Circulation最新文献

{"title":"Cardiovascular Health Promotion for US Veterans: Current State, Gaps, and Strategies: A Scientific Statement From the American Heart Association.","authors":"Neal Yuan, Dina H Griauzde, Elizabeth A Jackson, Tannaz Moin, Zaid Almarzooq, Jennifer Ballard-Hernandez, William C Cushman, Salomeh Keyhani, Jennifer L Martin, John M Gaziano","doi":"10.1161/CIR.0000000000001452","DOIUrl":"https://doi.org/10.1161/CIR.0000000000001452","url":null,"abstract":"<p><p>US veterans represent a large and diverse population with distinctive demographic characteristics, comorbidity profiles, and social determinants of health shaped by military service. These factors contribute to a high burden of cardiovascular risk and low attainment of ideal cardiovascular health. At the same time, the Department of Veterans Affairs, which operates the nation's largest integrated healthcare system, provides a unique infrastructure for delivering population-level cardiovascular disease prevention for veterans. Understanding its successes and ongoing challenges can inform broader strategies across all health systems for promoting health among veterans. This scientific statement applies the American Heart Association's Life's Essential 8 framework, expanded to include mental health and substance use, to evaluate veteran cardiovascular health. For each domain, we review guideline recommendations, barriers to achieving optimal health, and major Veterans Affairs programs such as Patient Aligned Care Teams, the MOVE! Weight Management Program for Veterans, Whole Health, telehealth-based interventions, and integrated mental health and substance use disorder services. Across domains, veterans receiving Veterans Affairs care often achieve outcomes that are equal to or better than those of their non-Veterans Affairs counterparts, reflecting the strengths of the system in coordinated, team-based care and research-driven implementation. Despite substantial progress, opportunities remain to improve veteran lifestyle behaviors, metabolic health, lipid and blood pressure control, engagement in mental health and substance use care, and detection and management of sleep disorders. Addressing these challenges at the Veterans Affairs will require continuing to expand care access, enhancing digital data integration, tailoring interventions to high-risk subgroups, and strengthening implementation strategies to improve uptake and engagement across Veterans Affairs services.</p>","PeriodicalId":10331,"journal":{"name":"Circulation","volume":" ","pages":""},"PeriodicalIF":41.3,"publicationDate":"2026-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149385588","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 Al Said et al to Letter Regarding Article, \"Systemic Embolic Events in Atrial Fibrillation: An Individual Patient Data Meta-Analysis of 71 683 Participants Randomized to NOAC Versus Warfarin\".","authors":"Samer Al Said, Michael G Palazzolo, Robert P Giugliano","doi":"10.1161/CIRCULATIONAHA.126.081475","DOIUrl":"https://doi.org/10.1161/CIRCULATIONAHA.126.081475","url":null,"abstract":"","PeriodicalId":10331,"journal":{"name":"Circulation","volume":"154 19","pages":"e685-e686"},"PeriodicalIF":41.3,"publicationDate":"2026-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149377783","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":"Epigenome-Wide Association Study of Abdominal Aortic Aneurysm Identifies Central Role for Inflammatory Pathways.","authors":"Shuai Yuan, Michael G Clark, Gabrielle Shakt, Michael G Levin, Katherine Hartmann, Renae Judy, Tia Dinatale, Amy Voorhees, Julie A Lynch, Saiju Pyarajan, Daniel Levy, Roby Joehanes, Kyong-Mi Chang, Jennifer A Brody, Joshua C Bis, Bruce M Psaty, Benjamin F Voight, Philip S Tsao, Gregory T Jones, Scott M Damrauer","doi":"10.1161/CIRCULATIONAHA.126.079863","DOIUrl":"10.1161/CIRCULATIONAHA.126.079863","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Epigenetic mechanisms underlying susceptibility to abdominal aortic aneurysm (AAA) remain poorly understood. Identifying causal DNA methylation markers for AAA can elucidate the regulatory processes that drive aneurysm formation and accelerate translational applications. We leveraged the Veterans Affairs (VA) Million Veteran Program to identify methylation biomarkers and delineate underlying pathways.