Pub Date : 2026-01-06Epub Date: 2025-12-29DOI: 10.1161/CIRCULATIONAHA.125.078640
{"title":"Highlights From the Circulation Family of Journals.","authors":"","doi":"10.1161/CIRCULATIONAHA.125.078640","DOIUrl":"https://doi.org/10.1161/CIRCULATIONAHA.125.078640","url":null,"abstract":"","PeriodicalId":10331,"journal":{"name":"Circulation","volume":"153 1","pages":"59-63"},"PeriodicalIF":38.6,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145854722","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-06Epub Date: 2025-12-29DOI: 10.1161/CIRCULATIONAHA.125.077507
Varsha K Tanguturi, Sammy Elmariah
{"title":"Response by Tanguturi and Elmariah to Letter Regarding Article, \"Electronic Provider Notification to Facilitate the Recognition and Management of Severe Aortic Stenosis: A Randomized Clinical Trial\".","authors":"Varsha K Tanguturi, Sammy Elmariah","doi":"10.1161/CIRCULATIONAHA.125.077507","DOIUrl":"https://doi.org/10.1161/CIRCULATIONAHA.125.077507","url":null,"abstract":"","PeriodicalId":10331,"journal":{"name":"Circulation","volume":"153 1","pages":"e2-e3"},"PeriodicalIF":38.6,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145854731","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-06Epub Date: 2025-12-29DOI: 10.1161/CIRCULATIONAHA.125.077852
Lauren K Truby, Michael D Shapiro
{"title":"When the Target Is Not the Driver: Rethinking LDL in Cardiac Allograft Vasculopathy.","authors":"Lauren K Truby, Michael D Shapiro","doi":"10.1161/CIRCULATIONAHA.125.077852","DOIUrl":"10.1161/CIRCULATIONAHA.125.077852","url":null,"abstract":"","PeriodicalId":10331,"journal":{"name":"Circulation","volume":"153 1","pages":"18-20"},"PeriodicalIF":38.6,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12752930/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145854692","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-06Epub Date: 2025-12-29DOI: 10.1161/CIRCULATIONAHA.125.076105
Qing Huang, Xiangyu Jian, Feng Wu
{"title":"Letter by Huang et al Regarding Article, \"Electronic Provider Notification to Facilitate the Recognition and Management of Severe Aortic Stenosis: A Randomized Clinical Trial\".","authors":"Qing Huang, Xiangyu Jian, Feng Wu","doi":"10.1161/CIRCULATIONAHA.125.076105","DOIUrl":"https://doi.org/10.1161/CIRCULATIONAHA.125.076105","url":null,"abstract":"","PeriodicalId":10331,"journal":{"name":"Circulation","volume":"153 1","pages":"e1"},"PeriodicalIF":38.6,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145854667","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}
BACKGROUNDImbalances in cardiac branched-chain amino acid (BCAA) metabolism and mitochondrial homeostasis are implicated in the onset and development of heart failure. However, the mechanisms triggering the downregulation of cardiac BCAA metabolism in heart failure remain unclear. Here, we identify a novel role of the RNA-binding protein GRSF1 (guanine-rich RNA sequence binding factor 1) in post-transcriptionally regulating cell-intrinsic BCAA metabolic pathways, ultimately contributing to the pathogenesis of heart failure.METHODSWe examined GRSF1 expression in the heart tissues of patients with dilated cardiomyopathy and generated mice with cardiomyocyte-specific deletion or overexpression of GRSF1 in vivo to investigate its role in heart failure. The effect of GRSF1 on BCAA homeostasis was assessed through untargeted and targeted metabolomics and mitochondrial function analysis. To elucidate the mechanisms underlying GRSF1-mediated metabolic regulation, we employed mice with cardiomyocyte-specific deletion of BCKDHB (branched-chain keto acid dehydrogenase E1 subunit β) and mice with cardiomyocyte-specific expression of GRSF1 lacking a quasi-RNA recognition motif.RESULTSGRSF1 expression was significantly decreased in the hearts of patients with heart failure and failing murine hearts. Cardiomyocyte-specific GRSF1 deletion resulted in cardiac dysfunction, spontaneous progression to dilated cardiomyopathy, and heart failure, accompanied by increased cardiac hypertrophy and fibrosis. Conversely, GRSF1 overexpression attenuated cardiac remodeling and heart failure induced by transverse aortic constriction. Mechanistically, GRSF1 maintained BCAA homeostasis and mitochondrial function by directly interacting with the G-tracts in the coding region of BCKDHB mRNA through a quasi-RNA recognition motif to promote the stability of BCKDHB mRNA at the post-transcriptional level, thereby increasing its protein expression. Functional recovery mediated by GRSF1 overexpression in cardiomyocytes was partially blocked upon cardiac-specific deletion of BCKDHB.CONCLUSIONSOur study identified GRSF1 as a cell-intrinsic metabolic checkpoint that maintains cardiac BCAA homeostasis by regulating BCKDHB mRNA turnover. Targeting GRSF1 may offer therapeutic benefits for heart failure and other cardiometabolic diseases requiring BCAA manipulation.
