JACC: Basic to Translational Science最新文献

{"title":"Carvedilol Activates a Myofilament Signaling Circuitry to Restore Cardiac Contractility in Heart Failure","authors":"Ying Wang PhD ,&nbsp;Meimi Zhao PhD ,&nbsp;Xianhui Liu PhD ,&nbsp;Bing Xu BS ,&nbsp;Gopireddy R. Reddy PhD ,&nbsp;Aleksandra Jovanovic PhD ,&nbsp;Qingtong Wang MD, PhD ,&nbsp;Chaoqun Zhu ,&nbsp;Heli Xu PhD ,&nbsp;Elizabeth F. Bayne PhD ,&nbsp;Wenjing Xiang BS ,&nbsp;Douglas G. Tilley PhD ,&nbsp;Ying Ge PhD ,&nbsp;Christopher G. Tate PhD ,&nbsp;Robert Feil PhD ,&nbsp;Joanna C. Chiu PhD ,&nbsp;Donald M. Bers PhD ,&nbsp;Yang K. Xiang PhD","doi":"10.1016/j.jacbts.2024.03.007","DOIUrl":"10.1016/j.jacbts.2024.03.007","url":null,"abstract":"<div><p>Phosphorylation of myofilament proteins critically regulates beat-to-beat cardiac contraction and is typically altered in heart failure (HF). β-Adrenergic activation induces phosphorylation in numerous substrates at the myofilament. Nevertheless, how cardiac β-adrenoceptors (βARs) signal to the myofilament in healthy and diseased hearts remains poorly understood. The aim of this study was to uncover the spatiotemporal regulation of local βAR signaling at the myofilament and thus identify a potential therapeutic target for HF. Phosphoproteomic analysis of substrate phosphorylation induced by different βAR ligands in mouse hearts was performed. Genetically encoded biosensors were used to characterize cyclic adenosine and guanosine monophosphate signaling and the impacts on excitation-contraction coupling induced by β₁AR ligands at both the cardiomyocyte and whole-heart levels. Myofilament signaling circuitry was identified, including protein kinase G1 (PKG1)–dependent phosphorylation of myosin light chain kinase, myosin phosphatase target subunit 1, and myosin light chain at the myofilaments. The increased phosphorylation of myosin light chain enhances cardiac contractility, with a minimal increase in calcium (Ca²⁺) cycling. This myofilament signaling paradigm is promoted by carvedilol-induced β₁AR–nitric oxide synthetase 3 (NOS3)–dependent cyclic guanosine monophosphate signaling, drawing a parallel to the β₁AR–cyclic adenosine monophosphate–protein kinase A pathway. In patients with HF and a mouse HF model of myocardial infarction, increasing expression and association of NOS3 with β₁AR were observed. Stimulating β₁AR-NOS3-PKG1 signaling increased cardiac contraction in the mouse HF model. This research has characterized myofilament β₁AR-PKG1-dependent signaling circuitry to increase phosphorylation of myosin light chain and enhance cardiac contractility, with a minimal increase in Ca²⁺ cycling. The present findings raise the possibility of targeting this myofilament signaling circuitry for treatment of patients with HF.</p></div>","PeriodicalId":14831,"journal":{"name":"JACC: Basic to Translational Science","volume":"9 8","pages":"Pages 982-1001"},"PeriodicalIF":8.4,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2452302X24001049/pdfft?md5=b769b8c6532a03aacea9aeb17875e508&pid=1-s2.0-S2452302X24001049-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142076942","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":"Exploring Cardiac Fibrosis","authors":"Rudolf A. de Boer MD, PhD ,&nbsp;Reza Ardehali MD, PhD","doi":"10.1016/j.jacbts.2024.06.006","DOIUrl":"10.1016/j.jacbts.2024.06.006","url":null,"abstract":"","PeriodicalId":14831,"journal":{"name":"JACC: Basic to Translational Science","volume":"9 8","pages":"Pages 1023-1025"},"PeriodicalIF":8.4,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2452302X24002511/pdfft?md5=ecb69569eada2b1e5ced361205683ac9&pid=1-s2.0-S2452302X24002511-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142077105","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":"Recognizing Early Career Translational Investigators","authors":"Douglas L. Mann MD (Editor-in-Chief: JACC: Basic to Translational Science)","doi":"10.1016/j.jacbts.2024.07.001","DOIUrl":"10.1016/j.jacbts.2024.07.001","url":null,"abstract":"","PeriodicalId":14831,"journal":{"name":"JACC: Basic to Translational Science","volume":"9 8","pages":"Pages 1053-1054"},"PeriodicalIF":8.4,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2452302X24002559/pdfft?md5=62b9566391e44a42b2e7a00c62149ea9&pid=1-s2.0-S2452302X24002559-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142076972","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":"Percutaneous LAAO and Pulsed-Field Isolation in a Canine Model","authors":"Fengyuan Yu MD ,&nbsp;Xiaonan Dong MD, PhD ,&nbsp;Yang Sun PhD ,&nbsp;Vivek Reddy MD ,&nbsp;Horst Sievert MD ,&nbsp;Min Tang MD, PhD","doi":"10.1016/j.jacbts.2024.05.008","DOIUrl":"10.1016/j.jacbts.2024.05.008","url":null,"abstract":"<div><p>In this study, we investigated the feasibility, safety, and efficiency of using a novel device system to perform percutaneous left atrial appendage occlusion concomitant with left atrial appendage electrical isolation (LAAEI) via pulsed field ablation. In the acute phase, LAAEI was successful in 10 of 10 canines. At follow-up, full endothelialization was observed in 5 of 5 (100%) cases at 6 months. LAAEI was durable in 8 of 10 (80.00%) canines. Histologic examination in 4 of 6 LAAs with durable isolation showed transmural scars comprising fibrosis and fat. No pericardial effusion or phrenic paralysis was observed at follow-up. This preliminary study provides the scientific basis for first-in-human studies.