Pub Date : 2024-09-04DOI: 10.1038/s44161-024-00522-z
Divyesh Joshi, Brian G. Coon, Raja Chakraborty, Hanqiang Deng, Ziyu Yang, Muhammad Usman Babar, Pablo Fernandez-Tussy, Emily Meredith, John Attanasio, Nikhil Joshi, James G. Traylor Jr., Anthony Wayne Orr, Carlos Fernandez-Hernando, Stephania Libreros, Martin A. Schwartz
Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of mortality worldwide. Laminar shear stress from blood flow, sensed by vascular endothelial cells, protects from ASCVD by upregulating the transcription factors KLF2 and KLF4, which induces an anti-inflammatory program that promotes vascular resilience. Here we identify clustered γ-protocadherins as therapeutically targetable, potent KLF2 and KLF4 suppressors whose upregulation contributes to ASCVD. Mechanistic studies show that γ-protocadherin cleavage results in translocation of the conserved intracellular domain to the nucleus where it physically associates with and suppresses signaling by the Notch intracellular domain. γ-Protocadherins are elevated in human ASCVD endothelium; their genetic deletion or antibody blockade protects from ASCVD in mice without detectably compromising host defense against bacterial or viral infection. These results elucidate a fundamental mechanism of vascular inflammation and reveal a method to target the endothelium rather than the immune system as a protective strategy in ASCVD. Joshi et al. show that γ-protocadherins suppress the anti-inflammatory KLF2 and KLF4 pathway and that targeting them is a viable therapeutic strategy to protect against atherosclerosis.
{"title":"Endothelial γ-protocadherins inhibit KLF2 and KLF4 to promote atherosclerosis","authors":"Divyesh Joshi, Brian G. Coon, Raja Chakraborty, Hanqiang Deng, Ziyu Yang, Muhammad Usman Babar, Pablo Fernandez-Tussy, Emily Meredith, John Attanasio, Nikhil Joshi, James G. Traylor Jr., Anthony Wayne Orr, Carlos Fernandez-Hernando, Stephania Libreros, Martin A. Schwartz","doi":"10.1038/s44161-024-00522-z","DOIUrl":"10.1038/s44161-024-00522-z","url":null,"abstract":"Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of mortality worldwide. Laminar shear stress from blood flow, sensed by vascular endothelial cells, protects from ASCVD by upregulating the transcription factors KLF2 and KLF4, which induces an anti-inflammatory program that promotes vascular resilience. Here we identify clustered γ-protocadherins as therapeutically targetable, potent KLF2 and KLF4 suppressors whose upregulation contributes to ASCVD. Mechanistic studies show that γ-protocadherin cleavage results in translocation of the conserved intracellular domain to the nucleus where it physically associates with and suppresses signaling by the Notch intracellular domain. γ-Protocadherins are elevated in human ASCVD endothelium; their genetic deletion or antibody blockade protects from ASCVD in mice without detectably compromising host defense against bacterial or viral infection. These results elucidate a fundamental mechanism of vascular inflammation and reveal a method to target the endothelium rather than the immune system as a protective strategy in ASCVD. Joshi et al. show that γ-protocadherins suppress the anti-inflammatory KLF2 and KLF4 pathway and that targeting them is a viable therapeutic strategy to protect against atherosclerosis.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"3 9","pages":"1035-1048"},"PeriodicalIF":9.4,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s44161-024-00522-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142134664","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}
The neonatal mammalian heart can regenerate following injury through cardiomyocyte proliferation but loses this potential by postnatal day 7. Stimulating adult cardiomyocytes to reenter the cell cycle remains unclear. Here we show that cardiomyocyte proliferation depends on its metabolic state. Given the connection between the tricarboxylic acid cycle and cell proliferation, we analyzed these metabolites in mouse hearts from postnatal day 0.5 to day 7 and found that α-ketoglutarate ranked highest among the decreased metabolites. Injection of α-ketoglutarate extended the window of cardiomyocyte proliferation during heart development and promoted heart regeneration after myocardial infarction by inducing adult cardiomyocyte proliferation. This was confirmed in Ogdh-siRNA-treated mice with increased α-ketoglutarate levels. Mechanistically, α-ketoglutarate decreases H3K27me3 deposition at the promoters of cell cycle genes in cardiomyocytes. Thus, α-ketoglutarate promotes cardiomyocyte proliferation through JMJD3-dependent demethylation, offering a potential approach for treating myocardial infarction. Yu Shi et al. show that the citric acid cycle metabolite α-ketoglutarate promotes cardiomyocyte proliferation during heart development and promotes heart regeneration after myocardial infarction.
