Pub Date : 2026-01-05DOI: 10.1038/s44161-025-00763-6
Odai Darawshi, Besim Ogretmen
Defects in elastin trigger hyperproliferation of smooth muscle cells, which leads to arterial and congenital heart diseases. Research now shows that elastin deficiency induces SPHK1 and S1P signaling by EGR1 in SMCs, and inhibitors of SPHK1 or S1PR1 attenuate smooth muscle cell proliferation and mitigate aortic disease.
{"title":"Sphingolipid signaling links elastin deficiency to arterial hyper-muscularization and congenital heart disease","authors":"Odai Darawshi, Besim Ogretmen","doi":"10.1038/s44161-025-00763-6","DOIUrl":"10.1038/s44161-025-00763-6","url":null,"abstract":"Defects in elastin trigger hyperproliferation of smooth muscle cells, which leads to arterial and congenital heart diseases. Research now shows that elastin deficiency induces SPHK1 and S1P signaling by EGR1 in SMCs, and inhibitors of SPHK1 or S1PR1 attenuate smooth muscle cell proliferation and mitigate aortic disease.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"5 1","pages":"10-11"},"PeriodicalIF":10.8,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145907346","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-02DOI: 10.1038/s44161-025-00760-9
Jennifer L. Hall
Most drugs in phase 2 trials fail to reach regulatory approval. By leveraging machine learning to identify connections between different types of data, including genes, diseases, medications, existing drugs and images, a new approach is shown to increase the level of evidence in identifying drug targets for cardiovascular disease.
{"title":"Connecting to improve drug discovery","authors":"Jennifer L. Hall","doi":"10.1038/s44161-025-00760-9","DOIUrl":"10.1038/s44161-025-00760-9","url":null,"abstract":"Most drugs in phase 2 trials fail to reach regulatory approval. By leveraging machine learning to identify connections between different types of data, including genes, diseases, medications, existing drugs and images, a new approach is shown to increase the level of evidence in identifying drug targets for cardiovascular disease.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"5 1","pages":"8-9"},"PeriodicalIF":10.8,"publicationDate":"2026-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145893561","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-02DOI: 10.1038/s44161-025-00766-3
The transcription factor TBX5 regulates early cardiac progenitor cells and genes that encode essential patterning cues for the correct formation of the interventricular septum and separation of cardiac chambers in mice. Disruption of a compartment boundary at the developing interventricular septum reveals potential mechanisms that might underlie some congenital heart defects.
{"title":"Insights on the origins of the interventricular septum","authors":"","doi":"10.1038/s44161-025-00766-3","DOIUrl":"10.1038/s44161-025-00766-3","url":null,"abstract":"The transcription factor TBX5 regulates early cardiac progenitor cells and genes that encode essential patterning cues for the correct formation of the interventricular septum and separation of cardiac chambers in mice. Disruption of a compartment boundary at the developing interventricular septum reveals potential mechanisms that might underlie some congenital heart defects.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"5 1","pages":"14-15"},"PeriodicalIF":10.8,"publicationDate":"2026-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145893535","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-02DOI: 10.1038/s44161-025-00767-2
Correlating the mitochondrial membrane potential with the redox status of endogenous mitochondrial cytochromes in vitro enabled the real-time determination of the mitochondrial membrane potential in an isolated perfused mouse heart. This model was used to provide insights into cardiac ischemia–reperfusion injury.