{"title":"GRSF1 Protects Against Heart Failure by Maintaining BCAA Homeostasis.","authors":"Hu Wang,Jiaxing Wang,Min Zhu,Ling Jin,Hao Cui,Cihang Liu,Chenyu Fan,Hui Li,Jichun Yang,Ming Cui,Jiangping Song,Wengong Wang,Ming Xu","doi":"10.1161/circulationaha.125.074700","DOIUrl":"https://doi.org/10.1161/circulationaha.125.074700","url":null,"abstract":"BACKGROUNDImbalances in cardiac branched-chain amino acid (BCAA) metabolism and mitochondrial homeostasis are implicated in the onset and development of heart failure. However, the mechanisms triggering the downregulation of cardiac BCAA metabolism in heart failure remain unclear. Here, we identify a novel role of the RNA-binding protein GRSF1 (guanine-rich RNA sequence binding factor 1) in post-transcriptionally regulating cell-intrinsic BCAA metabolic pathways, ultimately contributing to the pathogenesis of heart failure.METHODSWe examined GRSF1 expression in the heart tissues of patients with dilated cardiomyopathy and generated mice with cardiomyocyte-specific deletion or overexpression of GRSF1 in vivo to investigate its role in heart failure. The effect of GRSF1 on BCAA homeostasis was assessed through untargeted and targeted metabolomics and mitochondrial function analysis. To elucidate the mechanisms underlying GRSF1-mediated metabolic regulation, we employed mice with cardiomyocyte-specific deletion of BCKDHB (branched-chain keto acid dehydrogenase E1 subunit β) and mice with cardiomyocyte-specific expression of GRSF1 lacking a quasi-RNA recognition motif.RESULTSGRSF1 expression was significantly decreased in the hearts of patients with heart failure and failing murine hearts. Cardiomyocyte-specific GRSF1 deletion resulted in cardiac dysfunction, spontaneous progression to dilated cardiomyopathy, and heart failure, accompanied by increased cardiac hypertrophy and fibrosis. Conversely, GRSF1 overexpression attenuated cardiac remodeling and heart failure induced by transverse aortic constriction. Mechanistically, GRSF1 maintained BCAA homeostasis and mitochondrial function by directly interacting with the G-tracts in the coding region of BCKDHB mRNA through a quasi-RNA recognition motif to promote the stability of BCKDHB mRNA at the post-transcriptional level, thereby increasing its protein expression. Functional recovery mediated by GRSF1 overexpression in cardiomyocytes was partially blocked upon cardiac-specific deletion of BCKDHB.CONCLUSIONSOur study identified GRSF1 as a cell-intrinsic metabolic checkpoint that maintains cardiac BCAA homeostasis by regulating BCKDHB mRNA turnover. Targeting GRSF1 may offer therapeutic benefits for heart failure and other cardiometabolic diseases requiring BCAA manipulation.","PeriodicalId":10331,"journal":{"name":"Circulation","volume":"23 1","pages":""},"PeriodicalIF":37.8,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145897449","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-05DOI: 10.1161/circulationaha.125.075789
Thomas G Martin,Dakota R Hunt,Christopher C Ebmeier,Abhishek P Dhand,Christina Alamana,Joseph C Cleveland,Sharon L Graw,Sarah Bruner,Michael R Bristow,Luisa Mestroni,Matthew R G Taylor,Jason A Burdick,Amrut V Ambardekar,Peter M Buttrick,Leslie A Leinwand
BACKGROUNDCardiac reverse remodeling occurs in a small subset of patients with heart failure treated with guideline-directed therapies. This phenomenon, which is defined by reduced ventricular dilatation and improved systolic function, is most common in patients receiving left ventricular assist device (LVAD) therapy. Identifying therapeutic targets for initiating reverse remodeling is an area of great clinical interest, because these patients experience improved outcomes and quality of life. Targets may be discovered among the unique molecular changes associated with LVAD-induced partial myocardial functional recovery; however, the mechanisms underlying this favorable response are incompletely understood.METHODSTo identify molecular signatures of recovery, we studied paired pre-LVAD and post-LVAD