Circulation最新文献

{"title":"Characterizing the Immune Response in Pig-to-human Heart Xenografts Using a Multimodal Diagnostic System.","authors":"Alessia Giarraputo,Erwan Morgand,Jeffrey Stern,Fariza Mezine,Guillaume Coutance,Valentin Goutaudier,Aurelie Sannier,Anais Certain,Thierry Hauet,Sebastien Giraud,Thomas Kerforne,Geraldine Allain,David Ayares,Karen Khalil,Jaqueline Kim,Sapna Mehta,Navneet Narula,Alex Reyentovich,Deane Smith,Renaud Tissier,Tajinderpal Saraon,Bernard Kadosh,Michael DiVita,Randal Goldberg,Harvey Pass,Massimo Mangiola,Patrick Bruneval,Adam Griesemer,Nader Moazami,Robert A Montgomery,Alexandre Loupy","doi":"10.1161/circulationaha.125.074971","DOIUrl":"https://doi.org/10.1161/circulationaha.125.074971","url":null,"abstract":"BACKGROUNDPorcine genome editing has revolutionized xenotransplantation, recently enabling the first pig-to-human heart xenotransplants. However, the xeno-immune response in heart xenografts remains largely unexplored. This study aimed to precisely characterize the xeno-immune response and injury in two heart xenografts, transplanted from 10-gene-edited pigs into brain-dead human recipients.METHODSWe analyzed xenograft biopsies at 66-hour post-reperfusion using a multimodal phenotyping approach combining: morphological evaluation, immunophenotyping, ultrastructural assessment, automated quantification of multiplex immunofluorescence staining and gene expression profiling. Xenografts before implantation and wild-type pig hearts with and without ischemia reperfusion injury and brain death were used as controls.RESULTSBoth xenografts showed evidence of endothelial activation and mild microvascular inflammation without capillary C4d deposition. Immune infiltrates were mainly composed of CD15+ and CD68+ innate immune cells. Ultrastructural assessment showed endothelial swelling with occasional intravascular leucocytes. Deep-learning based automated multiplex immunofluorescence analysis confirmed that microvascular inflammation was primarily associated with CD15+ and CD68+ innate immune cells. Both xenografts showed increased expression of genes and pathways associated with monocyte/macrophage activation, neutrophil activation, interferon-gamma response, natural killer cell burden, endothelial activation, apoptosis and injury repair. This phenotype was absent in all control pig hearts, independently from ischemia reperfusion injury and brain death.CONCLUSIONSMultimodal phenotyping of pig-to-human heart xenografts revealed early signs of xeno-immune response, characterized by mild innate microvascular inflammation, endothelial activation, and molecular signature characteristic of antibody-mediated rejection. Developing such precision diagnostic system could improve graft monitoring in future clinical settings.","PeriodicalId":10331,"journal":{"name":"Circulation","volume":"39 1","pages":""},"PeriodicalIF":37.8,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145203669","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An Aberrant Resurgence of Endogenous Retroviruses Prompts Myocarditis and Heart Failure.","authors":"Junhao Xiong, Shasha Zhang, Zilong Geng, Juntao Lin, Kang Cheng, Huan Hu, Yuze Wang, Xing Liu, Yuanzhe Sheng, Ping Yang, Yige Li, Shuo Wu, Xiao Cheng, Yelan Li, Aijun Sun, Alex F Chen, Daowen Wang, Chen Chen, Yan Zhang, Gengze Wu, Chunyu Zeng, Xiaoling Guo, Xumin Hou, Ruogu Li, Yuliang Feng, Dan Zhu, Kun Sun, Bing Zhang","doi":"10.1161/CIRCULATIONAHA.125.074845","DOIUrl":"10.1161/CIRCULATIONAHA.125.074845","url":null,"abstract":"<p><strong>Background: </strong>Endogenous retroviruses (ERVs) occupy >8% of the human genome. Aberrant resurgence of ERVs has been implicated recently in several critical pathologies. However, the possible incidence and role of ERV resurgence in heart failure (HF), a leading cause of global morbidity and mortality, remain unexplored.</p><p><strong>Methods: </strong>We established a total RNA sequencing analyzing pipeline to assess the ERV occurrence in human and murine HF models. We generated 2 myocardium-specific mouse lines by crossing <i>Myh6</i>-MerCreMer (<i>Myosin heavy chain 6</i> promoter driving <i>MerCreMer</i> recombinase) with TRIM28^f/f and SETDB1^f/f mice to identify the molecular regulators of ERV resurgence and the downstream pathways in the heart. We evaluated ERV expression by total RNA sequencing, reverse transcription-quantitative polymerase chain reaction and RNA fluorescence in situ hybridization. We restrained ERV activation by overexpressing TRIM28 (tripartite motif-containing 28) using adeno-associated virus serotype 9. The therapeutic potential of the ERV-mediated inflammatory pathway was tested in a myocardial ischemia/reperfusion model.