{"title":"Real-time measurement of the mitochondrial membrane potential in the intact mouse heart","authors":"","doi":"10.1038/s44161-025-00767-2","DOIUrl":"10.1038/s44161-025-00767-2","url":null,"abstract":"Correlating the mitochondrial membrane potential with the redox status of endogenous mitochondrial cytochromes in vitro enabled the real-time determination of the mitochondrial membrane potential in an isolated perfused mouse heart. This model was used to provide insights into cardiac ischemia–reperfusion injury.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"5 1","pages":"12-13"},"PeriodicalIF":10.8,"publicationDate":"2026-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145893536","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-02DOI: 10.1038/s44161-025-00764-5
Elisa Martini
{"title":"Loss of function of the obesity-associated gene MC4R reduces cardiovascular risk and increases lipid clearance","authors":"Elisa Martini","doi":"10.1038/s44161-025-00764-5","DOIUrl":"10.1038/s44161-025-00764-5","url":null,"abstract":"","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"5 1","pages":"4-4"},"PeriodicalIF":10.8,"publicationDate":"2026-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145893547","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-29DOI: 10.1038/s44161-025-00755-6
Irfan S. Kathiriya, Martin H. Dominguez, Kavitha S. Rao, Jonathon M. Muncie-Vasic, W. Patrick Devine, Kevin M. Hu, Swetansu K. Hota, Bayardo I. Garay, Diego Quintero, Piyush Goyal, Megan N. Matthews, Reuben Thomas, Tatyana Sukonnik, Dario Miguel-Perez, Sarah Winchester, Emily F. Brower, André Forjaz, Pei-Hsun Wu, Denis Wirtz, Ashley L. Kiemen, Benoit G. Bruneau
Failure of septation of the interventricular septum (IVS) is the most common congenital heart defect, but mechanisms for patterning the IVS are largely unknown. Here we show that a Tbx5+/Mef2cAHF+ progenitor lineage forms a compartment boundary bisecting the IVS. This coordinated population originates at a first and second heart field interface. Ablation of Tbx5+/Mef2cAHF+ progenitors causes IVS disorganization, right ventricular hypoplasia and mixing of IVS lineages. Reduced dosage of the congenital heart defect transcription factor TBX5 disrupts boundary position and integrity, resulting in ventricular septation defects and patterning defects, including misexpression of Slit2 and Ntn1, which encode guidance cues. Reducing NTN1 dosage partly rescues cardiac defects in Tbx5 mutant embryos. Loss of Slit2 or Ntn1 causes ventricular septation defects and perturbed septal lineage distributions. Thus, we identify Tbx5 as a candidate selector gene, directing progenitors and regulating essential cues, to pattern a compartment boundary for proper cardiac septation, revealing mechanisms for cardiac birth defects. Kathiriya et al. identify a cardiac progenitor lineage with expression of Tbx5 and anterior heart field-specific expression of Mef2c that bisects the intraventricular septum during development and show that alterations in this lineage lead to congenital heart defects in mice.
{"title":"A disrupted compartment boundary underlies abnormal cardiac patterning and congenital heart defects","authors":"Irfan S. Kathiriya, Martin H. Dominguez, Kavitha S. Rao, Jonathon M. Muncie-Vasic, W. Patrick Devine, Kevin M. Hu, Swetansu K. Hota, Bayardo I. Garay, Diego Quintero, Piyush Goyal, Megan N. Matthews, Reuben Thomas, Tatyana Sukonnik, Dario Miguel-Perez, Sarah Winchester, Emily F. Brower, André Forjaz, Pei-Hsun Wu, Denis Wirtz, Ashley L. Kiemen, Benoit G. Bruneau","doi":"10.1038/s44161-025-00755-6","DOIUrl":"10.1038/s44161-025-00755-6","url":null,"abstract":"Failure of septation of the interventricular septum (IVS) is the most common congenital heart defect, but mechanisms for patterning the IVS are largely unknown. Here we show that a Tbx5+/Mef2cAHF+ progenitor lineage forms a compartment boundary bisecting the IVS. This coordinated population originates at a first and second heart field interface. Ablation of Tbx5+/Mef2cAHF+ progenitors causes IVS disorganization, right ventricular hypoplasia and mixing of IVS lineages. Reduced dosage of the congenital heart defect transcription factor TBX5 disrupts boundary position and integrity, resulting in ventricular septation defects and patterning defects, including misexpression of Slit2 and Ntn1, which encode guidance cues. Reducing NTN1 dosage partly rescues cardiac defects in Tbx5 mutant embryos. Loss of Slit2 or Ntn1 causes ventricular septation defects and perturbed septal lineage distributions. Thus, we identify Tbx5 as a candidate selector gene, directing progenitors and regulating essential cues, to pattern a compartment boundary for proper cardiac septation, revealing mechanisms for cardiac birth defects. Kathiriya et al. identify a cardiac progenitor lineage with expression of Tbx5 and anterior heart field-specific expression of Mef2c that bisects the intraventricular septum during development and show that alterations in this lineage lead to congenital heart defects in mice.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"5 1","pages":"67-83"},"PeriodicalIF":10.8,"publicationDate":"2025-12-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s44161-025-00755-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145859468","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-29DOI: 10.1038/s44161-025-00757-4
