CirculationPub Date : 2025-04-29Epub Date: 2025-03-24DOI: 10.1161/CIRCULATIONAHA.124.072226
Liang Chen, Yuxiao Hu, Ardan M Saguner, Barbara Bauce, Yaxin Liu, Anteng Shi, Fu Guan, Zhongli Chen, Maria Bueno Marinas, Lingmin Wu, Deborah Foltran, Alexis Hermida, Veronique Fressart, Serena Pinci, Rudy Celeghin, Zixian Chen, Baowei Zhang, Yubi Lin, Xiaorui Liu, Marco Cason, Marika Martini, Ilaria Rigato, Corinna Brunckhorst, Ruth Biller, Cristina Basso, Bing Yang, Xiaoyan Zhao, Julia Cadrin-Tourigny, Alessio Gasperetti, Cynthia A James, Xianliang Zhou, Estelle Gandjbakhch, Kalliopi Pilichou, Firat Duru, Shengshou Hu
{"title":"Natural History and Clinical Outcomes of Patients With <i>DSG2/DSC2</i> Variant-Related Arrhythmogenic Right Ventricular Cardiomyopathy.","authors":"Liang Chen, Yuxiao Hu, Ardan M Saguner, Barbara Bauce, Yaxin Liu, Anteng Shi, Fu Guan, Zhongli Chen, Maria Bueno Marinas, Lingmin Wu, Deborah Foltran, Alexis Hermida, Veronique Fressart, Serena Pinci, Rudy Celeghin, Zixian Chen, Baowei Zhang, Yubi Lin, Xiaorui Liu, Marco Cason, Marika Martini, Ilaria Rigato, Corinna Brunckhorst, Ruth Biller, Cristina Basso, Bing Yang, Xiaoyan Zhao, Julia Cadrin-Tourigny, Alessio Gasperetti, Cynthia A James, Xianliang Zhou, Estelle Gandjbakhch, Kalliopi Pilichou, Firat Duru, Shengshou Hu","doi":"10.1161/CIRCULATIONAHA.124.072226","DOIUrl":"10.1161/CIRCULATIONAHA.124.072226","url":null,"abstract":"<p><strong>Background: </strong>Genetic variants in desmosomal cadherins, desmoglein 2 (<i>DSG2</i>) and desmocollin 2 (<i>DSC2</i>), cause a distinct form of arrhythmogenic right ventricular cardiomyopathy (ARVC), which remains poorly reported. In this study, we aimed to provide a comprehensive description of the phenotypic expression, natural history, and clinical outcomes of patients with this ARVC subset.</p><p><strong>Methods: </strong>Genetic and clinical data of <i>DSG2</i> and <i>DSC2</i> variant carriers were collected from 5 countries in Europe and Asia. We assessed the phenotypic profile of these patients and their clinical outcomes, focusing on heart failure and ventricular arrhythmia events.</p><p><strong>Results: </strong>Overall, 271 subjects, 254 with <i>DSG2</i> variants, were included in this study (median age, 38 years [interquartile range, 25-52]; 62.7% male). Of these, 165 were probands, and 200 were diagnosed with definite ARVC. A total of 181 (66.8%) individuals carried missense variants, mainly distributed in the extracellular domains. Notably, we included 78 (28.8%) individuals with multiple variants. Of the 200 cases with diagnosed ARVC, 41 (20.5%) experienced premature cardiac death before the age of 65. Among the 81 individuals for whom both left ventricular ejection fraction and right ventricular fractional area change data were available at presentation, 29 (35.8%) had isolated right ventricular dysfunction, and 16 (19.8%) had biventricular dysfunction. Single-variant carriers who engaged in intense physical exercise were younger at disease onset compared with those who did not (<i>P</i>=0.001). Compared with single-variant carriers, those with multiple variants were more likely to be diagnosed with ARVC (96.2% versus 64.8%; <i>P</i><0.001) and exhibited more severe left ventricular dysfunction (44.4% versus 22.1%; <i>P</i>=0.001) and right ventricular dilation (88.9% versus 55.8%, <i>P</i><0.001). Multiple-variant carriers were significantly younger at ARVC diagnosis compared with single-variant carriers (33 [18-49] years versus 42 [27-54] years; <i>P</i><0.001]. During follow-up, end-stage heart failure (<i>P</i><0.001) and malignant ventricular arrhythmias (<i>P</i>=0.004) were significantly more frequent in multiple-variant compared with single-variant carriers. Compared with <i>PKP2</i> patients, <i>DSG2/DSC2</i> patients exhibited a significantly higher risk of end-stage heart failure (<i>P</i><0.001).</p><p><strong>Conclusions: </strong>ARVC attributable to variants in desmosomal cadherins mostly present with right ventricular or biventricular disease. Multiple variants are common in these patients and are associated with more frequent clinical penetrance, earlier onset of disease, and adverse clinical outcomes.</p>","PeriodicalId":10331,"journal":{"name":"Circulation","volume":" ","pages":"1213-1230"},"PeriodicalIF":35.5,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143691367","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}
