Pub Date : 2025-12-16DOI: 10.1038/s44161-025-00756-5
Frederik Denorme, Robert A. Campbell
Long COVID is a major global health challenge but the underlying mechanisms are unclear, hampering the development of effective therapies. Evidence points to a causal link between thromboembolic processes and symptom persistence, suggesting a role for vascular and coagulation abnormalities in the pathogenesis of this complex syndrome.
{"title":"Linking thromboembolism to the pathogenesis of long COVID","authors":"Frederik Denorme, Robert A. Campbell","doi":"10.1038/s44161-025-00756-5","DOIUrl":"10.1038/s44161-025-00756-5","url":null,"abstract":"Long COVID is a major global health challenge but the underlying mechanisms are unclear, hampering the development of effective therapies. Evidence points to a causal link between thromboembolic processes and symptom persistence, suggesting a role for vascular and coagulation abnormalities in the pathogenesis of this complex syndrome.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"4 12","pages":"1594-1595"},"PeriodicalIF":10.8,"publicationDate":"2025-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145761501","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 : 2025-12-11DOI: 10.1038/s44161-025-00752-9
Abigail V. Giles, Raul Covian, Hiran A. Prag, Nils Burger, Bertrand Lucotte, Chak Shun Yu, Junhui Sun, Elizabeth Murphy, Thomas Krieg, Michael P. Murphy, Robert S. Balaban
The mitochondrial membrane potential (ΔΨm) drives oxidative phosphorylation and alterations contribute to cardiac pathologies, but real-time assessment of ΔΨm has not been possible. Here we describe noninvasive measurements using mitochondrial heme bL and bH absorbances, which rapidly respond to ΔΨm. Multi-wavelength absorbance spectroscopy enabled their continuous monitoring in isolated mitochondria and the perfused heart. Calibration of heme b absorbance in isolated mitochondria revealed that reduced heme bL relative to total reduced heme b (fbL = bL/(bL + bH)) exhibits a sigmoidal relationship with ΔΨm. Extrapolating this relationship to the heart enabled estimation of ΔΨm as 166 ± 18 mV (n = 25, mean ± s.d.). We used this approach to assess how ΔΨm changes during ischemia–reperfusion injury, an unknown limiting the understanding of ischemia–reperfusion injury. In perfused hearts, ΔΨm declined during ischemia and rapidly reestablished upon reperfusion, supported by oxidation of the succinate accumulated during ischemia. These findings expand our understanding of ischemia–reperfusion injury. Giles et al. developed a method for noninvasive absorbance measurement of mitochondrial hemes to monitor the mitochondrial membrane potential in the perfused heart. They then applied this approach to show how the mitochondrial membrane potential changed during cardiac ischemia.
{"title":"Rapid mitochondrial repolarization upon reperfusion after cardiac ischemia","authors":"Abigail V. Giles, Raul Covian, Hiran A. Prag, Nils Burger, Bertrand Lucotte, Chak Shun Yu, Junhui Sun, Elizabeth Murphy, Thomas Krieg, Michael P. Murphy, Robert S. Balaban","doi":"10.1038/s44161-025-00752-9","DOIUrl":"10.1038/s44161-025-00752-9","url":null,"abstract":"The mitochondrial membrane potential (ΔΨm) drives oxidative phosphorylation and alterations contribute to cardiac pathologies, but real-time assessment of ΔΨm has not been possible. Here we describe noninvasive measurements using mitochondrial heme bL and bH absorbances, which rapidly respond to ΔΨm. Multi-wavelength absorbance spectroscopy enabled their continuous monitoring in isolated mitochondria and the perfused heart. Calibration of heme b absorbance in isolated mitochondria revealed that reduced heme bL relative to total reduced heme b (fbL = bL/(bL + bH)) exhibits a sigmoidal relationship with ΔΨm. Extrapolating this relationship to the heart enabled estimation of ΔΨm as 166 ± 18 mV (n = 25, mean ± s.d.). We used this approach to assess how ΔΨm changes during ischemia–reperfusion injury, an unknown limiting the understanding of ischemia–reperfusion injury. In perfused hearts, ΔΨm declined during ischemia and rapidly reestablished upon reperfusion, supported by oxidation of the succinate accumulated during ischemia. These findings expand our understanding of ischemia–reperfusion injury. Giles et al. developed a method for noninvasive absorbance measurement of mitochondrial hemes to monitor the mitochondrial membrane potential in the perfused heart. They then applied this approach to show how the mitochondrial membrane potential changed during cardiac ischemia.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"4 12","pages":"1627-1641"},"PeriodicalIF":10.8,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s44161-025-00752-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145746016","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}
Autonomic innervation is important for heart development and function, as well as for the response to injury and hemodynamic stress. However, the mechanisms underlying neurocardiac interactions are difficult to investigate in vivo, prompting the need for advanced engineering of in vitro models of innervated cardiac tissues. Here, we review the embryonic development of the heart and postganglionic autonomic neurons and discuss the functional consequences of cardiac autonomic innervation, focusing on its trophic roles in neonatal and adult hearts. We highlight methods for generating functional cardiomyocytes and autonomic neurons from human pluripotent stem cells and discuss the benefits and limitations of existing in vivo and in vitro cardiac innervation models. Lastly, we present a roadmap for the development of high-fidelity, mature pluripotent stem cell-derived models of cardiac autonomic innervation to address outstanding questions in the field. Patsy et al. review the relationship between the heart and the nervous system during development and the functional consequences of cardiac innervation. They describe the generation of cardiomyocytes and autonomic neurons and propose a roadmap toward the development of cardiac innervation models.