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;We first conducted an epigenome-wide association study of incident AAA (1324 cases and 42 065 noncases), performed stratified analyses by population group and smoking status, and conducted Mendelian randomization to facilitate causal inference of the cytosine-phosphate-guanine (CpG)-AAA association. Chromatin state, island context, and transcription factor binding were implicated through functional annotation of identified CpGs. To identify genes impacted by change in methylation state, we aligned associations with transcriptional data obtained in blood, aorta, and liver. We performed expression quantitative trait methylation to capture CpG-gene-expression links across the genome. Network Mendelian randomization was used to test cardiometabolic and inflammatory mediation. Finally, we developed a methylation risk score for AAA using penalized regression and evaluated its performance against a clinical model in the Million Veteran Program and 2 external studies.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Epigenome-wide association study identified 1253 CpGs associated with incident AAA, and Mendelian randomization supported a putative causal role for 143 of these associations. Functional annotation pointed to predominantly distal, enhancer-centered regulation and enrichment of inflammatory transcription factor programs (eg, activator protein-1 and nuclear factor κB). This distal architecture was consistent with expression quantitative trait methylation results, which showed a larger number of trans associations. Among 143 CpGs associated with AAA in Mendelian randomization analyses, we identified 213 CpG-gene expression pairs with strong colocalization support, including &lt;i&gt;AGER, C2&lt;/i&gt;, and &lt;i&gt;DDR1&lt;/i&gt;. Multi-trait colocalization further prioritized 8 CpG-gene expression-AAA links with evidence of a shared genetic signal. Network Mendelian randomization identified 135 putative mediation pathways linking CpGs to AAA, including 58 via cardiometabolic traits and 77 via inflammation-related traits. Blood lipid traits mediated &gt;40% of the associations between AAA risk and CpGs near &lt;i&gt;LDLR&lt;/i&gt; (cg19305903) and &lt;i&gt;TRIB1&lt;/i&gt; (cg14128479). Among inflammation-related mediators, circulating DAG1, NEXN, MMP9, IL1RN, and MMP13 were prioritized as potential intermediates. Additionally, a CpG selection process was used to develop a methylation risk score for AAA, which strongly associated with disease in both the discovery cohort and 2 external validation cohorts, even after adjustment for a full suite of clinic","PeriodicalId":10331,"journal":{"name":"Circulation","volume":" ","pages":"1950-1965"},"PeriodicalIF":41.3,"publicationDate":"2026-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13629486/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149073663","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":"Generation of Human Cardiomyocytes With Adult-Like Metabolism by a Chemically Defined Medium for Mitochondrial Disease Modeling.","authors":"Chengyi Tu, Arianne Caudal, Yu Liu, Nadjet Belbachir, Ana Kojic, Brett Stern, Lu Ren, Erin Hu, Nathan Cunningham, Brian Yu, Yi-Ing Chen, Patrick Jurney, Jill S Napierala, Marek Napierala, Julia Ritterhoff, Rong Tian, Joseph C Wu","doi":"10.1161/CIRCULATIONAHA.126.080472","DOIUrl":"https://doi.org/10.1161/CIRCULATIONAHA.126.080472","url":null,"abstract":"<p><strong>Background: </strong>Human induced pluripotent stem cell (iPSC)-derived cardiomyocytes (iPSC cardiomyocytes) as a model for cardiac disease have become increasingly important, bolstered by the Food and Drug Administration's initiative to promote novel alternative methods for biomedical research. A key limitation of metabolically immature iPSC cardiomyocytes is their limited ability to accurately recapitulate mitochondria-dependent pathologies, such as Friedreich ataxia-associated cardiomyopathy. Adult cardiomyocytes are characterized by a high density of interfibrillar mitochondria, abundant respiratory complexes (I-V) that form supercomplexes, and efficient utilization of fatty acids to drive mitochondrial respiration. These unique metabolic structures and functions are largely missing in iPSC cardiomyocytes. Further, whether iPSC cardiomyocytes can efficiently utilize fatty acids for respiration in the presence of glucose, a unique adult feature, remains unclear.</p><p><strong>Methods: </strong>We developed a chemically defined, 11-component maturation medium (MM11) designed using a bioinformatics-guided strategy that identified high-fidelity transcriptional markers of adult cardiac metabolic maturity. Human iPSC cardiomyocytes were treated with MM11 for 2 weeks and evaluated at the molecular, structural, and functional levels, with an emphasis on mitochondrial maturity. We benchmarked our results with isolated primary adult human cardiomyocytes. Last, we tested whether this method could enable us to more accurately model Friedreich ataxia cardiomyopathy.