{"title":"α-Ketoglutarate promotes cardiomyocyte proliferation and heart regeneration after myocardial infarction","authors":"Yu Shi, Miao Tian, Xiaofang Zhao, Luxun Tang, Feng Wang, Hao Wu, Qiao Liao, Hongmei Ren, Wenbin Fu, Shuo Zheng, Pedro A. Jose, Liangpeng Li, Chunyu Zeng","doi":"10.1038/s44161-024-00531-y","DOIUrl":"10.1038/s44161-024-00531-y","url":null,"abstract":"The neonatal mammalian heart can regenerate following injury through cardiomyocyte proliferation but loses this potential by postnatal day 7. Stimulating adult cardiomyocytes to reenter the cell cycle remains unclear. Here we show that cardiomyocyte proliferation depends on its metabolic state. Given the connection between the tricarboxylic acid cycle and cell proliferation, we analyzed these metabolites in mouse hearts from postnatal day 0.5 to day 7 and found that α-ketoglutarate ranked highest among the decreased metabolites. Injection of α-ketoglutarate extended the window of cardiomyocyte proliferation during heart development and promoted heart regeneration after myocardial infarction by inducing adult cardiomyocyte proliferation. This was confirmed in Ogdh-siRNA-treated mice with increased α-ketoglutarate levels. Mechanistically, α-ketoglutarate decreases H3K27me3 deposition at the promoters of cell cycle genes in cardiomyocytes. Thus, α-ketoglutarate promotes cardiomyocyte proliferation through JMJD3-dependent demethylation, offering a potential approach for treating myocardial infarction. Yu Shi et al. show that the citric acid cycle metabolite α-ketoglutarate promotes cardiomyocyte proliferation during heart development and promotes heart regeneration after myocardial infarction.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"3 9","pages":"1083-1097"},"PeriodicalIF":9.4,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142121286","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 : 2024-08-29DOI: 10.1038/s44161-024-00535-8
Madeleine W. Cunningham
IgG autoantibodies from patients with systemic lupus erythematosus (SLE) and systolic dysfunction directly affect engineered human heart tissue, altering cellular composition, respiration and calcium handling. Four pathogenic autoantibodies that may target cardiomyocyte function provide insights into myocardial injury in SLE.
{"title":"Engineered human heart tissue reveals pathogenicity of autoantibodies in systemic lupus erythematosus","authors":"Madeleine W. Cunningham","doi":"10.1038/s44161-024-00535-8","DOIUrl":"10.1038/s44161-024-00535-8","url":null,"abstract":"IgG autoantibodies from patients with systemic lupus erythematosus (SLE) and systolic dysfunction directly affect engineered human heart tissue, altering cellular composition, respiration and calcium handling. Four pathogenic autoantibodies that may target cardiomyocyte function provide insights into myocardial injury in SLE.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"3 9","pages":"1028-1030"},"PeriodicalIF":9.4,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142115647","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 : 2024-08-29DOI: 10.1038/s44161-024-00536-7
Gerburg Schwaerzer
This summer, we have witnessed several high-level sports events, the UEFA European Football Championship, the Tour de France/Tour de France Femmes and the Olympic Games. As we admired these impressive athletic performances, the issue of performance-enhancing drugs (PEDs) inevitably resurfaced. Although PEDs are sometimes used to treat cardiovascular diseases, they can also cause severe side effects such as atherosclerosis, thrombosis, arrhythmias and sudden cardiac death. Here we discuss the use of PEDs, their direct effects and side effects on the cardiovascular system with Aaron Baggish, a professor of medicine at the University of Lausanne’s Institut des Sciences du Sport (ISSUL), chief of sports cardiology at the Centre Hospitalier Universitaire Vaudois (CHUV), and founder and emeritus director of the Massachusetts General Hospital Cardiovascular Performance Program (CPP) affiliated with Harvard Medical School. Baggish has been working with athletes for over 10 years and is a consultant for numerous sports and sports-related organizations including the World Anti-Doping Agency (WADA).