</p><p><strong>Results: </strong>ERVs, particularly class I ERVs, were prominently activated in multiple cross-species models of HF. Depletion of TRIM28, an epigenetic repressor, attenuated the epigenetic surveillance of trimethylation at lysine 9 of histone H3 and <i>N</i>⁶-methyladenosine, leading to the activation of ERVs in the failing heart. This ERV activation stimulated the antiviral innate immune pathways of TLR7/9 (Toll-like receptor 7/9) and NF-κB and lead to myocarditis and acute HF. Furthermore, restraining ERV activation and ERV-mediated innate immune responses by either adeno-associated virus serotype 9-mediated TRIM28 expression or a small-molecule TLR7/9 inhibitor improved heart function and alleviated HF in an ischemia/reperfusion model.</p><p><strong>Conclusions: </strong>ERV resurgence is a specific molecular trait of HF, driven by TRIM28 depletion in cardiomyocytes. ERV resurgence activates the innate immune TLR7/9-NF-κB pathway and induces myocarditis and HF. Inception of ERVs and the ERV-mediated immune pathway confers cardiac protection. These results identify TRIM28-ERV-TLR7/9-NF-κB as a target for therapeutic management of myocarditis and HF.</p>","PeriodicalId":10331,"journal":{"name":"Circulation","volume":" ","pages":"939-956"},"PeriodicalIF":38.6,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12466171/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144871749","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical Presentation and Outcomes After Surgery for Mitral Regurgitation: Real-World Insights From the MITRACURE International Registry.","authors":"David Messika-Zeitoun, Michael W A Chu, Denis Bouchard, Thierry Le Tourneau, Julien Ternacle, Philippe Demers, Linrui Guo, Angel Yi Nam Fu, Jean Claude Dib, Charmaine Lam, Thays Sokolov, Amedeo Anselmi, Didier Tchétché, Ophélie Brault Meslin, Ange Goutondji, Yoan Lavie-Badie, Patrick Seknadji, Augustin Coisne, Dimitri Arangalage, Anne Bernard, Usha Manian, Malek Kass, Antonio Fiore, Arnaud Maudiere, Yohann Bohbot, Aurélien Seemann, Nadjib Hammoudi, Loïc Bière, Pierre-Yves Leroux, Jessica Forcillo, Antoine Jeu, Benjamin Elegamandji, Christine Selton-Suty, Martine Gilard, Claire Bouleti, Omair Arshad, Jean-Francois Legare, Thiziri Si Moussi, Jian Ye, Catherine Sportouch, Bindu Bittira, Laura Munte, Fabrice Bauer, Geraldine Ong, Ali Fatehi Hassanabad, Jordan Bernick, George A Wells, Roja Gauda, Bernard Iung, William D T Kent, Jean-François Obadia, Julien Dreyfus","doi":"10.1161/CIRCULATIONAHA.124.073674","DOIUrl":"10.1161/CIRCULATIONAHA.124.073674","url":null,"abstract":"<p><strong>Background: </strong>Comprehensive knowledge of the clinical presentation, contemporary management, and outcomes on \"all-comer\" patients referred for mitral valve surgery (MVS) are critical to evaluate current practice and adherence to guidelines, understand selection biases, and inform key stakeholders on quality improvement.</p><p><strong>Methods: </strong>MITRACURE is a large international retrospective registry of consecutive adult patients who underwent isolated or combined MVS for mitral regurgitation (MR) in France or Canada in 2019 with in-depth clinical and echocardiographic characterization. Patients operated on for isolated mitral stenosis or who had a prior mitral valve intervention were excluded. Data were obtained from detailed chart abstraction and were site reported.</p><p><strong>Results: </strong>In 2019, 3522 patients underwent MVS (48% combined) across 40 centers (88±46 MVSs/center, median 80, interquartile [51-131]). Mean age was 65±12 years, and 35% were women. The most common MR etiology was myxomatous (61%), followed by functional (9%), infective endocarditis (9%), and rheumatic disease (7%). MR quantification was performed in only 43%. Advanced clinical presentation was common: 43% were in New York Heart Association class III/IV, 30% exhibited congestive heart failure, 47% were on diuretics, 22% had atrial fibrillation/flutter, 35% presented with reduced ejection fraction, and 22% had pulmonary hypertension (≥50 mm Hg). Most patients were symptomatic or presented with class I/IIa indication for intervention, and an early intervention was performed only in 3% of patients. The repair rate was 62% overall and 80% in myxomatous disease. In-hospital mortality was 4.5% overall but 2.3% in patients with myxomatous MR (1.8% isolated, 3.1% combined).