Circulation最新文献

{"title":"An NRF2/β3-Adrenoreceptor Axis Drives a Sustained Antioxidant and Metabolic Rewiring Through the Pentose-Phosphate Pathway to Alleviate Cardiac Stress.","authors":"Lauriane Y M Michel, Hrag Esfahani, Delphine De Mulder, Roxane Verdoy, Jérôme Ambroise, Véronique Roelants, Bertrand Bouchard, Nathalie Fabian, Jérôme Savary, Joseph P Dewulf, Thomas Doumont, Caroline Bouzin, Vincent Haufroid, Joost J F P Luiken, Miranda Nabben, Michael L Singleton, Luc Bertrand, Matthieu Ruiz, Christine Des Rosiers, Jean-Luc Balligand","doi":"10.1161/CIRCULATIONAHA.124.067876","DOIUrl":"10.1161/CIRCULATIONAHA.124.067876","url":null,"abstract":"<p><strong>Background: </strong>Cardiac β3-adrenergic receptors (ARs) are upregulated in diseased hearts and mediate antithetic effects to those of β1AR and β2AR. β3AR agonists were recently shown to protect against myocardial remodeling in preclinical studies and to improve systolic function in patients with severe heart failure. However, the underlying mechanisms remain elusive.</p><p><strong>Methods: </strong>To dissect functional, transcriptional, and metabolic effects, hearts and isolated ventricular myocytes from mice harboring a moderate, cardiac-specific expression of a human <i>ADRB3</i> transgene (β3AR-Tg) and subjected to transverse aortic constriction were assessed with echocardiography, RNA sequencing, positron emission tomography scan, metabolomics, and metabolic flux analysis. Subsequently, signaling and metabolic pathways were further investigated in vivo in β3AR-Tg and ex vivo in neonatal rat ventricular myocytes adenovirally infected to express β3AR and subjected to neurohormonal stress. These results were complemented with an analysis of single-nucleus RNA-sequencing data from human cardiac myocytes from patients with heart failure.</p><p><strong>Results: </strong>Compared with wild-type littermates, β3AR-Tg mice were protected from hypertrophy after transaortic constriction, and systolic function was preserved. β3AR-expressing hearts displayed enhanced myocardial glucose uptake under stress in the absence of increased lactate levels. Instead, metabolomic and metabolic flux analyses in stressed hearts revealed an increase in intermediates of the pentose-phosphate pathway in β3AR-Tg, an alternative route of glucose utilization, paralleled with increased transcript levels of NADPH-producing and rate-limiting enzymes of the pentose-phosphate pathway, without fueling the hexosamine metabolism. The ensuing increased content of NADPH and of reduced glutathione decreased myocyte oxidant stress, whereas downstream oxidative metabolism assessed by oxygen consumption was preserved with higher glucose oxidation in β3AR-Tg mice after transaortic constriction compared with wild type, together with increased mitochondrial biogenesis. Unbiased transcriptomics and pathway analysis identified NRF2 (NFE2L2) as an upstream transcription factor that was functionally verified in vivo and in β3AR-expressing cardiac myocytes, where its translocation and nuclear activity were dependent on β3AR activation of nitric oxide synthase and nitric oxide production through S-nitrosation of the NRF2-negative regulator Keap1.</p><p><strong>Conclusions: </strong>Moderate expression of cardiac β3AR, at levels observed in human cardiac myocardium, exerts metabolic and antioxidant effects through activation of the pentose-phosphate pathway and NRF2 pathway through S-nitrosation of Keap1, thereby preserving myocardial oxidative metabolism, function, and integrity under pathophysiological stress.</p>","PeriodicalId":10331,"journal":{"name":"Circulation","volume":" ","pages":"1312-1328"},"PeriodicalIF":35.5,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12052078/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143604079","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":"Aortic Valve Calcification Is Induced by the Loss of ALDH1A1 and Can Be Prevented by Agonists of Retinoic Acid Receptor Alpha: Preclinical Evidence for Drug Repositioning.","authors":"Mickael Rosa, Annabelle Dupont, David M Smadja, Jérôme Soquet, Johan Abdoul, Thibault Pamart, Flavien Vincent, Christina Le Tanno, Eloise Borowczak, Timothée Bigot, Alexandre Ung, Bertrand Vaast, Mélanie Daniel, Ramadan Jashari, Frédéric Mouquet, Cedric Delhaye, Yoann Sottejeau, Jeanne Rancic, Delphine Corseaux, Francis Juthier, Bart Staels, Sophie Susen, Eric Van Belle","doi":"10.1161/CIRCULATIONAHA.124.071954","DOIUrl":"10.1161/CIRCULATIONAHA.124.071954","url":null,"abstract":"<p><strong>Background: </strong>To date, the only effective treatment of severe aortic stenosis is valve replacement. With the introduction of transcatheter aortic valve replacement and extending indications to younger patients, the use of bioprosthetic valves (BPVs) has considerably increased. The main inconvenience of BPVs is their limited durability because of mechanisms similar as the fibro-calcifying processes observed in native aortic stenosis. One of the major gaps of the field is to identify therapeutic targets to prevent or slow the fibro-calcifying process leading to severe and symptomatic aortic stenosis.