CirculationPub Date : 2025-04-29Epub Date: 2025-04-28DOI: 10.1161/CIR.0000000000001338
Todd M Brown, Quinn R Pack, Ellen Aberegg, LaPrincess C Brewer, Yvonne R Ford, Daniel E Forman, Emily C Gathright, Sherrie Khadanga, Cemal Ozemek, Randal J Thomas
{"title":"Correction to: Core Components of Cardiac Rehabilitation Programs: 2024 Update: A Scientific Statement From the American Heart Association and the American Association of Cardiovascular and Pulmonary Rehabilitation.","authors":"Todd M Brown, Quinn R Pack, Ellen Aberegg, LaPrincess C Brewer, Yvonne R Ford, Daniel E Forman, Emily C Gathright, Sherrie Khadanga, Cemal Ozemek, Randal J Thomas","doi":"10.1161/CIR.0000000000001338","DOIUrl":"https://doi.org/10.1161/CIR.0000000000001338","url":null,"abstract":"","PeriodicalId":10331,"journal":{"name":"Circulation","volume":"151 17","pages":"e965-e966"},"PeriodicalIF":35.5,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143953595","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}
CirculationPub Date : 2025-04-29Epub Date: 2025-02-10DOI: 10.1161/CIRCULATIONAHA.124.070782
Ximeng Han, Yi Li, Enci Wang, Huan Zhu, Xiuzhen Huang, Wenjuan Pu, Mingjun Zhang, Kuo Liu, Huan Zhao, Zixin Liu, Yufei Zhao, Linghong Shen, Yan Li, Xiao Yang, Qing-Dong Wang, Xin Ma, Ruling Shen, Kathy O Lui, Lixin Wang, Ben He, Bin Zhou
{"title":"Exploring Origin-Dependent Susceptibility of Smooth Muscle Cells to Aortic Diseases Through Intersectional Genetics.","authors":"Ximeng Han, Yi Li, Enci Wang, Huan Zhu, Xiuzhen Huang, Wenjuan Pu, Mingjun Zhang, Kuo Liu, Huan Zhao, Zixin Liu, Yufei Zhao, Linghong Shen, Yan Li, Xiao Yang, Qing-Dong Wang, Xin Ma, Ruling Shen, Kathy O Lui, Lixin Wang, Ben He, Bin Zhou","doi":"10.1161/CIRCULATIONAHA.124.070782","DOIUrl":"10.1161/CIRCULATIONAHA.124.070782","url":null,"abstract":"<p><strong>Background: </strong>The developmental diversity among smooth muscle cells (SMCs) plays a crucial role in segment-specific aortic diseases. However, traditional genetic approaches are inadequate for enabling in vivo analysis of disease susceptibility associated with cellular origin. There is an urgent need to build genetic technologies that target different developmental origins to investigate the mechanisms of aortopathies, thereby facilitating the development of effective therapeutics.</p><p><strong>Methods: </strong>To address this challenge, we developed an advanced dual recombinase-mediated intersectional genetic system, specifically designed to precisely target SMCs from various developmental origins in mice. Specifically, we used <i>Isl1-Dre</i>, <i>Wnt1-Dre</i>, <i>Meox1-DreER</i>, and <i>Upk3b-Dre</i> to target SMC progenitors from the second heart field, cardiac neural crest, somites, and mesothelium, respectively. This system was combined with single-cell RNA sequencing to investigate the impact of TGF-β (transforming growth factor-β) signaling in different segments of the aorta by selectively knocking out Tgfbr2 in the ascending aorta and Smad4 in the aortic arch, respectively.</p><p><strong>Results: </strong>Through intersectional genetic approaches, we use the <i>Myh11-Cre(ER</i>) driver along with origin-specific Dre drivers to trace cells of diverse developmental origins within the SMC population. We found that a deficiency of Tgfbr2 in SMCs of the ascending aorta leads to aneurysm formation in this specific region. We also demonstrate the critical role of Smad4 in preserving aortic wall integrity and homeostasis in SMCs of the aortic arch.</p><p><strong>Conclusions: </strong>Our approach to genetically targeting SMC subtypes provides a novel platform for exploring origin-dependent or location-specific aortic vascular diseases. This genetic system enables comprehensive analysis of contributions from different cell lineages to SMC behavior and pathology, thereby paving the way for targeted research and therapeutic interventions in the future.</p>","PeriodicalId":10331,"journal":{"name":"Circulation","volume":" ","pages":"1248-1267"},"PeriodicalIF":35.5,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143381739","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 Bonnesen et al to Letter Regarding Article, \"Comparative Cardiovascular Effectiveness of Empagliflozin Versus Dapagliflozin in Adults With Treated Type 2 Diabetes: A Target Trial Emulation\".","authors":"Kasper Bonnesen,Uffe Heide-Jørgensen,Morten Schmidt","doi":"10.1161/circulationaha.125.073970","DOIUrl":"https://doi.org/10.1161/circulationaha.125.073970","url":null,"abstract":"","PeriodicalId":10331,"journal":{"name":"Circulation","volume":"17 1","pages":"e964"},"PeriodicalIF":37.8,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143889257","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}
