracellular matrix?-smooth muscle fate in pulmonary hypertension secondary to left heart disease.","authors":"Oleg Pak,Norbert Weissmann","doi":"10.1093/cvr/cvaf261","DOIUrl":"https://doi.org/10.1093/cvr/cvaf261","url":null,"abstract":"","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"123 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145907761","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}
{"title":"Trained immunity links cardiovascular disease and COVID-19.","authors":"Jéssica C Dos Santos,Mihai G Netea,Niels P Riksen","doi":"10.1093/cvr/cvaf278","DOIUrl":"https://doi.org/10.1093/cvr/cvaf278","url":null,"abstract":"","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"42 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145903696","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}
Jaideep Singh, Christopher Peter Stanley, Mary Meltem Kavurma
Mitochondria are essential organelles that generate adenosine triphosphate during oxidative phosphorylation by the electron transport chain. Beyond energy production, mitochondria regulate intracellular calcium homeostasis, generate signalling molecules, modulate metabolic pathways, and control cell survival. Mitochondrial dysfunction is characterised by excessive reactive oxygen species production, loss of membrane potential, calcium leakage, and structural abnormalities, ultimately lead to cell death. In endothelial cells, mitochondrial dysfunction drives endothelial impairment and contributes to cardiovascular diseases. This review explores the mechanisms underlying endothelial mitochondrial dysfunction and examines its role in the development and progression of hypertension, atherosclerosis, and diabetes.
{"title":"Endothelial mitochondrial dysfunction in hypertension, diabetes and atherosclerosis","authors":"Jaideep Singh, Christopher Peter Stanley, Mary Meltem Kavurma","doi":"10.1093/cvr/cvaf282","DOIUrl":"https://doi.org/10.1093/cvr/cvaf282","url":null,"abstract":"Mitochondria are essential organelles that generate adenosine triphosphate during oxidative phosphorylation by the electron transport chain. Beyond energy production, mitochondria regulate intracellular calcium homeostasis, generate signalling molecules, modulate metabolic pathways, and control cell survival. Mitochondrial dysfunction is characterised by excessive reactive oxygen species production, loss of membrane potential, calcium leakage, and structural abnormalities, ultimately lead to cell death. In endothelial cells, mitochondrial dysfunction drives endothelial impairment and contributes to cardiovascular diseases. This review explores the mechanisms underlying endothelial mitochondrial dysfunction and examines its role in the development and progression of hypertension, atherosclerosis, and diabetes.","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"22 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145903701","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}
Cardiac arrest (CA) remains a leading cause of global mortality, largely due to hypoxic-ischaemic brain injury sustained during periods of absent cardiac output. MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression and have demonstrated diagnostic and prognostic potential in neurological and cardiovascular disease. This review assessed the value of miRNAs for predicting six-month neurological outcomes following CA and return of spontaneous circulation (ROSC). Following PRISMA guidelines, PubMed and Cochrane Library searches identified ten clinical studies, comprising four biomarker studies and six post-hoc biomarker analyses from a large randomised controlled trial (RCT). Data on miRNA expression, patient characteristics, predictive accuracy (area under the receiver operating characteristic curve, AUC), and associations with outcome were extracted. Eleven miRNAs were differentially expressed within 72 hours of ROSC; only miR-124-3p (up-regulated at 6 hours) was replicated across studies. Eight studies contributed fifteen AUC values ranging from 0.62 to 0.89. Strong predictors included miR-6511b-5p (6 h, AUC = 0.85), miR-191-5p (48 h, AUC = 0.89), and miR-124 (48 h, AUC = 0.89). Four studies report associations between altered miRNA expression and unfavourable neurological outcomes, whilst one identified miR-122-5p as a positive prognostic biomarker. To conclude, miRNAs demonstrate distinct expression profiles following CA and ROSC, with several showing clinically useful prediction accuracy for six-month neurological outcomes. Larger, unbiased studies using standardised methodologies are required to validate these findings and clarify confounding factors. Despite the current evidence limitations, this data supports further investigation of circulating miRNAs as neuro-prognostic biomarkers after cardiac arrest.