myocardial samples from patients with heart failure who received LVAD as a bridge to transplant (10 responders and 9 nonresponders) and controls without heart failure. We performed bulk RNA sequencing, tandem mass tag quantitative proteomics, and tandem mass tag quantitative phosphoproteomics with follow-up mechanistic and functional investigations in primary rat cardiomyocytes and human engineered heart tissues.RESULTSAlternative RNA splicing was the leading pathway associated with a favorable response to LVAD. Responders had increased RNA splicing factor expression and unique gene splice variant expression compared with nonresponders. Alternative splicing of CAMK2D (calcium/calmodulin-dependent protein kinase 2δ) was a particularly strong predictor of recovery; increased inclusion of exon 14, which encodes the nuclear splice variant CAMK2D-B, was inversely correlated with functional recovery. Nonresponders also displayed hyperphosphorylation near the nuclear localization signal in CAMK2D-B. Investigations in primary cardiomyocytes and subcellular organelle fractions from the human hearts revealed that nuclear localization signal phosphorylation prevented adrenergic stress-dependent nuclear targeting of CAMK2D-B. Expression of a cytoplasm-restricted CAMK2D-B uniquely remodeled the phosphoproteome of primary rat cardiomyocytes compared with a nuclear-competent version and blunted calcium transients in engineered heart tissues.CONCLUSIONSThis is the first study to integrate transcriptome, alternative transcriptome, proteome, and phosphoproteome analyses of heart samples from LVAD-supported patients to investigate myocardial recovery. We identified that increased expression and phosphorylation of the nuclear CAMK2D splice variant predicted poor outcomes. This phosphorylation restricted CAMK2D-B to the cytosol, leading to impaired cardiomyocyte calcium handling. These findings suggest that LVAD nonresponder patients may benefit from therapies that modulate subcellular localization of CAMK2D or inhibit its activity.
{"title":"Myocardial Recovery With Mechanical Circulatory Support Is Linked to Alternative Splicing and Subcellular Localization of CAMK2D.","authors":"Thomas G Martin,Dakota R Hunt,Christopher C Ebmeier,Abhishek P Dhand,Christina Alamana,Joseph C Cleveland,Sharon L Graw,Sarah Bruner,Michael R Bristow,Luisa Mestroni,Matthew R G Taylor,Jason A Burdick,Amrut V Ambardekar,Peter M Buttrick,Leslie A Leinwand","doi":"10.1161/circulationaha.125.075789","DOIUrl":"https://doi.org/10.1161/circulationaha.125.075789","url":null,"abstract":"BACKGROUNDCardiac reverse remodeling occurs in a small subset of patients with heart failure treated with guideline-directed therapies. This phenomenon, which is defined by reduced ventricular dilatation and improved systolic function, is most common in patients receiving left ventricular assist device (LVAD) therapy. Identifying therapeutic targets for initiating reverse remodeling is an area of great clinical interest, because these patients experience improved outcomes and quality of life. Targets may be discovered among the unique molecular changes associated with LVAD-induced partial myocardial functional recovery; however, the mechanisms underlying this favorable response are incompletely understood.METHODSTo identify molecular signatures of recovery, we studied paired pre-LVAD and post-LVAD myocardial samples from patients with heart failure who received LVAD as a bridge to transplant (10 responders and 9 nonresponders) and controls without heart failure. We performed bulk RNA sequencing, tandem mass tag quantitative proteomics, and tandem mass tag quantitative phosphoproteomics with follow-up mechanistic and functional investigations in primary rat cardiomyocytes and human engineered heart tissues.RESULTSAlternative RNA splicing was the leading pathway associated with a favorable response to LVAD. Responders had increased RNA splicing factor expression and unique gene splice variant expression compared with