CirculationPub Date : 2025-04-28DOI: 10.1161/circulationaha.124.072362
Jiayang Dong,Xinyue Yang,Wenjuan Zhang
{"title":"Letter by Dong et al Regarding Article, \"Comparative Cardiovascular Effectiveness of Empagliflozin Versus Dapagliflozin in Adults With Treated Type 2 Diabetes: A Target Trial Emulation\".","authors":"Jiayang Dong,Xinyue Yang,Wenjuan Zhang","doi":"10.1161/circulationaha.124.072362","DOIUrl":"https://doi.org/10.1161/circulationaha.124.072362","url":null,"abstract":"","PeriodicalId":10331,"journal":{"name":"Circulation","volume":"69 1","pages":"e962-e963"},"PeriodicalIF":37.8,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143889258","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}
CirculationPub Date : 2025-04-28DOI: 10.1161/CIRCULATIONAHA.124.071772
Mohamed Ameen Ismahil, Guihua Zhou, Shreya Rajasekar, Min Gao, Shyam S Bansal, Bindiya Patel, Nita Limdi, Min Xie, Sergey Antipenko, Gregg Rokosh, Tariq Hamid, Sumanth D Prabhu
{"title":"Splenic CD169<sup>+</sup>Tim4<sup>+</sup> Marginal Metallophilic Macrophages Are Essential for Wound Healing After Myocardial Infarction.","authors":"Mohamed Ameen Ismahil, Guihua Zhou, Shreya Rajasekar, Min Gao, Shyam S Bansal, Bindiya Patel, Nita Limdi, Min Xie, Sergey Antipenko, Gregg Rokosh, Tariq Hamid, Sumanth D Prabhu","doi":"10.1161/CIRCULATIONAHA.124.071772","DOIUrl":"https://doi.org/10.1161/CIRCULATIONAHA.124.071772","url":null,"abstract":"<p><strong>Background: </strong>Fidelity of wound healing after myocardial infarction (MI) is an important determinant of subsequent adverse cardiac remodeling and failure. Macrophages derived from infiltrating Ly6C<sup>hi</sup> (lymphocyte antigen 6 complex, locus C) blood monocytes are a key component of this healing response; however, the importance of other macrophage populations is unclear.</p><p><strong>Methods: </strong>We used a variety of in vivo murine models and orthogonal approaches, including surgical MI, flow cytometry and single-cell RNA sequencing, lineage tracing and cell tracking, splenectomy, parabiosis, cell adoptive transfer, and functional characterization, to establish an essential role for splenic CD169<sup>+</sup>Tim4<sup>+</sup> (cluster of differentiation 169<sup>+</sup>; T cell immunoglobulin- and mucin-domain-containing molecule 4) marginal metallophilic macrophages (MMMs) in post-MI wound healing in mice. Flow cytometry was used to measure circulating CD169<sup>+</sup>Tim4<sup>+</sup> monocytes in humans with ST-segment-elevation MI and control participants with stable coronary artery disease undergoing elective percutaneous coronary intervention.</p><p><strong>Results: </strong>Splenic CD169<sup>+</sup>Tim4<sup>+</sup> MMMs circulate in blood as Ly6C<sup>low</sup> monocytes expressing macrophage markers and help populate CD169<sup>+</sup>Tim4<sup>+</sup>CCR2<sup>-</sup>LYVE1<sup>low</sup> macrophages in the naive heart. After acute MI, splenic MMMs augment phagocytosis and CCR (C-C motif chemokine receptor) 3 and CCR4 expression, and robustly mobilize to the heart, resulting in marked expansion of cardiac CD169<sup>+</sup>Tim4<sup>+</sup>LYVE1<sup>low</sup> macrophages with an immunomodulatory and proresolving gene signature. These macrophages are obligatory for apoptotic neutrophil clearance, suppression of inflammation, and induction of a reparative macrophage phenotype in the infarcted heart. Splenic MMMs are both necessary and sufficient for post-MI wound healing, and limit late pathological remodeling. Liver X receptor-α agonist-induced expansion of the splenic marginal zone and MMMs during acute MI alleviates inflammation and improves short- and long-term cardiac remodeling. Humans with acute ST-segment-elevation MI also exhibit expansion of circulating CD169<sup>+</sup>Tim4<sup>+</sup> cells, primarily within the intermediate (CD14<sup>+</sup>CD16<sup>+</sup>) monocyte population.