{"title":"MicroRNAs as neuro-prognostic biomarkers after cardiac arrest: a systematic review.","authors":"Jack Mellon, Maria Bahilo-Martinez","doi":"10.1093/cvr/cvaf283","DOIUrl":"https://doi.org/10.1093/cvr/cvaf283","url":null,"abstract":"<p><p>Cardiac arrest (CA) remains a leading cause of global mortality, largely due to hypoxic-ischaemic brain injury sustained during periods of absent cardiac output. MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression and have demonstrated diagnostic and prognostic potential in neurological and cardiovascular disease. This review assessed the value of miRNAs for predicting six-month neurological outcomes following CA and return of spontaneous circulation (ROSC). Following PRISMA guidelines, PubMed and Cochrane Library searches identified ten clinical studies, comprising four biomarker studies and six post-hoc biomarker analyses from a large randomised controlled trial (RCT). Data on miRNA expression, patient characteristics, predictive accuracy (area under the receiver operating characteristic curve, AUC), and associations with outcome were extracted. Eleven miRNAs were differentially expressed within 72 hours of ROSC; only miR-124-3p (up-regulated at 6 hours) was replicated across studies. Eight studies contributed fifteen AUC values ranging from 0.62 to 0.89. Strong predictors included miR-6511b-5p (6 h, AUC = 0.85), miR-191-5p (48 h, AUC = 0.89), and miR-124 (48 h, AUC = 0.89). Four studies report associations between altered miRNA expression and unfavourable neurological outcomes, whilst one identified miR-122-5p as a positive prognostic biomarker. To conclude, miRNAs demonstrate distinct expression profiles following CA and ROSC, with several showing clinically useful prediction accuracy for six-month neurological outcomes. Larger, unbiased studies using standardised methodologies are required to validate these findings and clarify confounding factors. Despite the current evidence limitations, this data supports further investigation of circulating miRNAs as neuro-prognostic biomarkers after cardiac arrest.</p>","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":""},"PeriodicalIF":13.3,"publicationDate":"2026-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145892170","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}
{"title":"Abstract writing in the modern era of artificial intelligence.","authors":"Kenneth Chan, Pok-Tin Tang","doi":"10.1093/cvr/cvaf253","DOIUrl":"https://doi.org/10.1093/cvr/cvaf253","url":null,"abstract":"","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"121 17","pages":"2611-2613"},"PeriodicalIF":13.3,"publicationDate":"2025-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145862331","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}
Christian Park, Kyung In Baek, Ruei-Chun Hung, Leandro Choi, Kiyoung Jeong, Paul Kim, Andrew Keunho Jahng, Jung Hyun Kim, Yerin Kim, Mostafa Meselhe, Ashwin Kannan, Chien-Ling Chou, Dong Won Kang, Eun Ju Song, Jay Aaron Bowman-Kirigin, Michael David Clark, Sander W van der Laan, Gerard Pasterkamp, Nicolas Villa-Roel, Alyssa Panitch, Hanjoong Jo
<p><strong>Aims: </strong>Atherosclerosis occurs preferentially in the arteries exposed to disturbed flow (d-flow), while the stable flow (s-flow) regions are protected even under hypercholesterolaemic conditions. We recently showed that d-flow alone initiates flow-induced reprogramming of endothelial cells (FIRE), including the novel concept of partial endothelial-to-immune-cell-like transition (partial EndIT), but it was not validated using a genetic lineage-tracing model. In addition, the combined effect of d-flow and hypercholesterolaemia has not been tested. Here, we tested and validated the two-hit hypothesis that d-flow is an initial instigator of partial FIRE but requires hypercholesterolaemia to induce a full-blown FIRE and atherosclerotic plaque development.</p><p><strong>Methods and results: </strong>Mice were treated with AAV-PCSK9 and a Western diet to induce hypercholesterolaemia and/or partial carotid ligation (PCL) surgery to expose the left common carotid artery (LCA) to d-flow. Single-cell RNA sequencing (scRNA-seq) analysis was performed using single cells obtained from the LCAs and the control right common carotid arteries at 2 and 4 weeks post-PCL. Immunohistochemical staining was performed on EC-specific confetti mice at 4 weeks post-PCL and hypercholesterolaemia to validate endothelial reprogramming. Human aortic endothelial cells (HAECs) exposed to d-flow and hypercholesterolaemic conditions were used to validate FIRE. Atherosclerotic plaques developed by d-flow under hypercholesterolaemia, but not by d-flow or hypercholesterolaemia alone. The scRNA-seq results of 98 553 single cells from 95 mice revealed 25 cell clusters: 5 EC, 3 vascular smooth muscle cell (SMC), 5 macrophage (MΦ), and additional fibroblast, T cell, natural killer cell, dendritic cell, neutrophil, and B-cell clusters. Our scRNA-seq analysis results raised a hypothesis that d-flow under hypercholesterolaemia transitioned healthy ECs to full immune-like (EndIT) and, more surprisingly, foam-like cells (EndFT), in addition to inflammatory and mesenchymal cells (EndMT). Further, ECs with characteristics of foam cells shared remarkably similar transcriptomic profiles with foam cells derived from SMCs and MΦs. Lineage-tracing studies using immunohistochemical staining of canonical protein and lipid markers in the EC-specific confetti mice exposed to d-flow and hypercholesterolaemia demonstrated evidence supporting the novel FIRE hypothesis, including EndIT and EndFT. Moreover, reanalysis of the two publicly available human plaque scRNA-seq datasets and our immunostaining studies suggest that FIRE occurs in human atherosclerotic plaques. Additionally, HAECs exposed to d-flow, high cholesterol, and proinflammatory cytokines (identified in our scRNA-seq data) show the markers of EndIT and EndFT at the mRNA, protein, and functional levels.</p><p><strong>Conclusion: </strong>The scRNA-seq study raised a two-hit hypothesis for FIRE, including EndIT and EndFT, which w