</p><p><strong>Conclusions: </strong>MITRACURE provides a contemporary, multicenter, \"real-world\" picture of the clinical presentation, management, and in-hospital outcomes of MVS for MR in two Western countries. Patients were often referred late in the disease process, with few patients undergoing early intervention. The higher mortality and lower repair rates reported may be more reflective of an unselected MR patient population but have room for improvement. Our results underline the need to develop strategies to improve management and outcomes of patients with MR.</p>","PeriodicalId":10331,"journal":{"name":"Circulation","volume":" ","pages":"927-938"},"PeriodicalIF":38.6,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144945202","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Percutaneous Solutions for Tricuspid Regurgitation: Current Approved Options and Identifying Ideal Candidates.","authors":"Gloria Ayuba,Anish Bhatt,Anthony Bavry","doi":"10.1161/circulationaha.125.074143","DOIUrl":"https://doi.org/10.1161/circulationaha.125.074143","url":null,"abstract":"","PeriodicalId":10331,"journal":{"name":"Circulation","volume":"54 1","pages":"909-912"},"PeriodicalIF":37.8,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145188436","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single-Cell Splicing Isoform Atlas of the Adult Human Heart and Heart Failure.","authors":"Timothy Pan,Lina Lu,Keith Youker,Cheng-Kai Shiau,Minhua Wang,Hsiao-Yun Lin,Anh Nguyen,Yueying He,Eric Tong,Pei Zhu,Rajul Ranka,Yuanqing Yan,Arjun Sinha,Ankit Bharat,Todd Eagar,Jane Wilcox,Arvind Bhimaraj,Ruli Gao","doi":"10.1161/circulationaha.125.074959","DOIUrl":"https://doi.org/10.1161/circulationaha.125.074959","url":null,"abstract":"BACKGROUNDAlternative splicing plays crucial roles in normal heart development and cardiac disease by influencing protein-coding sequences, functional domains, and molecular networks. However, a detailed characterization of the human heart isoform landscape remains incomplete.METHODSLeveraging long-read single-nucleus RNA sequencing and computational analysis, we dissected full-length isoform heterogeneities, expression patterns, and usage shifts across cell types, cell states, and cardiac conditions of the adult left ventricle. We applied in silico approaches to assess the functional relevance of identified isoforms; validated isoform compositions of representative cardiac genes using reverse transcription quantitative polymerase chain reaction and targeted amplicon sequencing; and developed a web server for interactive navigation of our results.RESULTSThe data revealed that isoform heterogeneity is widespread in the cardiac cellular system, serving as a posttranscriptional buffer system that calibrates the molecule reservoirs in human hearts. In healthy left ventricles, ≈30% of cell type-specific genes were polyform, using multiple isoforms tailored to cell type-specific programs. Among ubiquitously expressed genes, >300 showed differential isoform usage with cell type specificity. Compared with heart failure, 379 genes in cardiomyocytes demonstrated marked isoform usage shifts, most of which are predicted to change protein coding outcomes through direct changes in protein coding sequences and switches between intron retention and non-protein-coding biotypes. In contrast, cell state-specific programs tend to operate on monoform genes associated with changes among cell states. In addition, our data revealed heart failure-associated differential isoform usage events in stromal and immune cell types in the cardiac microenvironment.CONCLUSIONSWe present a comprehensive atlas of splicing isoforms in the normal adult heart and heart failure through long-read single-nucleus RNA sequencing and comprehensive computational analyses. The results suggest crucial roles of isoforms in buffering core cellular programs and contributing to