</p><p><strong>Conclusions: </strong>Splenic CD169<sup>+</sup>Tim4<sup>+</sup> MMMs are required for proresolving and reparative responses after MI and can be manipulated for therapeutic benefit to limit long-term heart failure.</p>","PeriodicalId":10331,"journal":{"name":"Circulation","volume":" ","pages":""},"PeriodicalIF":35.5,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143984044","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":"Suppression of the Prostaglandin I2-Type 1 Interferon Axis Induces Extramedullary Hematopoiesis to Promote Cardiac Repair After Myocardial Infarction.","authors":"Huizhen Lv,Chenchen Wang,Zening Liu,Meixi Quan,Kan Li,Fanglin Gou,Xuelian Shi,Qian Liu,Ying Yu,Ping Zhu,Hui Cheng,Tao Cheng,Ding Ai","doi":"10.1161/circulationaha.124.069420","DOIUrl":"https://doi.org/10.1161/circulationaha.124.069420","url":null,"abstract":"BACKGROUNDImmune cells are closely associated with all processes of cardiac repair after myocardial infarction (MI), including the initiation, development, and resolution of inflammation. Spleen extramedullary hematopoiesis (EMH) serves as a crucial source of emergency mature blood cells that are generated through the self-renewal and differentiation of hematopoietic stem/progenitor cells (HSPCs). However, how EMH responds to MI and the role of EMH in cardiac repair after MI remains unclear.METHODSTo assess the role of spleen EMH in MI, a Tcf21CreER Scfflox/flox MI mouse model with inhibited EMH was constructed. GFP+ (green fluorescent protein) hematopoietic stem cells were sorted from eGFP (enhanced green fluorescent protein) mouse spleen by flow cytometry and injected into Tcf21CreER Scfflox/flox mice to test the sources of local inflammatory cells during MI. Using highly specific liquid chromatography-tandem mass spectrometry and single-cell RNA sequencing, we analyzed the lipidomic profile of arachidonic acid metabolites and the transcriptomes of HSPCs in the spleen after MI.RESULTSWe found that MI enhanced EMH, as reflected by the increase in spleen weight and volume and the number of HSPCs in the spleen. The lack of EMH in Scf-deficient mice exacerbated tissue injury after MI. Analysis of the transcriptome of spleen HSPCs after MI revealed that the type 1 interferon pathway was substantially inhibited in hematopoietic stem cell/multipotent progenitor subclusters, and the absence of type 1 interferon signaling enhanced the MI-induced spleen EMH. Lipidomics analysis revealed that prostaglandin I2 (PGI2) was markedly reduced in the spleen. PGI2 suppressed MI-induced EMH through a PGI2 receptor (IP)-cyclic adenosine monophosphate-453p-SP1 cascade in spleen HSPCs. Hematopoietic cell-specific IP-deficient mice exhibited enhanced EMH and improved cardiac recovery after MI.CONCLUSIONSTogether, our findings revealed that a PGI2-IFN axis was involved in spleen EMH after MI, providing new mechanistic insights into spleen EMH after MI and offering a new therapeutic target for treating ischemic cardiac injury.","PeriodicalId":10331,"journal":{"name":"Circulation","volume":"36 1","pages":""},"PeriodicalIF":37.8,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143885488","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}
CirculationPub Date : 2025-04-28DOI: 10.1161/circulationaha.125.074022
Anneline S J M Te Riele,J Peter van Tintelen,Richard N W Hauer
{"title":"A Plea for a Genetics-First Approach in Arrhythmogenic Cardiomyopathies.","authors":"Anneline S J M Te Riele,J Peter van Tintelen,Richard N W Hauer","doi":"10.1161/circulationaha.125.074022","DOIUrl":"https://doi.org/10.1161/circulationaha.125.074022","url":null,"abstract":"","PeriodicalId":10331,"journal":{"name":"Circulation","volume":"36 1","pages":"1231-1234"},"PeriodicalIF":37.8,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143889255","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}
CirculationPub Date : 2025-04-28DOI: 10.1161/circulationaha.125.073364
Mark W Majesky
{"title":"New Tools for Precision Targeting of Origin-Specific Vascular Smooth Muscle Cells Using Intersectional Genetics.","authors":"Mark W Majesky","doi":"10.1161/circulationaha.125.073364","DOIUrl":"https://doi.org/10.1161/circulationaha.125.073364","url":null,"abstract":"","PeriodicalId":10331,"journal":{"name":"Circulation","volume":"140 1","pages":"1268-1271"},"PeriodicalIF":37.8,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143889256","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}