{"title":"Disturbed flow induces reprogramming of endothelial cells to immune-like and foam cells under hypercholesterolaemia during atherogenesis.","authors":"Christian Park, Kyung In Baek, Ruei-Chun Hung, Leandro Choi, Kiyoung Jeong, Paul Kim, Andrew Keunho Jahng, Jung Hyun Kim, Yerin Kim, Mostafa Meselhe, Ashwin Kannan, Chien-Ling Chou, Dong Won Kang, Eun Ju Song, Jay Aaron Bowman-Kirigin, Michael David Clark, Sander W van der Laan, Gerard Pasterkamp, Nicolas Villa-Roel, Alyssa Panitch, Hanjoong Jo","doi":"10.1093/cvr/cvaf233","DOIUrl":"10.1093/cvr/cvaf233","url":null,"abstract":"<p><strong>Aims: </strong>Atherosclerosis occurs preferentially in the arteries exposed to disturbed flow (d-flow), while the stable flow (s-flow) regions are protected even under hypercholesterolaemic conditions. We recently showed that d-flow alone initiates flow-induced reprogramming of endothelial cells (FIRE), including the novel concept of partial endothelial-to-immune-cell-like transition (partial EndIT), but it was not validated using a genetic lineage-tracing model. In addition, the combined effect of d-flow and hypercholesterolaemia has not been tested. Here, we tested and validated the two-hit hypothesis that d-flow is an initial instigator of partial FIRE but requires hypercholesterolaemia to induce a full-blown FIRE and atherosclerotic plaque development.</p><p><strong>Methods and results: </strong>Mice were treated with AAV-PCSK9 and a Western diet to induce hypercholesterolaemia and/or partial carotid ligation (PCL) surgery to expose the left common carotid artery (LCA) to d-flow. Single-cell RNA sequencing (scRNA-seq) analysis was performed using single cells obtained from the LCAs and the control right common carotid arteries at 2 and 4 weeks post-PCL. Immunohistochemical staining was performed on EC-specific confetti mice at 4 weeks post-PCL and hypercholesterolaemia to validate endothelial reprogramming. Human aortic endothelial cells (HAECs) exposed to d-flow and hypercholesterolaemic conditions were used to validate FIRE. Atherosclerotic plaques developed by d-flow under hypercholesterolaemia, but not by d-flow or hypercholesterolaemia alone. The scRNA-seq results of 98 553 single cells from 95 mice revealed 25 cell clusters: 5 EC, 3 vascular smooth muscle cell (SMC), 5 macrophage (MΦ), and additional fibroblast, T cell, natural killer cell, dendritic cell, neutrophil, and B-cell clusters. Our scRNA-seq analysis results raised a hypothesis that d-flow under hypercholesterolaemia transitioned healthy ECs to full immune-like (EndIT) and, more surprisingly, foam-like cells (EndFT), in addition to inflammatory and mesenchymal cells (EndMT). Further, ECs with characteristics of foam cells shared remarkably similar transcriptomic profiles with foam cells derived from SMCs and MΦs. Lineage-tracing studies using immunohistochemical staining of canonical protein and lipid markers in the EC-specific confetti mice exposed to d-flow and hypercholesterolaemia demonstrated evidence supporting the novel FIRE hypothesis, including EndIT and EndFT. Moreover, reanalysis of the two publicly available human plaque scRNA-seq datasets and our immunostaining studies suggest that FIRE occurs in human atherosclerotic plaques. Additionally, HAECs exposed to d-flow, high cholesterol, and proinflammatory cytokines (identified in our scRNA-seq data) show the markers of EndIT and EndFT at the mRNA, protein, and functional levels.</p><p><strong>Conclusion: </strong>The scRNA-seq study raised a two-hit hypothesis for FIRE, including EndIT and EndFT, which w","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":"2679-2699"},"PeriodicalIF":13.3,"publicationDate":"2025-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12860475/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145602638","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}
{"title":"Mechanotransduction as an emerging pathophysiological determinant of cardiovascular diseases.","authors":"Romain Capoulade,Nicola Smart","doi":"10.1093/cvr/cvaf275","DOIUrl":"https://doi.org/10.1093/cvr/cvaf275","url":null,"abstract":"","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"2 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145786157","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}
Ignacio Fernando Hall,Franceska Kishta,Jason C Kovacic
{"title":"Endothelial to mesenchymal transition, Ets2 and the aging heart.","authors":"Ignacio Fernando Hall,Franceska Kishta,Jason C Kovacic","doi":"10.1093/cvr/cvaf273","DOIUrl":"https://doi.org/10.1093/cvr/cvaf273","url":null,"abstract":"","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"22 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145786174","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}
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