{"title":"The effect of cardiovascular medicine on sports doping","authors":"Gerburg Schwaerzer","doi":"10.1038/s44161-024-00536-7","DOIUrl":"10.1038/s44161-024-00536-7","url":null,"abstract":"This summer, we have witnessed several high-level sports events, the UEFA European Football Championship, the Tour de France/Tour de France Femmes and the Olympic Games. As we admired these impressive athletic performances, the issue of performance-enhancing drugs (PEDs) inevitably resurfaced. Although PEDs are sometimes used to treat cardiovascular diseases, they can also cause severe side effects such as atherosclerosis, thrombosis, arrhythmias and sudden cardiac death. Here we discuss the use of PEDs, their direct effects and side effects on the cardiovascular system with Aaron Baggish, a professor of medicine at the University of Lausanne’s Institut des Sciences du Sport (ISSUL), chief of sports cardiology at the Centre Hospitalier Universitaire Vaudois (CHUV), and founder and emeritus director of the Massachusetts General Hospital Cardiovascular Performance Program (CPP) affiliated with Harvard Medical School. Baggish has been working with athletes for over 10 years and is a consultant for numerous sports and sports-related organizations including the World Anti-Doping Agency (WADA).","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"3 9","pages":"1017-1019"},"PeriodicalIF":9.4,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142115649","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 : 2024-08-28DOI: 10.1038/s44161-024-00530-z
Lucie Boulgakoff, Rachel Sturny, Veronika Olejnickova, David Sedmera, Robert G. Kelly, Lucile Miquerol
Unlike adult mammals, newborn mice can regenerate a functional heart after myocardial infarction; however, the precise origin of the newly formed cardiomyocytes and whether the distal part of the conduction system (the Purkinje fiber (PF) network) is properly formed in regenerated hearts remains unclear. PFs, as well as subendocardial contractile cardiomyocytes, are derived from trabeculae, transient myocardial ridges on the inner ventricular surface. Here, using connexin 40-driven genetic tracing, we uncover a substantial participation of the trabecular lineage in myocardial regeneration through dedifferentiation and proliferation. Concomitantly, regeneration disrupted PF network maturation, resulting in permanent PF hyperplasia and impaired ventricular conduction. Proliferation assays, genetic impairment of PF recruitment, lineage tracing and clonal analysis revealed that PF network hyperplasia results from excessive recruitment of PFs due to increased trabecular fate plasticity. These data indicate that PF network hyperplasia is a consequence of trabeculae participation in myocardial regeneration. Boulgakoff et al. show that during cardiac regeneration, ventricular trabeculae participate in the repair of the contractile myocardium resulting in an excessive production of immature Purkinje fibers forming a hyperplastic PF network and altered ventricular conduction.
{"title":"Participation of ventricular trabeculae in neonatal cardiac regeneration leads to ectopic recruitment of Purkinje-like cells","authors":"Lucie Boulgakoff, Rachel Sturny, Veronika Olejnickova, David Sedmera, Robert G. Kelly, Lucile Miquerol","doi":"10.1038/s44161-024-00530-z","DOIUrl":"10.1038/s44161-024-00530-z","url":null,"abstract":"Unlike adult mammals, newborn mice can regenerate a functional heart after myocardial infarction; however, the precise origin of the newly formed cardiomyocytes and whether the distal part of the conduction system (the Purkinje fiber (PF) network) is properly formed in regenerated hearts remains unclear. PFs, as well as subendocardial contractile cardiomyocytes, are derived from trabeculae, transient myocardial ridges on the inner ventricular surface. Here, using connexin 40-driven genetic tracing, we uncover a substantial participation of the trabecular lineage in myocardial regeneration through dedifferentiation and proliferation. Concomitantly, regeneration disrupted PF network maturation, resulting in permanent PF hyperplasia and impaired ventricular conduction. Proliferation assays, genetic impairment of PF recruitment, lineage tracing and clonal analysis revealed that PF network hyperplasia results from excessive recruitment of PFs due to increased trabecular fate plasticity. These data indicate that PF network hyperplasia is a consequence of trabeculae participation in myocardial regeneration. Boulgakoff et al. show that during cardiac regeneration, ventricular trabeculae participate in the repair of the contractile myocardium resulting in an excessive production of immature Purkinje fibers forming a hyperplastic PF network and altered ventricular conduction.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"3 9","pages":"1140-1157"},"PeriodicalIF":9.4,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142094273","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 : 2024-08-26DOI: 10.1038/s44161-024-00517-w
Ulrich Hofmann, Stefan Frantz
Glatiramer acetate, a drug with an established history of treating multiple sclerosis in clinical practice, improves cardiac function in rodent models of myocardial infarction and ischemic heart failure.