disease-associated cell states. The full-length details of these cell-specific isoforms serve as an important reference for downstream translational and mechanistic studies and are available on our online data portal at https://github.com/gaolabtools/heart-isoform-atlas.","PeriodicalId":10331,"journal":{"name":"Circulation","volume":"96 1","pages":""},"PeriodicalIF":37.8,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145182588","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Letter by Sechi et al Regarding Article, \"Independence of Lipoprotein(a) and Low-Density Lipoprotein Cholesterol-Medicated Cardiovascular Risk: A Participant-Level Meta-Analysis\".","authors":"Leonardo A Sechi,Luca Bulfone,Cristiana Catena","doi":"10.1161/circulationaha.124.073053","DOIUrl":"https://doi.org/10.1161/circulationaha.124.073053","url":null,"abstract":"","PeriodicalId":10331,"journal":{"name":"Circulation","volume":"114 1","pages":"e265-e266"},"PeriodicalIF":37.8,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145188433","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting Calcium Regulation for Heart Failure and Arrhythmia Therapeutics: A Critical Review.","authors":"Gabriel Redel-Traub,Steven O Marx,Andrew R Marks","doi":"10.1161/circulationaha.125.075150","DOIUrl":"https://doi.org/10.1161/circulationaha.125.075150","url":null,"abstract":"Despite advances in pharmacologic and procedural therapies, heart failure (HF) and cardiac arrhythmias remain significant global health burdens, highlighting the urgent need for novel therapeutic strategies. Defective Ca2+ handling in cardiac myocytes is recognized as a central pathogenic mechanism underlying both heart failure and atrial and ventricular arrhythmias. In this review, we critically assess the current state of research on Ca2+-handling proteins and their role in causing heart failure and arrhythmias, highlighting therapeutic implications. Recent paradigm-shifting discoveries, clinical trial outcomes, and challenges of targeting Ca2+-handling proteins are examined. As outlined in this review, an improved understanding of the relevant proteins and their differential expression and function in human health and disease is crucial for developing Ca2+ handling-targeted therapeutics that can fundamentally alter the natural history of heart failure and arrhythmias.","PeriodicalId":10331,"journal":{"name":"Circulation","volume":"114 1","pages":"957-970"},"PeriodicalIF":37.8,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145188444","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Subclinical Primary Aldosteronism: A Potential New Target in Cardiovascular Prevention?","authors":"Wanpen Vongpatanasin,Jesslin Abraham,John M Giacona","doi":"10.1161/circulationaha.125.076085","DOIUrl":"https://doi.org/10.1161/circulationaha.125.076085","url":null,"abstract":"","PeriodicalId":10331,"journal":{"name":"Circulation","volume":"16 1","pages":"924-926"},"PeriodicalIF":37.8,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145188491","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Response by Bhatia and Tsimikas to Letter Regarding Article, \"Independence of Lipoprotein(a) and Low-Density Lipoprotein Cholesterol-Medicated Cardiovascular Risk: A Participant-Level Meta-Analysis\".","authors":"Harpreet S Bhatia,Sotirios Tsimikas","doi":"10.1161/circulationaha.125.075455","DOIUrl":"https://doi.org/10.1161/circulationaha.125.075455","url":null,"abstract":"","PeriodicalId":10331,"journal":{"name":"Circulation","volume":"30 1","pages":"e267-e268"},"PeriodicalIF":37.8,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145188434","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sudden Cardiac Arrest and Death Secondary to Congenital Coronary Artery Abnormalities in Young Competitive Athletes.","authors":"Bradley J Petek,Timothy W Churchill,Nathaniel Moulson,Aaron L Baggish,Stephanie A Kliethermes,Joseph J Maleszewski,Randi Delong,Kristen L Kucera,Kimberly G Harmon,Jonathan A Drezner","doi":"10.1161/circulationaha.125.074330","DOIUrl":"https://doi.org/10.1161/circulationaha.125.074330","url":null,"abstract":"","PeriodicalId":10331,"journal":{"name":"Circulation","volume":"4 1","pages":"971-973"},"PeriodicalIF":37.8,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145188499","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}