nonresponders. Alternative splicing of CAMK2D (calcium/calmodulin-dependent protein kinase 2δ) was a particularly strong predictor of recovery; increased inclusion of exon 14, which encodes the nuclear splice variant CAMK2D-B, was inversely correlated with functional recovery. Nonresponders also displayed hyperphosphorylation near the nuclear localization signal in CAMK2D-B. Investigations in primary cardiomyocytes and subcellular organelle fractions from the human hearts revealed that nuclear localization signal phosphorylation prevented adrenergic stress-dependent nuclear targeting of CAMK2D-B. Expression of a cytoplasm-restricted CAMK2D-B uniquely remodeled the phosphoproteome of primary rat cardiomyocytes compared with a nuclear-competent version and blunted calcium transients in engineered heart tissues.CONCLUSIONSThis is the first study to integrate transcriptome, alternative transcriptome, proteome, and phosphoproteome analyses of heart samples from LVAD-supported patients to investigate myocardial recovery. We identified that increased expression and phosphorylation of the nuclear CAMK2D splice variant predicted poor outcomes. This phosphorylation restricted CAMK2D-B to the cytosol, leading to impaired cardiomyocyte calcium handling. These findings suggest that LVAD nonresponder patients may benefit from therapies that modulate subcellular localization of CAMK2D or inhibit its activity.","PeriodicalId":10331,"journal":{"name":"Circulation","volume":"1191 1","pages":""},"PeriodicalIF":37.8,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145897633","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}
BACKGROUNDParvovirus B19 is a DNA virus transmitted via respiratory droplets, commonly causing erythema infectiosum in children but also implicated in acute myocarditis. In 2024, an outbreak of parvovirus B19 infections was reported across Europe and the United States. Despite growing awareness, data on the clinical features and outcomes of children with parvovirus B19-associated acute myocarditis remain limited.METHODSThis multicenter retrospective observational study reviewed medical records of pediatric patients (<18 years of age) admitted with acute myocarditis to 11 Italian tertiary pediatric cardiac centers between January 1, 2022, and October 31, 2024. Of 217 cases, 66 had confirmed parvovirus B19 DNA in plasma (PVB19+), whereas 82 with negative parvovirus B19 testing served as a comparator group (PVB19-). Population-based incidence trends of pediatric myocarditis were also evaluated in the Lombardy region from 2004 through 2024.RESULTSAmong PVB19+ acute myocarditis cases, 58 of 66 (87.9%) were admitted in 2024. The median age was 32 months, with 51 of 66 (77.2%) ≤7 years of age, and 36 of 66 (54.5%) were boys. Median plasma viral load was 34 411 copies/mL, whereas only 30 of 56 (53.6%) had immunoglobulin M (IgM) positivity. Among 26 of 66 (39.4%) with available histology, 23 (88.4%) had lymphocytic myocarditis, and parvovirus B19 DNA was identified in 84.0% of myocardial specimens. Among 25 of 65 (38.4%) who underwent genetic testing, none had pathogenic or likely pathogenic variants. Overall, 13 of 66 (19.7%) died, underwent heart transplantation, or received a durable left ventricular assist device (in total, there were 6 deaths, 5 durable left ventricular assist devices, and 5 transplantations) compared with 1 of 82 (1.2%) among PVB19- acute myocarditis (one patient who received a durable left ventricular assist device and later underwent transplantation; P<0.001). A marked increase in regional and institutional myocarditis incidence in pediatric acute myocarditis was observed in 2024, predominantly in children ≤7 years of age, driven by PVB19+ cases.CONCLUSIONSDuring the 2024 parvovirus B19 outbreak, pediatric PVB19+ acute myocarditis cases surged in Italy and were associated with severe outcomes. A high index of suspicion is required for diagnosis, and early virological testing is essential to guide management and potentially improve outcomes.