{"title":"Cardioprotective effects of glatiramer acetate after ischemic myocardial injury","authors":"Ulrich Hofmann, Stefan Frantz","doi":"10.1038/s44161-024-00517-w","DOIUrl":"10.1038/s44161-024-00517-w","url":null,"abstract":"Glatiramer acetate, a drug with an established history of treating multiple sclerosis in clinical practice, improves cardiac function in rodent models of myocardial infarction and ischemic heart failure.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"3 9","pages":"1024-1025"},"PeriodicalIF":9.4,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142231151","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 : 2024-08-26DOI: 10.1038/s44161-024-00524-x
Gal Aviel, Jacob Elkahal, Kfir Baruch Umansky, Hanna Bueno-Levy, Zachary Petrover, Yulia Kotlovski, Daria Lendengolts, David Kain, Tali Shalit, Lingling Zhang, Shoval Miyara, Matthias P. Kramer, Yifat Merbl, Stav Kozlovski, Ronen Alon, Rina Aharoni, Ruth Arnon, David Mishali, Uriel Katz, Dean Nachman, Rabea Asleh, Offer Amir, Eldad Tzahor, Rachel Sarig
Myocardial injury may ultimately lead to adverse ventricular remodeling and development of heart failure (HF), which is a major cause of morbidity and mortality worldwide. Given the slow pace and substantial costs of developing new therapeutics, drug repurposing is an attractive alternative. Studies of many organs, including the heart, highlight the importance of the immune system in modulating injury and repair outcomes. Glatiramer acetate (GA) is an immunomodulatory drug prescribed for patients with multiple sclerosis. Here, we report that short-term GA treatment improves cardiac function and reduces scar area in a mouse model of acute myocardial infarction and a rat model of ischemic HF. We provide mechanistic evidence indicating that, in addition to its immunomodulatory functions, GA exerts beneficial pleiotropic effects, including cardiomyocyte protection and enhanced angiogenesis. Overall, these findings highlight the potential repurposing of GA as a future therapy for a myriad of heart diseases. Sarig and Tzahor et al. show that the multiple sclerosis drug glatiramer acetate improves cardiac function and reduces scar area in rodent models of acute myocardial infarction and ischemic heart failure.
心肌损伤最终可能导致心室重塑不良和心力衰竭（HF），而心力衰竭是全球发病率和死亡率的主要原因。鉴于开发新疗法的速度缓慢且成本高昂，药物再利用是一种极具吸引力的选择。对包括心脏在内的许多器官进行的研究强调了免疫系统在调节损伤和修复结果方面的重要性。醋酸格拉替雷（GA）是一种用于多发性硬化症患者的免疫调节药物。在此，我们报告了在急性心肌梗塞小鼠模型和缺血性高频房颤大鼠模型中，GA 的短期治疗可改善心脏功能并减少瘢痕面积。我们提供的机理证据表明，除了免疫调节功能外，GA 还能产生有益的多效应，包括保护心肌细胞和增强血管生成。总之，这些发现凸显了 GA 作为未来治疗多种心脏疾病的一种疗法的潜在用途。