</p></div>","PeriodicalId":14831,"journal":{"name":"JACC: Basic to Translational Science","volume":"9 8","pages":"Pages 971-981"},"PeriodicalIF":8.4,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2452302X24002158/pdfft?md5=bf8592b583224c93e5c2765c3e7770f5&pid=1-s2.0-S2452302X24002158-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141846809","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":"A New Ex Vivo Model to Study Cardiac Fibrosis in Whole Mouse Hearts","authors":"Boudewijn P.T. Kruithof PhD ,&nbsp;Babak Mousavi Gourabi ing ,&nbsp;Arjanneke F. van de Merbel MSc ,&nbsp;Marco C. DeRuiter PhD ,&nbsp;Marie-José Goumans PhD","doi":"10.1016/j.jacbts.2024.04.007","DOIUrl":"10.1016/j.jacbts.2024.04.007","url":null,"abstract":"<div><p>Fibrosis is a characteristic of many cardiac diseases for which no effective treatment exists. We have developed an ex vivo flow system, which allows induction of cardiac fibrosis in intact adult mouse hearts. Lineage-tracing studies indicated that the collagen-producing myofibroblasts originated from the resident fibroblasts. The extent of fibrosis was flow rate dependent, and pharmacological inhibition of the transforming growth factor beta signaling pathway prevented fibrosis. Therefore, in this powerful system, the cellular and molecular mechanisms underlying cardiac fibrosis can be studied. In addition, new targets can be tested on organ level for their ability to inhibit fibrosis.</p></div>","PeriodicalId":14831,"journal":{"name":"JACC: Basic to Translational Science","volume":"9 8","pages":"Pages 1005-1022"},"PeriodicalIF":8.4,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2452302X24001761/pdfft?md5=dc7f3b5d33dd035f87483d2e94ca8a78&pid=1-s2.0-S2452302X24001761-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142076944","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":"Empowering the Future: The Importance of Recognizing Early Career Scientists in JACC: Basic to Translational Science","authors":"Douglas L. Mann MD (Editor-in-Chief, JACC: Basic to Translational Science)","doi":"10.1016/j.jacbts.2024.07.002","DOIUrl":"10.1016/j.jacbts.2024.07.002","url":null,"abstract":"","PeriodicalId":14831,"journal":{"name":"JACC: Basic to Translational Science","volume":"9 8","pages":"Page 1055"},"PeriodicalIF":8.4,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2452302X24002572/pdfft?md5=036312729c00aed9480e98ea75b7b7b4&pid=1-s2.0-S2452302X24002572-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142076973","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":"Reduced Stroke Volume and Brain Perfusion Drive Postural Hyperventilation in Postural Orthostatic Tachycardia Syndrome","authors":"Jacquie R. Baker PhD ,&nbsp;Anthony V. Incognito PhD ,&nbsp;Shaun I. Ranada BSc ,&nbsp;Robert S. Sheldon MD, PhD ,&nbsp;Keith A. Sharkey PhD ,&nbsp;Aaron A. Phillips PhD ,&nbsp;Richard J.A. Wilson PhD ,&nbsp;Satish R. Raj MD","doi":"10.1016/j.jacbts.2024.04.011","DOIUrl":"10.1016/j.jacbts.2024.04.011","url":null,"abstract":"<div><p>Postural hyperventilation has been implicated as a cause of postural orthostatic tachycardia syndrome (POTS), yet the precise mechanisms underlying the heightened breathing response remain unclear. This study challenges current hypotheses by revealing that exaggerated peripheral chemoreceptor activity is not the primary driver of postural hyperventilation. Instead, significant contributions from reduced stroke volume and compromised brain perfusion during orthostatic stress were identified. These findings shed light on our understanding of POTS pathophysiology, emphasizing the critical roles of systemic hemodynamic status. Further research should explore interventions targeting stroke volume and brain perfusion for more effective clinical management of POTS.