{"title":"Development and modeling of cardiac autonomic innervation","authors":"Marisa Patsy, Kyle Ge, Alastair Khodabukus, Nenad Bursac","doi":"10.1038/s44161-025-00746-7","DOIUrl":"10.1038/s44161-025-00746-7","url":null,"abstract":"Autonomic innervation is important for heart development and function, as well as for the response to injury and hemodynamic stress. However, the mechanisms underlying neurocardiac interactions are difficult to investigate in vivo, prompting the need for advanced engineering of in vitro models of innervated cardiac tissues. Here, we review the embryonic development of the heart and postganglionic autonomic neurons and discuss the functional consequences of cardiac autonomic innervation, focusing on its trophic roles in neonatal and adult hearts. We highlight methods for generating functional cardiomyocytes and autonomic neurons from human pluripotent stem cells and discuss the benefits and limitations of existing in vivo and in vitro cardiac innervation models. Lastly, we present a roadmap for the development of high-fidelity, mature pluripotent stem cell-derived models of cardiac autonomic innervation to address outstanding questions in the field. Patsy et al. review the relationship between the heart and the nervous system during development and the functional consequences of cardiac innervation. They describe the generation of cardiomyocytes and autonomic neurons and propose a roadmap toward the development of cardiac innervation models.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"4 12","pages":"1598-1615"},"PeriodicalIF":10.8,"publicationDate":"2025-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145688816","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 : 2025-11-28DOI: 10.1038/s44161-025-00754-7
David A. Kass
There is great interest in modeling human HFpEF in animals to identify underlying mechanisms and ultimately improve sorely needed therapies. Our current models are a step forward but still fall short in several crucial ways, particularly by not capturing the severity of heart failure features common in patients.
{"title":"Modeling HFpEF in animals","authors":"David A. Kass","doi":"10.1038/s44161-025-00754-7","DOIUrl":"10.1038/s44161-025-00754-7","url":null,"abstract":"There is great interest in modeling human HFpEF in animals to identify underlying mechanisms and ultimately improve sorely needed therapies. Our current models are a step forward but still fall short in several crucial ways, particularly by not capturing the severity of heart failure features common in patients.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"4 12","pages":"1589-1591"},"PeriodicalIF":10.8,"publicationDate":"2025-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145643717","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 : 2025-11-25DOI: 10.1038/s44161-025-00759-2
Gerburg Schwaerzer
{"title":"A cardiotropic viral vector can safely and effectively facilitate therapeutic gene delivery to the heart","authors":"Gerburg Schwaerzer","doi":"10.1038/s44161-025-00759-2","DOIUrl":"10.1038/s44161-025-00759-2","url":null,"abstract":"","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"4 12","pages":"1592-1592"},"PeriodicalIF":10.8,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145607863","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 : 2025-11-14DOI: 10.1038/s44161-025-00747-6
We developed an adeno-associated virus-based, conditional and reversible gene therapy. Using this approach to transiently induce YAP activation in cardiomyocytes either before or after ischemic injury in mice, we could improve cardiac function.