{"title":"Repurposing of glatiramer acetate to treat cardiac ischemia in rodent models","authors":"Gal Aviel, Jacob Elkahal, Kfir Baruch Umansky, Hanna Bueno-Levy, Zachary Petrover, Yulia Kotlovski, Daria Lendengolts, David Kain, Tali Shalit, Lingling Zhang, Shoval Miyara, Matthias P. Kramer, Yifat Merbl, Stav Kozlovski, Ronen Alon, Rina Aharoni, Ruth Arnon, David Mishali, Uriel Katz, Dean Nachman, Rabea Asleh, Offer Amir, Eldad Tzahor, Rachel Sarig","doi":"10.1038/s44161-024-00524-x","DOIUrl":"10.1038/s44161-024-00524-x","url":null,"abstract":"Myocardial injury may ultimately lead to adverse ventricular remodeling and development of heart failure (HF), which is a major cause of morbidity and mortality worldwide. Given the slow pace and substantial costs of developing new therapeutics, drug repurposing is an attractive alternative. Studies of many organs, including the heart, highlight the importance of the immune system in modulating injury and repair outcomes. Glatiramer acetate (GA) is an immunomodulatory drug prescribed for patients with multiple sclerosis. Here, we report that short-term GA treatment improves cardiac function and reduces scar area in a mouse model of acute myocardial infarction and a rat model of ischemic HF. We provide mechanistic evidence indicating that, in addition to its immunomodulatory functions, GA exerts beneficial pleiotropic effects, including cardiomyocyte protection and enhanced angiogenesis. Overall, these findings highlight the potential repurposing of GA as a future therapy for a myriad of heart diseases. Sarig and Tzahor et al. show that the multiple sclerosis drug glatiramer acetate improves cardiac function and reduces scar area in rodent models of acute myocardial infarction and ischemic heart failure.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"3 9","pages":"1049-1066"},"PeriodicalIF":9.4,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142115648","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 : 2024-08-23DOI: 10.1038/s44161-024-00540-x
Bastian Stoffers, Hanna Wolf, Lucas Bacmeister, Svenja Kupsch, Tamara Vico, Timoteo Marchini, Maria A. Brehm, Isabell Yan, P. Moritz Becher, Armin Ardeshirdavani, Felicitas Escher, Sangwon V. Kim, Karin Klingel, Paulus Kirchhof, Stefan Blankenberg, Tanja Zeller, Dennis Wolf, Ingo Hilgendorf, Dirk Westermann, Diana Lindner
{"title":"Author Correction: GPR15-mediated T cell recruitment during acute viral myocarditis facilitated virus elimination and improved outcome","authors":"Bastian Stoffers, Hanna Wolf, Lucas Bacmeister, Svenja Kupsch, Tamara Vico, Timoteo Marchini, Maria A. Brehm, Isabell Yan, P. Moritz Becher, Armin Ardeshirdavani, Felicitas Escher, Sangwon V. Kim, Karin Klingel, Paulus Kirchhof, Stefan Blankenberg, Tanja Zeller, Dennis Wolf, Ingo Hilgendorf, Dirk Westermann, Diana Lindner","doi":"10.1038/s44161-024-00540-x","DOIUrl":"10.1038/s44161-024-00540-x","url":null,"abstract":"","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"3 9","pages":"1177-1177"},"PeriodicalIF":9.4,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s44161-024-00540-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142231167","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}
A resident memory T cell subpopulation that infiltrates epicardial adipose tissue is expanded in patients with atrial fibrillation and may affect cardiomyocyte physiology.