Khaled Rjoob, Kathryn A. McGurk, Sean L. Zheng, Lara Curran, Mahmoud Ibrahim, Lingyao Zeng, Vladislav Kim, Shamin Tahasildar, Soodeh Kalaie, Deva S. Senevirathne, Parisa Gifani, Vladimir Losev, Jin Zheng, Wenjia Bai, Antonio de Marvao, James S. Ware, Christian Bender, Declan P. O’Regan
Understanding gene–disease associations is important for uncovering pathological mechanisms and identifying potential therapeutic targets. Knowledge graphs can represent and integrate data from multiple biomedical sources, but lack individual-level information on target organ structure and function. Here we develop CardioKG, a knowledge graph that integrates over 200,000 computer vision-derived cardiovascular phenotypes from biomedical images with data extracted from 18 biological databases to model over a million relationships. We used a variational graph auto-encoder to generate node embeddings from the knowledge graph to predict gene–disease associations, assess druggability and identify drug repurposing strategies. The model predicted genetic associations and therapeutic opportunities for leading causes of cardiovascular disease, which were associated with improved survival. Candidate therapies included methotrexate for heart failure and gliptins for atrial fibrillation, and the addition of imaging data enhanced pathway discovery. These capabilities support the use of biomedical imaging to enhance graph-structured models for identifying treatable disease mechanisms. Rjoob et al. develop CardioKG, a knowledge graph built on cardiac imaging traits to identify genetic associations and potential therapeutic strategies and drug repurposing opportunities for cardiovascular diseases.
{"title":"A multimodal vision knowledge graph of cardiovascular disease","authors":"Khaled Rjoob, Kathryn A. McGurk, Sean L. Zheng, Lara Curran, Mahmoud Ibrahim, Lingyao Zeng, Vladislav Kim, Shamin Tahasildar, Soodeh Kalaie, Deva S. Senevirathne, Parisa Gifani, Vladimir Losev, Jin Zheng, Wenjia Bai, Antonio de Marvao, James S. Ware, Christian Bender, Declan P. O’Regan","doi":"10.1038/s44161-025-00757-4","DOIUrl":"10.1038/s44161-025-00757-4","url":null,"abstract":"Understanding gene–disease associations is important for uncovering pathological mechanisms and identifying potential therapeutic targets. Knowledge graphs can represent and integrate data from multiple biomedical sources, but lack individual-level information on target organ structure and function. Here we develop CardioKG, a knowledge graph that integrates over 200,000 computer vision-derived cardiovascular phenotypes from biomedical images with data extracted from 18 biological databases to model over a million relationships. We used a variational graph auto-encoder to generate node embeddings from the knowledge graph to predict gene–disease associations, assess druggability and identify drug repurposing strategies. The model predicted genetic associations and therapeutic opportunities for leading causes of cardiovascular disease, which were associated with improved survival. Candidate therapies included methotrexate for heart failure and gliptins for atrial fibrillation, and the addition of imaging data enhanced pathway discovery. These capabilities support the use of biomedical imaging to enhance graph-structured models for identifying treatable disease mechanisms. Rjoob et al. develop CardioKG, a knowledge graph built on cardiac imaging traits to identify genetic associations and potential therapeutic strategies and drug repurposing opportunities for cardiovascular diseases.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"5 1","pages":"18-33"},"PeriodicalIF":10.8,"publicationDate":"2025-12-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s44161-025-00757-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145859527","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-17DOI: 10.1038/s44161-025-00765-4
Ziad Mallat
The 2025 Nobel Prize in Physiology or Medicine honored a scientific breakthrough with hidden cardiovascular potential: regulatory T cells and peripheral immune tolerance. These mechanisms provide a paradigm shift for understanding and treating cardiovascular disease, dampening inflammation without compromising immunity, and offering safer and more effective therapies.