{"title":"Clinical Spectrum of Children With Parvovirus B19-Associated Acute Myocarditis.","authors":"Enrico Ammirati,Giacomo Veronese,Francesca Raimondi,Giuseppe Alberto Annoni,Domenico Sirico,Francesco Bianco,Alessio Franceschini,Gessica Ingrasciotta,Giovanni Meliota,Guglielmo Capponi,Isabella Pellicioli,Gaia Biancamaria Chiesa,Carlo Beretta,Giada Colombo,Giovanni Di Salvo,Sandra Nonini,Francesca Aresta,Luca Ragni,Tammam Hasan,Maurizio Brighenti,Giovanna Travi,Olivia Leoni,Paul Stefan Vrabie,Michele Ercolanoni,Giuseppe Limongelli,Emanuele Monda,Maria Giovanna Russo,Alessandra Corato,Elena Reffo,Valentina Bucciarelli,Sergio Filippelli,Susanna Breviario,Carlo Pace Napoleone,Ugo Vairo,Maristella Lombardi,Nadia Assanta,Pietro Marchese,Paolo Ferrero,Flavio Luciano Ribichini,Andrea Garascia,Michele Giovanni Mondino,Antonio Amodeo,Rachele Adorisio,Ezio Bonanomi","doi":"10.1161/circulationaha.125.075943","DOIUrl":"https://doi.org/10.1161/circulationaha.125.075943","url":null,"abstract":"BACKGROUNDParvovirus B19 is a DNA virus transmitted via respiratory droplets, commonly causing erythema infectiosum in children but also implicated in acute myocarditis. In 2024, an outbreak of parvovirus B19 infections was reported across Europe and the United States. Despite growing awareness, data on the clinical features and outcomes of children with parvovirus B19-associated acute myocarditis remain limited.METHODSThis multicenter retrospective observational study reviewed medical records of pediatric patients (<18 years of age) admitted with acute myocarditis to 11 Italian tertiary pediatric cardiac centers between January 1, 2022, and October 31, 2024. Of 217 cases, 66 had confirmed parvovirus B19 DNA in plasma (PVB19+), whereas 82 with negative parvovirus B19 testing served as a comparator group (PVB19-). Population-based incidence trends of pediatric myocarditis were also evaluated in the Lombardy region from 2004 through 2024.RESULTSAmong PVB19+ acute myocarditis cases, 58 of 66 (87.9%) were admitted in 2024. The median age was 32 months, with 51 of 66 (77.2%) ≤7 years of age, and 36 of 66 (54.5%) were boys. Median plasma viral load was 34 411 copies/mL, whereas only 30 of 56 (53.6%) had immunoglobulin M (IgM) positivity. Among 26 of 66 (39.4%) with available histology, 23 (88.4%) had lymphocytic myocarditis, and parvovirus B19 DNA was identified in 84.0% of myocardial specimens. Among 25 of 65 (38.4%) who underwent genetic testing, none had pathogenic or likely pathogenic variants. Overall, 13 of 66 (19.7%) died, underwent heart transplantation, or received a durable left ventricular assist device (in total, there were 6 deaths, 5 durable left ventricular assist devices, and 5 transplantations) compared with 1 of 82 (1.2%) among PVB19- acute myocarditis (one patient who received a durable left ventricular assist device and later underwent transplantation; P<0.001). A marked increase in regional and institutional myocarditis incidence in pediatric acute myocarditis was observed in 2024, predominantly in children ≤7 years of age, driven by PVB19+ cases.CONCLUSIONSDuring the 2024 parvovirus B19 outbreak, pediatric PVB19+ acute myocarditis cases surged in Italy and were associated with severe outcomes. A high index of suspicion is required for diagnosis, and early virological testing is essential to guide management and potentially improve outcomes.","PeriodicalId":10331,"journal":{"name":"Circulation","volume":"43 1","pages":""},"PeriodicalIF":37.8,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145897450","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}