{"title":"Reversible gene therapy for cardiac repair and protection","authors":"","doi":"10.1038/s44161-025-00747-6","DOIUrl":"10.1038/s44161-025-00747-6","url":null,"abstract":"We developed an adeno-associated virus-based, conditional and reversible gene therapy. Using this approach to transiently induce YAP activation in cardiomyocytes either before or after ischemic injury in mice, we could improve cardiac function.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"4 12","pages":"1596-1597"},"PeriodicalIF":10.8,"publicationDate":"2025-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145524744","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 : 2025-11-13DOI: 10.1038/s44161-025-00744-9
Fansen Meng, Jeffrey D. Steimle, Elizabeth Straight, Rich G. Li, Yuka Morikawa, Zohaib Iqbal, Bing Xie, Jun Wang, Wyatt G. Paltzer, Yi Zhao, Chang-Ru Tsai, Lin Liu, Maggie Lim, Rita A. Schack, Daniel Ramirez, Katherine Carlson, Vaibhav Deshmukh, Jason M. Karch, Robia G. Pautler, Xiao Li, James F. Martin
Myocardial infarction (MI) affects millions of people worldwide, causing irreversible injury to the heart and impairing cardiac function1. In both mouse and pig MI models, activating YAP in cardiomyocytes (CMs) stimulates regenerative repair2,3. Here we develop an adeno-associated virus 9-based therapy, termed CM-YAPon, which enables transient expression of an active YAP variant (YAP5SA) in CMs after exposure to the small molecule LMI070. A single LMI070 dose in mice triggers YAP5SA expression, CM cell cycle reentry and reprogramming of the cardiac microenvironment. YAP5SA induction after MI rapidly improves cardiac function while pre-MI induction confers cardioprotection and reduces cell death across multiple cardiac cell types. These findings reveal the therapeutic potential of reversible gene activation for ischemic heart disease. Meng et al. develop the adeno-associated virus 9-based therapy CM-YAPon to transiently and inducibly express YAP in the heart. In mice, CM-YAPon promoted cardiomyocyte cell cycle reentry and reprogrammed the cardiac microenvironment. The CM-YAPon gene therapy improved cardiac function after myocardial infarction (MI) and conferred cardioprotection before MI.
{"title":"Gene therapy CM-YAPon protects the mouse heart from myocardial infarction","authors":"Fansen Meng, Jeffrey D. Steimle, Elizabeth Straight, Rich G. Li, Yuka Morikawa, Zohaib Iqbal, Bing Xie, Jun Wang, Wyatt G. Paltzer, Yi Zhao, Chang-Ru Tsai, Lin Liu, Maggie Lim, Rita A. Schack, Daniel Ramirez, Katherine Carlson, Vaibhav Deshmukh, Jason M. Karch, Robia G. Pautler, Xiao Li, James F. Martin","doi":"10.1038/s44161-025-00744-9","DOIUrl":"10.1038/s44161-025-00744-9","url":null,"abstract":"Myocardial infarction (MI) affects millions of people worldwide, causing irreversible injury to the heart and impairing cardiac function1. In both mouse and pig MI models, activating YAP in cardiomyocytes (CMs) stimulates regenerative repair2,3. Here we develop an adeno-associated virus 9-based therapy, termed CM-YAPon, which enables transient expression of an active YAP variant (YAP5SA) in CMs after exposure to the small molecule LMI070. A single LMI070 dose in mice triggers YAP5SA expression, CM cell cycle reentry and reprogramming of the cardiac microenvironment. YAP5SA induction after MI rapidly improves cardiac function while pre-MI induction confers cardioprotection and reduces cell death across multiple cardiac cell types. These findings reveal the therapeutic potential of reversible gene activation for ischemic heart disease. Meng et al. develop the adeno-associated virus 9-based therapy CM-YAPon to transiently and inducibly express YAP in the heart. In mice, CM-YAPon promoted cardiomyocyte cell cycle reentry and reprogrammed the cardiac microenvironment. The CM-YAPon gene therapy improved cardiac function after myocardial infarction (MI) and conferred cardioprotection before MI.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"4 12","pages":"1616-1626"},"PeriodicalIF":10.8,"publicationDate":"2025-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145514789","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 : 2025-11-12DOI: 10.1038/s44161-025-00742-x
Reza Parvan, Joseph Pierre AbouMsallem, Wouter C. Meijers, Rudolf A. de Boer
Heart failure and cancer share risk factors and biological pathways, yet their interplay remains underexplored. This Comment calls for coordinated research, precision medicine approaches and policy changes to advance the emerging field of cardio-oncology.