{"title":"Translating Nobel Prize-winning Treg cell science into cardiovascular therapy","authors":"Ziad Mallat","doi":"10.1038/s44161-025-00765-4","DOIUrl":"10.1038/s44161-025-00765-4","url":null,"abstract":"The 2025 Nobel Prize in Physiology or Medicine honored a scientific breakthrough with hidden cardiovascular potential: regulatory T cells and peripheral immune tolerance. These mechanisms provide a paradigm shift for understanding and treating cardiovascular disease, dampening inflammation without compromising immunity, and offering safer and more effective therapies.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"5 1","pages":"1-3"},"PeriodicalIF":10.8,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145776525","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-16DOI: 10.1038/s44161-025-00749-4
Art Schuermans, Andreas Verstraete, Vilma Lammi, Tomoko Nakanishi, Maddalena Ardissino, Jef Van den Eynde, Benjamin B. Sun, Marios K. Georgakis, Beatriz Guillen-Guio, Louise V. Wain, Christopher E. Brightling, PHOSP-COVID Collaborative Group, Johan Van Weyenbergh, Adam J. Lewandowski, Betty Raman, Hugo Zeberg, Hanna M. Ollila, Stephen Burgess, Pradeep Natarajan, Michael C. Honigberg, Kathleen Freson, Thomas Vanassche, Peter Verhamme
SARS-CoV-2 infection can result in long COVID, characterized by post-acute symptoms from multiple organs. Current hypotheses on mechanisms underlying long COVID include persistent inflammation and thromboembolism; however, compelling evidence from humans is limited and causal associations remain unclear. In this study, we tested the association of thromboembolism-related genetic variants with long COVID in the Long COVID Host Genetics Initiative (ncases = 3,018; ncontrols = 994,582). Primary analyses revealed that each unit increase in the log odds of genetically predicted venous thromboembolism risk was associated with 1.21-fold odds of long COVID (95% confidence interval (CI): 1.08−1.35; P = 1.2 × 10−3). This association was independent of acute COVID-19 severity, was robust across various sensitivity analyses and was replicated in external datasets. Downstream analyses using gene-specific instruments, along with protein and gene expression data, suggested the protease-activated receptor 1 (PAR-1) as a potential molecular contributor to long COVID. These findings provide human genetic evidence implicating shared pathogenetic pathways in thromboembolism and long COVID. Schuermans et al. discovered that genetic predisposition to thromboembolism is associated with a greater risk of post-acute sequelae after SARS-CoV-2 infection, including long COVID, and downstream analyses implicated PAR-1 as a potential contributor to long COVID.
{"title":"Human genetics implicate thromboembolism in the pathogenesis of long COVID in individuals of European ancestry","authors":"Art Schuermans, Andreas Verstraete, Vilma Lammi, Tomoko Nakanishi, Maddalena Ardissino, Jef Van den Eynde, Benjamin B. Sun, Marios K. Georgakis, Beatriz Guillen-Guio, Louise V. Wain, Christopher E. Brightling, PHOSP-COVID Collaborative Group, Johan Van Weyenbergh, Adam J. Lewandowski, Betty Raman, Hugo Zeberg, Hanna M. Ollila, Stephen Burgess, Pradeep Natarajan, Michael C. Honigberg, Kathleen Freson, Thomas Vanassche, Peter Verhamme","doi":"10.1038/s44161-025-00749-4","DOIUrl":"10.1038/s44161-025-00749-4","url":null,"abstract":"SARS-CoV-2 infection can result in long COVID, characterized by post-acute symptoms from multiple organs. Current hypotheses on mechanisms underlying long COVID include persistent inflammation and thromboembolism; however, compelling evidence from humans is limited and causal associations remain unclear. In this study, we tested the association of thromboembolism-related genetic variants with long COVID in the Long COVID Host Genetics Initiative (ncases = 3,018; ncontrols = 994,582). Primary analyses revealed that each unit increase in the log odds of genetically predicted venous thromboembolism risk was associated with 1.21-fold odds of long COVID (95% confidence interval (CI): 1.08−1.35; P = 1.2 × 10−3). This association was independent of acute COVID-19 severity, was robust across various sensitivity analyses and was replicated in external datasets. Downstream analyses using gene-specific instruments, along with protein and gene expression data, suggested the protease-activated receptor 1 (PAR-1) as a potential molecular contributor to long COVID. These findings provide human genetic evidence implicating shared pathogenetic pathways in thromboembolism and long COVID. Schuermans et al. discovered that genetic predisposition to thromboembolism is associated with a greater risk of post-acute sequelae after SARS-CoV-2 infection, including long COVID, and downstream analyses implicated PAR-1 as a potential contributor to long COVID.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"4 12","pages":"1662-1676"},"PeriodicalIF":10.8,"publicationDate":"2025-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145761500","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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