</p><p><strong>Methods: </strong>Explanted valves were collected from patients and organ donor hearts. A comparative transcriptomic analysis was performed on valvular interstitial cells (VIC) obtained from calcified (bicuspid and tricuspid) versus control valves. The mechanisms and consequences of aldehyde dehydrogenase 1 family member A1 (ALDH1A1) downregulation were analyzed in VIC cultures from control human aortic valves. ALDH1A1 was inhibited or silenced and its impact on osteogenic marker expression and calcification processes assessed in VIC. The effect of all-trans retinoic acid on calcification was tested on human VIC cultures and on 2 animal models: the model of subcutaneous implantation of bovine pericardium in rats and the model of xenograft aortic valve replacement in juvenile sheep.</p><p><strong>Results: </strong>Transcriptome analysis of human VIC identified <i>ALDH1A1</i> as the most downregulated gene in VIC from calcified versus control valves. In human VIC, ALDH1A1 expression is downregulated by TGF-β in a SMAD2/3-dependent manner. ALDH1A1 inhibition promotes an osteoblast-like VIC phenotype and increases calcium deposition through inhibition of retinoic acid receptor alpha signaling. Conversely, VIC treatment with retinoids decreases calcium deposition and attenuates VIC osteoblast activity. Last, all-trans retinoic acid inhibits calcification development of aortic BPV in both in vivo models and improves aortic valve echocardiographic parameters in the xenograft sheep model.</p><p><strong>Conclusions: </strong>These results show that ALDH1A1 is downregulated in calcified valves, hence promoting VIC transition into an osteoblastic phenotype. Retinoic acid receptor alpha agonists, including all-trans retinoic acid through a drug repositioning strategy, represent a promising and innovative pharmacological approach to prevent calcification of native aortic valves and BPV.</p>","PeriodicalId":10331,"journal":{"name":"Circulation","volume":" ","pages":"1329-1341"},"PeriodicalIF":35.5,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143482259","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":"Highlights From the <i>Circulation</i> Family of Journals.","authors":"","doi":"10.1161/CIRCULATIONAHA.125.074967","DOIUrl":"https://doi.org/10.1161/CIRCULATIONAHA.125.074967","url":null,"abstract":"","PeriodicalId":10331,"journal":{"name":"Circulation","volume":"151 18","pages":"1364-1368"},"PeriodicalIF":35.5,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143983465","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":"Role of Technology in Promoting Heart Healthy Behavior Change to Increase Equity in Optimal Cardiovascular Health: A Scientific Statement From the American Heart Association.","authors":"Tiffany M Powell-Wiley, LaPrincess C Brewer, Lora E Burke, Rosalba Hernandez, Jill Landsbaugh Kaar, Maura Kepper, Christopher E Kline, Keila N Lopez, Shamarial Roberson, Colleen K Spees, Gerald J Jerome","doi":"10.1161/CIR.0000000000001314","DOIUrl":"10.1161/CIR.0000000000001314","url":null,"abstract":"<p><p>Populations most affected by cardiovascular health disparities, including underrepresented populations with lower socioeconomic status, people with disabilities, and those living in underserved rural communities, are disproportionately exposed to adverse social determinants of health. Specifically, economic instability and suboptimal living conditions within the neighborhood and built environment directly determine access to resources and opportunities for healthful behaviors. In this scientific statement, we examined the technology-enabled interventions that address cardiovascular health behaviors from adolescence to adulthood in populations most affected by health disparities. We used a broad definition of technology, including wearables, applications, and telehealth, for behavior tracking. Aligning with Life's Essential 8, we focused on interventions targeting behavior change related to physical activity, sedentary time, dietary intake, tobacco cessation, and sleep health to improve cardiovascular health. The digital determinants of health are important adjuncts to the social determinants and operate at the individual, interpersonal, community, and societal levels. The digital determinants of health include the impact of digital technologies (eg, wearables, telemedicine) across health outcomes. Evidence of effective interventions using technology to improve cardiovascular health through positive behavior change is critical for preventing cardiovascular disease events. Stronger evidence is needed to inform and implement effective approaches that are scalable and cost-effective across communities and health care institutions to advance digital equity in cardiovascular health. Dissemination of digital solutions to improve cardiovascular health in communities or across health care systems must ensure effective, feasible, available, and affordable solutions for populations most in need.