</p></div>","PeriodicalId":14831,"journal":{"name":"JACC: Basic to Translational Science","volume":"9 8","pages":"Pages 939-953"},"PeriodicalIF":8.4,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2452302X24001840/pdfft?md5=b5757b235b6cd1cded084a5319731689&pid=1-s2.0-S2452302X24001840-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142077103","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":"Association Between Clonal Hematopoiesis and Left Ventricular Reverse Remodeling in Nonischemic Dilated Cardiomyopathy","authors":"","doi":"10.1016/j.jacbts.2024.04.010","DOIUrl":"10.1016/j.jacbts.2024.04.010","url":null,"abstract":"<div><p>Although clonal hematopoiesis of indeterminate potential (CHIP) is an adverse prognostic factor for atherosclerotic disease, its impact on nonischemic dilated cardiomyopathy (DCM) is elusive. The authors performed whole-exome sequencing and deep target sequencing among 198 patients with DCM and detected germline mutations in cardiomyopathy-related genes and somatic mutations in CHIP driver genes. Twenty-five CHIP driver mutations were detected in 22 patients with DCM. Ninety-two patients had cardiomyopathy-related pathogenic mutations. Multivariable analysis revealed that CHIP was an independent risk factor of left ventricular reverse remodeling, irrespective of known prognostic factors. CHIP exacerbated cardiac systolic dysfunction and fibrosis in a DCM murine model. The identification of germline and somatic mutations in patients with DCM predicts clinical prognosis.</p></div>","PeriodicalId":14831,"journal":{"name":"JACC: Basic to Translational Science","volume":"9 8","pages":"Pages 956-967"},"PeriodicalIF":8.4,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2452302X24001839/pdfft?md5=cc874762764de0cd7d19f08b5f3343e6&pid=1-s2.0-S2452302X24001839-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141408407","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":"A Novel Pathway of Platelet Activation in ACS Mediated by LL-37 Immunoglobulin G Autoantibody Immune Complexes","authors":"Paul C. Dimayuga PhD ,&nbsp;Kuang-Yuh Chyu MD, PhD ,&nbsp;Xiaoning Zhao PhD ,&nbsp;Jianchang Zhou PhD ,&nbsp;Nicole Wai Man Lio BS ,&nbsp;Fernando Chernomordik MD ,&nbsp;Daniel Berman MD ,&nbsp;Prediman K. Shah MD ,&nbsp;Bojan Cercek MD, PhD","doi":"10.1016/j.jacbts.2024.04.012","DOIUrl":"10.1016/j.jacbts.2024.04.012","url":null,"abstract":"<div><p>The cathelicidin antimicrobial peptide LL-37 is a self-antigen in neutrophil extracellular traps that provokes autoantibody responses in autoimmune/autoinflammatory conditions. LL-37 immunoglobulin (Ig) G autoantibody levels were measured in subjects with and without atherosclerotic cardiovascular disease assessed using the coronary artery calcium score, in patients who had a future myocardial infarction and in a cohort of acute coronary syndrome (ACS) patients. LL-37 IgG levels were not associated with coronary artery calcium score, but future myocardial infarction patients had significantly higher LL-37 IgG at baseline. Reduced LL-37 IgG in ACS was associated with increased LL-37 IgG–immune complex. ACS plasma increased activated CD62P+ platelets from healthy donors mediated in part by LL-37 IgG–immune complexes and platelet Fc gamma receptor 2a.</p></div>","PeriodicalId":14831,"journal":{"name":"JACC: Basic to Translational Science","volume":"9 7","pages":"Pages 877-887"},"PeriodicalIF":8.4,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2452302X24001852/pdfft?md5=a6e5c6a86e9151e8b8e985941cfea515&pid=1-s2.0-S2452302X24001852-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141847709","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":"Human Aortic Stenotic Valve-Derived Extracellular Vesicles Induce Endothelial Dysfunction and Thrombogenicity Through AT1R/NADPH Oxidases/SGLT2 Pro-Oxidant Pathway","authors":"Sandy Hmadeh PhD ,&nbsp;Antonin Trimaille MD, MSc ,&nbsp;Kensuke Matsushita MD, PhD ,&nbsp;Benjamin Marchandot MD ,&nbsp;Adrien Carmona MD ,&nbsp;Fatiha Zobairi BSc ,&nbsp;Chisato Sato MD, PhD ,&nbsp;Michel Kindo MD, PhD ,&nbsp;Tam Minh Hoang MD ,&nbsp;Florence Toti PhD ,&nbsp;Kazem Zibara PhD ,&nbsp;Eva Hamade PhD ,&nbsp;Valérie Schini-Kerth PhD ,&nbsp;Gilles Kauffenstein PhD ,&nbsp;Olivier Morel MD, PhD","doi":"10.1016/j.jacbts.2024.02.012","DOIUrl":"10.1016/j.jacbts.2024.02.012","url":null,"abstract":"<div><p>Pathological tissues release a variety of factors, including extracellular vesicles (EVs) shed by activated or apoptotic cells. EVs trapped within the native pathological valves may act as key mediators of valve thrombosis. Human aortic stenosis EVs promote activation of valvular endothelial cells, leading to endothelial dysfunction, and proadhesive and procoagulant responses.</p></div>","PeriodicalId":14831,"journal":{"name":"JACC: Basic to Translational Science","volume":"9 7","pages":"Pages 845-864"},"PeriodicalIF":8.4,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2452302X24000901/pdfft?md5=01e109e05e1c49392f43b2d6319c6c96&pid=1-s2.0-S2452302X24000901-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141614402","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}