</p><p><strong>Results: </strong>MM11 treatment increased expression of metabolic pathways, including mitochondrial respiration and fatty acid metabolism, at the transcript and protein levels. Ultrastructural analyses revealed the formation of interfibrillar mitochondria and mitochondrial respiratory supercomplexes, a feature never shown in previous reports. Functionally, MM11-treated iPSC cardiomyocytes exhibited substantially increased oxidative phosphorylation and a metabolic preference for fatty acid utilization in the presence of physiologic substrates, as determined by oxygen consumption assays and ¹³C isotope tracing.</p><p><strong>Conclusions: </strong>MM11 promotes robust metabolic maturation of human iPSC cardiomyocytes, enabling sophisticated mitochondrial architecture and substrate utilization. These metabolically matured cardiomyocytes more faithfully model mitochondria-dependent cardiac pathologies, including ischemia-reperfusion injury and Friedreich ataxia cardiomyopathy, improving the use of iPSC cardiomyocytes for mechanistic studies of human heart disease.</p>","PeriodicalId":10331,"journal":{"name":"Circulation","volume":" ","pages":""},"PeriodicalIF":41.3,"publicationDate":"2026-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149377775","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":"Real-World Experience With the Extravascular Implantable Cardioverter Defibrillator Through 1 Year: The Enlighten Post Approval Registry Study.","authors":"Lucas V A Boersma, Anish Amin, Francis Murgatroyd, Maciej Sterliński, Jens Brock Johansen, Karim Saleh, Pamela K Mason, Jaime Casares, Gregory Engel, David Duncker, Alexander Breitenstein, Theodore Takata, Laurence M Epstein, Jurren M van Opstal, Nicolas Clémenty, Paul Friedman, Oliver Monfredi, Marianne Gwechenberger, Nobuhiro Nishii, Christopher Wiggenhorn, Jeff D Lande, Jennifer Lee, Amy E Thompson, Thomas R Holmes, Ian Crozier","doi":"10.1161/CIRCULATIONAHA.126.080942","DOIUrl":"10.1161/CIRCULATIONAHA.126.080942","url":null,"abstract":"<p><strong>Background: </strong>The extravascular implantable cardioverter defibrillator (EV-ICD) was developed to provide defibrillation and antitachycardia pacing therapy without the need for intravascular lead placement. Premarket clinical trials reported EV-ICD safety and efficacy through 3 years, but a real-world assessment of the Aurora EV-ICD system, which includes a novel sensing discriminator, is needed. The objective of this analysis was to assess real-world therapy efficacy and safety of the EV-ICD through 1 year.</p><p><strong>Methods: </strong>Enlighten: The EV-ICD Post Approval Registry is a prospective, global, real-world registry that included patients who underwent an EV-ICD implantation attempt. The main safety analysis was freedom from all system- or procedure-related major complications through 1 year. Event rates at 1 year were calculated using the Kaplan-Meier method.</p><p><strong>Results: </strong>EV-ICD system implantation was attempted by 168 implanters in 787 patients (49.1±15.2 years old; 28.7% women; 34.1% secondary prevention). Tunneling and lead placement in the substernal space were achieved in 781 of 787 patients (99.2%), with 758 patients (96.3%) remaining implanted following defibrillation and electrical testing. One-year freedom from major system- or procedure-related complications was 89.1% (95% CI, 86.3%-91.3%). The 1-year rate of first appropriate therapy (shock, antitachycardia pacing, or both) was 7.3% (95% CI, 5.5-9.6). Shock success for discrete spontaneous episodes was 100% (61 of 61), and the generalized estimating equations antitachycardia pacing success rate, to account for multiple episodes per patient, was 74.2% for monomorphic ventricular tachycardia. The 1-year rate of first inappropriate shock was 7.1% (95% CI, 5.4-9.4), with noncardiac oversensing as the main cause (40.5% of inappropriately shocked episodes).</p><p><strong>Conclusions: </strong>In the largest prospective worldwide cohort of patients with an EV-ICD to date, both antitachycardia pacing and shock therapy were effective, while the rate of major complications agreed with the premarket experience through 1 year. These data demonstrate that positive outcomes of the EV-ICD are retained in everyday clinical practice in a large, global cohort with an expanded number of implanters.</p><p><strong>Registration: </strong>URL: https://www.clinicaltrials.gov; Unique identifier: NCT06048731.