BACKGROUNDVascular smooth muscle cells (VSMCs) undergo phenotypic changes during the development of aortic aneurysm and dissection (AAD). Metabolism shifts from oxidative phosphorylation to glycolysis. Recent studies suggest that epigenetics plays a crucial role in AAD.METHODSThe epigenetic regulation of histone lactylation was analyzed in the aorta of patients with aortic aneurysm and in a murine model of AAD. Histone lactylation was also studied in VSMCs treated with angiotensin II. The epigenetic pathway involving H4K16 lactylation (H4K16la) was explored in vitro and in vivo. To examine the role of H4K16la in AAD formation, mice lacking Pdk1 or Kat7 in VSMCs were created. Mice were treated with pharmacological inhibitors of Pdk1 or Kat7. The levels of blood lactate, aortic lactate, and aortic H4K16la were compared between patients with aortic aneurysm and controls.RESULTSHistone lactylation (H4K16la) was increased in the aortic tissues of patients with AAD and mice. Enhanced histone lactylation was linked to increased pyruvate dehydrogenase kinase 1 (PDK1) transcription, which accelerated lactate production in VSMCs. A positive feedback loop was identified involving H4K16la, PDK1, and lactate; this pathway alters the metabolism and phenotype of VSMCs. KAT7 (lysine acetyltransferase 7) was found to be a histone lactyltransferase for histone lactylation in VSMCs. Genetic or pharmacological inhibition of PDK1 or KAT7 decreased AAD injury by disrupting the H4K16la/PDK1/lactate pathway. Patients with AAD have elevated lactate in blood and aortic tissues and elevated H4K16la in aortic tissues compared with control patients.CONCLUSIONSHistone lactylation changes the metabolism and phenotype of VSMC in AAD. Inhibition of PDK1 or KAT7 may be a novel approach to treat or prevent AAD.
{"title":"Histone Lactylation-Mediated Metabolic Remodeling in Vascular Smooth Muscle Cells Aggravates Aortic Aneurysm and Dissection by Promoting Lactate Accumulation.","authors":"Liwei Liu,Jinyan Zhang,Zhen Dong,Yikai Cui,Xiaoyi Zou,Hao Lai,Jiawei Gu,Xingyu Weng,Xuejuan Jin,Tianyi Qiu,Zhiqiang Pei,Wenxuan Hong,Ya Huang,Wei Luo,Lihong Pan,Xiaolei Sun,Beijian Zhang,Adilan Shalamu,Aijun Sun,Junbo Ge","doi":"10.1161/circulationaha.125.072576","DOIUrl":"https://doi.org/10.1161/circulationaha.125.072576","url":null,"abstract":"BACKGROUNDVascular smooth muscle cells (VSMCs) undergo phenotypic changes during the development of aortic aneurysm and dissection (AAD). Metabolism shifts from oxidative phosphorylation to glycolysis. Recent studies suggest that epigenetics plays a crucial role in AAD.METHODSThe epigenetic regulation of histone lactylation was analyzed in the aorta of patients with aortic aneurysm and in a murine model of AAD. Histone lactylation was also studied in VSMCs treated with angiotensin II. The epigenetic pathway involving H4K16 lactylation (H4K16la) was explored in vitro and in vivo. To examine the role of H4K16la in AAD formation, mice lacking Pdk1 or Kat7 in VSMCs were created. Mice were treated with pharmacological inhibitors of Pdk1 or Kat7. The levels of blood lactate, aortic lactate, and aortic H4K16la were compared between patients with aortic aneurysm and controls.RESULTSHistone lactylation (H4K16la) was increased in the aortic tissues of patients with AAD and mice. Enhanced histone lactylation was linked to increased pyruvate dehydrogenase kinase 1 (PDK1) transcription, which accelerated lactate production in VSMCs. A positive feedback loop was identified involving H4K16la, PDK1, and lactate; this pathway alters the metabolism and phenotype of VSMCs. KAT7 (lysine