{"title":"A call to action for the evolving field of cardio-oncology","authors":"Reza Parvan, Joseph Pierre AbouMsallem, Wouter C. Meijers, Rudolf A. de Boer","doi":"10.1038/s44161-025-00742-x","DOIUrl":"10.1038/s44161-025-00742-x","url":null,"abstract":"Heart failure and cancer share risk factors and biological pathways, yet their interplay remains underexplored. This Comment calls for coordinated research, precision medicine approaches and policy changes to advance the emerging field of cardio-oncology.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"4 11","pages":"1441-1446"},"PeriodicalIF":10.8,"publicationDate":"2025-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145493762","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 : 2025-11-11DOI: 10.1038/s44161-025-00740-z
Wen Hao Neo, Muhammad Zaki Hidayatullah Fadlullah, Harshangda Bhatnagar, Cristiana Barone, Giulia Quattrini, Filipa Timóteo-Ferreira, Joana Carrelha, Gianluca Sala, Robert Sellers, John Weightman, Wolfgang Breitwieser, Natalia Moncaut, Roshana Thambyrajah, Sten Eirik W. Jacobsen, Mudassar Iqbal, Syed Murtuza Baker, Emanuele Azzoni, Michael Lie-A-Ling, Georges Lacaud
Hemogenic endothelium (HE) is recognized as the origin of all definitive blood cells, including hematopoietic stem cells (HSCs); however, the mechanisms governing the hematopoietic progenitor versus HSC fate choice within the HE remain unknown. Here we combine differentiation assays with full-length single-cell transcriptome data for extra-embryonic yolk sac (YS) and intra-embryonic aorta–gonad–mesonephros (AGM) region HE populations. We identified and localized three differentiation trajectories, each containing a distinct HE subset: erythromyeloid progenitor-primed HE in the YS plexus, lymphomyeloid progenitor-primed HE in large YS arteries and hematopoietic stem and progenitor cell-primed HE in the AGM. Chromatin modifiers and spliceosome components were enriched in AGM HE. This correlated with a higher isoform complexity of the AGM HE transcriptome. Distinct AGM HE-specific isoform expression patterns were observed for a broad range of genes, including stemness-associated factors like Runx1. Our data form a unique resource for studying cell fate decisions in different HE populations. Neo et al. map blood emergence from three hemogenic endothelial (HE) populations biased toward distinct blood fates. HE primed for stem progenitors shows elevated chromatin and RNA splicing gene expression and greater isoform diversity.
{"title":"Single-cell profiling reveals three endothelial-to-hematopoietic transitions with divergent isoform expression landscapes","authors":"Wen Hao Neo, Muhammad Zaki Hidayatullah Fadlullah, Harshangda Bhatnagar, Cristiana Barone, Giulia Quattrini, Filipa Timóteo-Ferreira, Joana Carrelha, Gianluca Sala, Robert Sellers, John Weightman, Wolfgang Breitwieser, Natalia Moncaut, Roshana Thambyrajah, Sten Eirik W. Jacobsen, Mudassar Iqbal, Syed Murtuza Baker, Emanuele Azzoni, Michael Lie-A-Ling, Georges Lacaud","doi":"10.1038/s44161-025-00740-z","DOIUrl":"10.1038/s44161-025-00740-z","url":null,"abstract":"Hemogenic endothelium (HE) is recognized as the origin of all definitive blood cells, including hematopoietic stem cells (HSCs); however, the mechanisms governing the hematopoietic progenitor versus HSC fate choice within the HE remain unknown. Here we combine differentiation assays with full-length single-cell transcriptome data for extra-embryonic yolk sac (YS) and intra-embryonic aorta–gonad–mesonephros (AGM) region HE populations. We identified and localized three differentiation trajectories, each containing a distinct HE subset: erythromyeloid progenitor-primed HE in the YS plexus, lymphomyeloid progenitor-primed HE in large YS arteries and hematopoietic stem and progenitor cell-primed HE in the AGM. Chromatin modifiers and spliceosome components were enriched in AGM HE. This correlated with a higher isoform complexity of the AGM HE transcriptome. Distinct AGM HE-specific isoform expression patterns were observed for a broad range of genes, including stemness-associated factors like Runx1. Our data form a unique resource for studying cell fate decisions in different HE populations. Neo et al. map blood emergence from three hemogenic endothelial (HE) populations biased toward distinct blood fates. HE primed for stem progenitors shows elevated chromatin and RNA splicing gene expression and greater isoform diversity.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"4 12","pages":"1642-1661"},"PeriodicalIF":10.8,"publicationDate":"2025-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s44161-025-00740-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145497723","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}
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