</p>","PeriodicalId":10331,"journal":{"name":"Circulation","volume":" ","pages":"1925-1938"},"PeriodicalIF":41.3,"publicationDate":"2026-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13742346/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149015845","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":"Off-Pump versus On-Pump Coronary Artery Bypass Grafting in Prefrail and Frail Patients: 30-Day and 1-Year Outcomes From the FRAGILE Randomized Trial.","authors":"Omar Asdrúbal Vilca Mejia, Bianca Meneghini, Fabiane Letícia de Freitas, Maurilio Onofre Deininger, Rodrigo Coelho Segalote, Felipe Cosentino, Alexandre Ciappina Hueb, Mauricio Landulfo Jorge Guerrieri, Fernando Faglioni Ribas, Fabiano Gonçalves Jucá, Luís Roberto Palma Dallan, Bruno Mahler Mioto, Ludhmila Abrahão Hajjar, Carlos Vicente Serrano, Pedro Gabriel Melo de Barros E Silva, Renato Delascio Lopes, David Paul Taggart, Torsten Doenst, John Daniel Puskas, Luiz Augusto Ferreira Lisboa, Fabio Biscegli Jatene","doi":"10.1161/CIRCULATIONAHA.125.078842","DOIUrl":"https://doi.org/10.1161/CIRCULATIONAHA.125.078842","url":null,"abstract":"<p><strong>Background: </strong>Frailty is associated with worse outcomes after coronary artery bypass grafting (CABG). However, the comparative effectiveness of off-pump CABG (OPCAB) versus on-pump CABG (ONCAB) in prefrail and frail patients remains uncertain.</p><p><strong>Methods: </strong>This multicenter, randomized, open-label trial enrolled patients ≥60 years of age classified as prefrail or frail, randomized 1:1, between January 2018 and December 2024. The primary outcome was a 30-day composite of death, myocardial infarction, stroke, renal failure, acute respiratory distress syndrome, or reoperation for bleeding. Secondary outcomes included ventilation time, intensive care unit and hospital stay, transfusion requirements, completeness of revascularization, surgical wound infection at 30 days, and neurocognitive function preoperatively and at 1 year. Analyses followed the intention-to-treat principle; relative risks with 95% CIs were estimated.</p><p><strong>Results: </strong>A total of 508 patients were included (OPCAB, n=258; ONCAB, n=250; median age, 68 years [interquartile range, 65.0-73]; 30.5% female). The primary composite outcome occurred in 28 patients receiving OPCAB (10.9%) and 40 patients receiving ONCAB (16.0%; relative risk, 1.47 [95% CI, 0.94-2.31]; <i>P</i>=0.09). Surgical wound infection was more frequent with ONCAB (20 [8.0%] versus 9 [3.5%]; <i>P</i>=0.04). No significant differences were observed in neurocognitive or quality of life outcomes at 1 year. Estimated 1-year survival probabilities were 96.1% and 92.8% in the OPCAB and ONCAB groups, respectively (<i>P</i>=0.099).</p><p><strong>Conclusion: </strong>In prefrail and frail patients undergoing CABG, OPCAB and ONCAB resulted in similar rates of the primary composite outcome. No significant differences between OPCAB and ONCAB were found in neurocognitive outcomes.</p><p><strong>Registration: </strong>URL: https://www.clinicaltrials.gov; Unique identifier: NCT02338947.</p>","PeriodicalId":10331,"journal":{"name":"Circulation","volume":" ","pages":""},"PeriodicalIF":41.3,"publicationDate":"2026-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149377778","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":"Multidisciplinary Approach to Antiplatelet Management in Coronary Syndromes: A Scientific Statement From the American Heart Association.","authors":"Craig J Beavers, Paul P Dobesh, Mary Cushman, Robert J DiDomenico, Nkechinyere Ijioma, Ravi V Joshi, Jonathan Medina-Beckwith, Naveen Pereira, Marc Ruel, Rachel G Tabak","doi":"10.1161/CIR.0000000000001478","DOIUrl":"10.1161/CIR.0000000000001478","url":null,"abstract":"<p><p>Antiplatelet therapy is a cornerstone of care for patients with acute coronary syndrome and chronic coronary disease, yet its optimal use requires careful balancing of thrombotic risk reduction with bleeding complications. Since the mid-2000s, advances in stent technology, antiplatelet pharmacotherapy, procedural technique, and risk stratification tools have led to increasingly individualized approaches to antiplatelet management. Current guidelines and evidence emphasize tailoring agent selection, intensity, and duration of therapy according to patient-, procedure-, and disease-specific factors rather than a uniform strategy. However, the growing complexity of evidence, frequent care transitions, social determinants of health, and variability in patient characteristics have increased the risk of inappropriate prescribing, nonadherence, and adverse outcomes. This scientific statement reviews contemporary evidence informing antiplatelet strategies and highlights the critical role of the multidisciplinary cardiovascular team (interventional cardiology, general cardiology, pharmacists, advanced practice nurses) and the importance of their collective expertise in ensuring antithrombotic stewardship in patients with acute coronary syndrome and chronic coronary disease.