acetyltransferase 7) was found to be a histone lactyltransferase for histone lactylation in VSMCs. Genetic or pharmacological inhibition of PDK1 or KAT7 decreased AAD injury by disrupting the H4K16la/PDK1/lactate pathway. Patients with AAD have elevated lactate in blood and aortic tissues and elevated H4K16la in aortic tissues compared with control patients.CONCLUSIONSHistone lactylation changes the metabolism and phenotype of VSMC in AAD. Inhibition of PDK1 or KAT7 may be a novel approach to treat or prevent AAD.","PeriodicalId":10331,"journal":{"name":"Circulation","volume":"24 1","pages":""},"PeriodicalIF":37.8,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145897451","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}
BACKGROUNDMyocardial infarction (MI) initiates a dysregulated healing process characterized by excessive fibrosis and unresolved inflammation, resulting in suboptimal cardiac repair in clinical settings. Regulatory T lymphocytes (Tregs) naturally orchestrate cardiac repair after MI, but their therapeutic potential is limited by inefficient homing to ischemic myocardium. We hypothesize that FAP (fibroblast activation protein)-specific CAR (chimeric antigen receptor) engineering overcomes this barrier by enabling precise delivery of Tregs to FAP⁺-enriched infarct zones, thereby focally amplifying reparative activity within injured myocardium.METHODSIn murine MI and ischemia-reperfusion models, C57BL/6J mice were injected with lentivirus-engineered FAP CAR Tregs (FCTRs) or mock Tregs derived from wild-type, IL-10 (interleukin-10) knockout (IL-10-/-) or Areg (amphiregulin) knockout (Areg-/-) donors after infarction. The cardiac outcomes and underlying mechanisms mediated by FCTRs were thoroughly analyzed. Systemic toxicity was evaluated to ensure safety.RESULTSIntravenous injections of FCTRs on day 3 after injury led to targeted engraftment in the damaged cardiac tissue. Compared with controls treated with vehicle or mock Tregs, mice receiving FCTRs exhibited remarkable cardiac functional recovery in both MI and ischemia-reperfusion models by day 14, accompanied by reduced fibrosis and decreased inflammation, all achieved without compromising the integrity of cardiac tissue. Absence of IL-10 in the engineered CAR Tregs abrogated their therapeutic efficacy, whereas the ablation of Areg showed no functional impairment. We further demonstrated that the beneficial effects of FCTRs depended on IL-10 production, which inhibited pathogenic myofibroblast differentiation by suppressing Smad2/3-dependent signaling. In addition, IL-10 secretion by these engineered Tregs promoted the polarization of inflammatory monocytes into reparative M2 macrophages and resolved excessive inflammatory responses. No treatment-related adverse effects were observed.CONCLUSIONSWe pioneered FAP-targeted CAR Tregs as a dual-action precision therapy resolving post-MI fibrosis and inflammation through IL-10-dependent mechanisms. By spatiotemporally suppressing myofibroblast differentiation and remodeling immune niches, this strategy prevents maladaptive remodeling while accelerating functional recovery, establishing a translational platform for fibrotic diseases across organ systems.