</p>","PeriodicalId":10331,"journal":{"name":"Circulation","volume":" ","pages":"e972-e985"},"PeriodicalIF":35.5,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143794863","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":"MYSTERY-HF: Myeloperoxidase Inhibition in Patients With Heart Failure and Reduced Ejection Fraction: A Phase II Randomized Controlled Trial.","authors":"Simon Braumann, Sascha Macherey-Meyer, Amin Polzin, Angelika Costard-Jäckle, Caroline Morbach, Bernhard Haring, Harald Lapp, Vincent Ten Cate, Alexander Gieswinkel, Jithmi Weliwitage, Martin Hellmich, Erik Michaëlsson, Karin Nelander, Nelli Ens-Jäger, Stephan Rosenkranz, Simon Geißen, Norbert Frey, P Christian Schulze, Malin Aurell, Michael Böhm, Stefan Frantz, Malte Kelm, Volker Rudolph, Sanjiv J Shah, Philipp S Wild, Stephan Baldus","doi":"10.1161/CIRCULATIONAHA.125.074085","DOIUrl":"10.1161/CIRCULATIONAHA.125.074085","url":null,"abstract":"","PeriodicalId":10331,"journal":{"name":"Circulation","volume":" ","pages":"1372-1374"},"PeriodicalIF":35.5,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143398282","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":"From the Literature.","authors":"Tracy Hampton","doi":"10.1161/CIRCULATIONAHA.125.074787","DOIUrl":"https://doi.org/10.1161/CIRCULATIONAHA.125.074787","url":null,"abstract":"","PeriodicalId":10331,"journal":{"name":"Circulation","volume":"151 18","pages":"1369-1371"},"PeriodicalIF":35.5,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143963851","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":"Low-Salt Diet <i>and</i> Thiazide Diuretics.","authors":"Franz H Messerli, C Venkata S Ram, Michel Burnier","doi":"10.1161/CIRCULATIONAHA.125.074388","DOIUrl":"https://doi.org/10.1161/CIRCULATIONAHA.125.074388","url":null,"abstract":"","PeriodicalId":10331,"journal":{"name":"Circulation","volume":"151 18","pages":"1297-1298"},"PeriodicalIF":35.5,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143966086","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":"Evidence Generation and Implementation of Transcatheter Interventions for Atrioventricular Valvular Heart Disease in Heart Failure: Current Status and Future Directions.","authors":"Marco Metra,Daniela Tomasoni,Marianna Adamo,Stefan D Anker,Antoni Bayes-Genis,Ralph Stephan von Bardeleben,Michael Böhm,Erwan Donal,Gerasimos S Filippatos,Francesco Maisano,Piotr Ponikowski,Gianluigi Savarese,Fabien Praz,Javed Butler","doi":"10.1161/circulationaha.124.070411","DOIUrl":"https://doi.org/10.1161/circulationaha.124.070411","url":null,"abstract":"Mitral regurgitation and tricuspid regurgitation are the most common valvular heart diseases in patients with heart failure and have independent prognostic value. Transcatheter interventions are now available for the treatment of valvular heart disease, and their efficacy and safety have been tested in randomized controlled trials. However, evidence is still limited and sometimes inconclusive because several aspects of these trials limit their interpretation or consistency. These include heterogeneity in the pathogenesis and clinical characteristics of patients, the dynamic nature of secondary atrioventricular valve disease severity, the role of heart failure medications and devices, dependency on procedural results and operators' skills, smaller number of patients enrolled and the power to detect differences in trials, and limitations to use patients' reported outcomes with unblinded study protocols. These specific aspects of trials in patients with atrioventricular valve disease are reviewed in this article with a focus on possible solutions to generate further evidence for the efficacy and safety for transcatheter treatments of atrioventricular valve disease in patients with heart failure.","PeriodicalId":10331,"journal":{"name":"Circulation","volume":"68 1","pages":"1342-1363"},"PeriodicalIF":37.8,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143914801","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 Gu et al Regarding Article, \"Antisense Oligonucleotide Therapy for Calmodulinopathy\".","authors":"Siyuan Gu,Ye Chen,Xiaojian Shi","doi":"10.1161/circulationaha.124.073198","DOIUrl":"https://doi.org/10.1161/circulationaha.124.073198","url":null,"abstract":"","PeriodicalId":10331,"journal":{"name":"Circulation","volume":"15 1","pages":"e968-e969"},"PeriodicalIF":37.8,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143914803","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":"Does Coronary Calcium Mean the Same in Active and Sedentary Individuals?","authors":"Paul D Thompson","doi":"10.1161/circulationaha.125.074396","DOIUrl":"https://doi.org/10.1161/circulationaha.125.074396","url":null,"abstract":"","PeriodicalId":10331,"journal":{"name":"Circulation","volume":"38 1","pages":"1309-1311"},"PeriodicalIF":37.8,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143914802","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}