</p>","PeriodicalId":10331,"journal":{"name":"Circulation","volume":" ","pages":"e687-e701"},"PeriodicalIF":41.3,"publicationDate":"2026-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149179843","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":"Triglycerides and Risk of Atherosclerotic Cardiovascular Disease and Acute Pancreatitis: 4 Population-Based Cohorts.","authors":"Takahito Doi, Shoaib Afzal, Gorm Boje Jensen, Børge Grønne Nordestgaard","doi":"10.1161/CIRCULATIONAHA.126.082218","DOIUrl":"https://doi.org/10.1161/CIRCULATIONAHA.126.082218","url":null,"abstract":"","PeriodicalId":10331,"journal":{"name":"Circulation","volume":"154 19","pages":"1966-1968"},"PeriodicalIF":41.3,"publicationDate":"2026-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149377785","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":"Dysregulated Ribonucleoprotein Granules Impair Mitochondrial Function in <i>RBM20</i>-Related Dilated Cardiomyopathy.","authors":"Julia Kornienko, Linda H Müller, Alexander Nickel, Michael Kohlhaas, Mandy Börmel, Carlos Alfonso-Gonzalez, Viola M J Oorschot, Michel Fungate, Susanne Lewey, Jacob Kees, Johanna Müller, Dominik Lindenhofer, Kai Fenzl, Laura Schraft, Sandra Clauder-Münster, Laura Konrad, Per Haberkant, Frank D M Montoya, Vita Dauksaite, Michael Gotthardt, Maarten M G van den Hoogenhof, Christoph Maack, Lars M Steinmetz","doi":"10.1161/CIRCULATIONAHA.125.077061","DOIUrl":"10.1161/CIRCULATIONAHA.125.077061","url":null,"abstract":"<p><strong>Background: </strong>Pathogenic variants in <i>RBM20</i> cause severe dilated cardiomyopathy. Loss-of-function variants disrupt splicing; neomorphic gain-of-function (GoF) variants also mislocalize RBM20 to cytoplasmic ribonucleoprotein granules and are associated with more aggressive disease. The mechanism by which RBM20 mislocalization drives cardiac dysfunction remains unknown.</p><p><strong>Methods: </strong>We investigated the effects of <i>Rbm20</i> GoF and loss-of-function (LoF) variants using proteomic profiling, protein solubility assays, mitochondrial respiration and calcium flux analyses, and ultrastructural imaging in mouse models. Human induced pluripotent stem cell-derived cardioids were used to validate variant-specific phenotypes.</p><p><strong>Results: </strong><i>Rbm20</i> GoF, but not LoF, variants caused posttranscriptional downregulation of soluble mitochondrial proteins, including the calcium efflux regulator TMEM65 (transmembrane protein 65), and reduced solubility of mitochondrial membrane proteins. Electron microscopy revealed enlarged mitochondria with cristae disorganization. Functional assays confirmed impaired oxidative phosphorylation, reduced mitochondrial membrane potential, and abnormal calcium handling in <i>Rbm20</i> GoF models. Human cardioids reproduced these findings, demonstrating that cytoplasmic mislocalization, rather than splicing deficiency, drives mitochondrial dysfunction.</p><p><strong>Conclusions: </strong>Cytoplasmic mislocalization of RBM20 disrupts mitochondrial function by reducing mitochondrial protein abundance, leading to oxidative phosphorylation failure and abnormal mitochondrial calcium handling. This mechanism distinguishes <i>RBM20</i> GoF from LoF variants and may explain the more severe heart failure phenotype observed in patients with <i>RBM20</i> GoF variants. These insights advance the mechanistic understanding of <i>RBM20</i>-related cardiomyopathy and identify mitochondrial mRNA/protein regulation as a key node in cardiac energetics.</p>","PeriodicalId":10331,"journal":{"name":"Circulation","volume":" ","pages":"1884-1903"},"PeriodicalIF":41.3,"publicationDate":"2026-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148966831","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 Peak Volume of Oxygen Consumption on Cardiopulmonary Exercise Testing.","authors":"Robert F Bentley, Susanna Mak","doi":"10.1161/CIRCULATIONAHA.126.080522","DOIUrl":"https://doi.org/10.1161/CIRCULATIONAHA.126.080522","url":null,"abstract":"","PeriodicalId":10331,"journal":{"name":"Circulation","volume":"154 19","pages":"1969-1972"},"PeriodicalIF":41.3,"publicationDate":"2026-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149377780","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}