浸润心外膜脂肪组织的常驻记忆 T 细胞亚群在心房颤动患者中扩大，可能会影响心肌细胞的生理机能。
{"title":"Epicardial adipose tissue resident memory T cells in atrial fibrillation","authors":"Federica Ruggeri, Vasiliki Papadopoulou, Marinos Kallikourdis","doi":"10.1038/s44161-024-00528-7","DOIUrl":"10.1038/s44161-024-00528-7","url":null,"abstract":"A resident memory T cell subpopulation that infiltrates epicardial adipose tissue is expanded in patients with atrial fibrillation and may affect cardiomyocyte physiology.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"3 9","pages":"1026-1027"},"PeriodicalIF":9.4,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142231148","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 : 2024-08-23DOI: 10.1038/s44161-024-00532-x
Vishal Vyas, Balraj Sandhar, Jack M. Keane, Elizabeth G. Wood, Hazel Blythe, Aled Jones, Eriomina Shahaj, Silvia Fanti, Jack Williams, Nasrine Metic, Mirjana Efremova, Han Leng Ng, Gayathri Nageswaran, Suzanne Byrne, Niklas Feldhahn, Federica Marelli-Berg, Benny Chain, Andrew Tinker, Malcolm C. Finlay, M. Paula Longhi
Atrial fibrillation (AF) is the most common sustained arrhythmia and carries an increased risk of stroke and heart failure. Here we investigated how the immune infiltrate of human epicardial adipose tissue (EAT), which directly overlies the myocardium, contributes to AF. Flow cytometry analysis revealed an enrichment of tissue-resident memory T (TRM) cells in patients with AF. Cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) and single-cell T cell receptor (TCR) sequencing identified two transcriptionally distinct CD8+ TRM cells that are modulated in AF. Spatial transcriptomic analysis of EAT and atrial tissue identified the border region between the tissues to be a region of intense inflammatory and fibrotic activity, and the addition of TRM populations to atrial cardiomyocytes demonstrated their ability to differentially alter calcium flux as well as activate inflammatory and apoptotic signaling pathways. This study identified EAT as a reservoir of TRM cells that can directly modulate vulnerability to cardiac arrhythmia. Vyas et al. show that epicardial adipose tissue is a reservoir for a subpopulation of tissue-resident memory T cells that can increase the vulnerability of the heart to atrial fibrillation.
心房颤动（房颤）是最常见的持续性心律失常，会增加中风和心力衰竭的风险。在此，我们研究了直接覆盖心肌的人体心外膜脂肪组织（EAT）的免疫浸润是如何导致房颤的。流式细胞术分析显示，房颤患者体内富含组织驻留记忆 T 细胞（TRM）。通过测序对转录组和表位进行细胞索引（CITE-seq）和单细胞 T 细胞受体（TCR）测序发现了两种在转录上不同的 CD8+ TRM 细胞，它们在房颤中受到调节。EAT和心房组织的空间转录组学分析确定了这两种组织之间的边界区域是炎症和纤维化活动剧烈的区域，将TRM群体加入心房心肌细胞证明了它们有能力以不同方式改变钙通量以及激活炎症和凋亡信号通路。这项研究发现 EAT 是 TRM 细胞的储库，可直接调节心律失常的易感性。Vyas 等人的研究表明，心外膜脂肪组织是组织驻留记忆 T 细胞亚群的储库，可增加心脏对心房颤动的脆弱性。
{"title":"Tissue-resident memory T cells in epicardial adipose tissue comprise transcriptionally distinct subsets that are modulated in atrial fibrillation","authors":"Vishal Vyas, Balraj Sandhar, Jack M. Keane, Elizabeth G. Wood, Hazel Blythe, Aled Jones, Eriomina Shahaj, Silvia Fanti, Jack Williams, Nasrine Metic, Mirjana Efremova, Han Leng Ng, Gayathri Nageswaran, Suzanne Byrne, Niklas Feldhahn, Federica Marelli-Berg, Benny Chain, Andrew Tinker, Malcolm C. Finlay, M. Paula Longhi","doi":"10.1038/s44161-024-00532-x","DOIUrl":"10.1038/s44161-024-00532-x","url":null,"abstract":"Atrial fibrillation (AF) is the most common sustained arrhythmia and carries an increased risk of stroke and heart failure. Here we investigated how the immune infiltrate of human epicardial adipose tissue (EAT), which directly overlies the myocardium, contributes to AF. Flow cytometry analysis revealed an enrichment of tissue-resident memory T (TRM) cells in patients with AF. Cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) and single-cell T cell receptor (TCR) sequencing identified two transcriptionally distinct CD8+ TRM cells that are modulated in AF. Spatial transcriptomic analysis of EAT and atrial tissue identified the border region between the tissues to be a region of intense inflammatory and fibrotic activity, and the addition of TRM populations to atrial cardiomyocytes demonstrated their ability to differentially alter calcium flux as well as activate inflammatory and apoptotic signaling pathways. This study identified EAT as a reservoir of TRM cells that can directly modulate vulnerability to cardiac arrhythmia. Vyas et al. show that epicardial adipose tissue is a reservoir for a subpopulation of tissue-resident memory T cells that can increase the vulnerability of the heart to atrial fibrillation.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"3 9","pages":"1067-1082"},"PeriodicalIF":9.4,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s44161-024-00532-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142231154","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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