背景：心肌梗死（MI）启动了一个失调的愈合过程，其特征是过度纤维化和未解决的炎症，在临床环境中导致心脏修复不理想。调节性T淋巴细胞（Tregs）自然地协调心肌梗死后的心脏修复，但它们的治疗潜力受到缺血心肌的低效归家的限制。我们假设FAP（成纤维细胞激活蛋白）特异性CAR（嵌合抗原受体）工程通过将Tregs精确递送到FAP +富集的梗死区来克服这一障碍，从而局部放大受损心肌的修复活性。方法在小鼠心肌梗死和缺血再灌注模型中，C57BL/6J小鼠在梗死后注射慢病毒工程FAP CAR treg （FCTRs）或来自野生型、IL-10（白细胞介素-10）敲除（IL-10-/-）或Areg（双调节蛋白）敲除（Areg-/-）供体的模拟treg。深入分析了FCTRs介导的心脏结局和潜在机制。系统毒性评估以确保安全性。结果损伤后第3天静脉注射FCTRs可在受损心脏组织中靶向植入。与用载体或模拟Tregs治疗的对照组相比，在心肌梗死和缺血-再灌注模型中，接受FCTRs的小鼠在第14天都表现出显著的心功能恢复，同时纤维化减少，炎症减少，所有这些都在不损害心脏组织完整性的情况下实现。工程CAR - treg中IL-10的缺失使其治疗效果失效，而Areg的消融没有显示出功能损伤。我们进一步证明，FCTRs的有益作用依赖于IL-10的产生，IL-10通过抑制smad2 /3依赖性信号传导抑制致病性肌成纤维细胞分化。此外，这些工程Tregs分泌IL-10促进炎症单核细胞极化为修复性M2巨噬细胞，解决过度炎症反应。未观察到与治疗相关的不良反应。我们率先采用靶向fap的CAR Tregs作为双作用精准疗法，通过il -10依赖机制解决心肌梗死后纤维化和炎症。通过在时空上抑制肌成纤维细胞分化和重塑免疫龛，该策略在加速功能恢复的同时防止了适应性不良的重塑，建立了跨器官系统纤维化疾病的翻译平台。
{"title":"Engineered Regulatory T Lymphocytes Promote Infarcted Heart Repair.","authors":"Min Zhang,Yongying Qin,Ting Zhou,Meilin Liu,Tingting Tang,Ni Xia,Shaofang Nie,Bingjie Lv,Zhengfeng Zhu,Jiao Jiao,Muyang Gu,Jingyong Li,Chen Chen,Desheng Hu,Weimin Wang,Li Zhang,Chaolong Wang,Zhilei Shan,Xiang Cheng","doi":"10.1161/circulationaha.125.076321","DOIUrl":"https://doi.org/10.1161/circulationaha.125.076321","url":null,"abstract":"BACKGROUNDMyocardial infarction (MI) initiates a dysregulated healing process characterized by excessive fibrosis and unresolved inflammation, resulting in suboptimal cardiac repair in clinical settings. Regulatory T lymphocytes (Tregs) naturally orchestrate cardiac repair after MI, but their therapeutic potential is limited by inefficient homing to ischemic myocardium. We hypothesize that FAP (fibroblast activation protein)-specific CAR (chimeric antigen receptor) engineering overcomes this barrier by enabling precise delivery of Tregs to FAP⁺-enriched infarct zones, thereby focally amplifying reparative activity within injured myocardium.METHODSIn murine MI and ischemia-reperfusion models, C57BL/6J mice were injected with lentivirus-engineered FAP CAR Tregs (FCTRs) or mock Tregs derived from wild-type, IL-10 (interleukin-10) knockout (IL-10-/-) or Areg (amphiregulin) knockout (Areg-/-) donors after infarction. The cardiac outcomes and underlying mechanisms mediated by FCTRs were thoroughly analyzed. Systemic toxicity was evaluated to ensure safety.RESULTSIntravenous injections of FCTRs on day 3 after injury led to targeted engraftment in the damaged cardiac tissue. Compared with controls treated with vehicle or mock Tregs, mice receiving FCTRs exhibited remarkable cardiac functional recovery in both MI and ischemia-reperfusion models by day 14, accompanied by reduced fibrosis and decreased inflammation, all achieved without compromising the integrity of cardiac tissue. Absence of IL-10 in the engineered CAR Tregs abrogated their therapeutic efficacy, whereas the ablation of Areg showed no functional impairment. We further demonstrated that the beneficial effects of FCTRs depended on IL-10 production, which inhibited pathogenic myofibroblast differentiation by suppressing Smad2/3-dependent signaling. In addition, IL-10 secretion by these engineered Tregs promoted the polarization of inflammatory monocytes into reparative M2 macrophages and resolved excessive inflammatory responses. No treatment-related adverse effects were observed.CONCLUSIONSWe pioneered FAP-targeted CAR Tregs as a dual-action precision therapy resolving post-MI fibrosis and inflammation through IL-10-dependent mechanisms. By spatiotemporally suppressing myofibroblast differentiation and remodeling immune niches, this strategy prevents maladaptive remodeling while accelerating functional recovery, establishing a translational platform for fibrotic diseases across organ systems.","PeriodicalId":10331,"journal":{"name":"Circulation","volume":"29 1","pages":""},"PeriodicalIF":37.8,"publicationDate":"2025-12-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145847258","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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