BACKGROUNDMitophagy is critically involved in cardiac injury and repair after myocardial infarction (MI), whereas the annexin A family plays an important role in mitophagy. However, the intrinsic molecular underpinnings that orchestrate the homeostasis of mitophagy in the infarcted heart remain to be fully characterized. Here, we aimed to evaluate the role of ANXA2 (annexin A2) in cardiac mitophagy in response to MI.METHODSTranscriptome analyses were conducted to identify differentially expressed genes and enriched pathways. Mitophagy, mitochondrial function, and cardiac injury and remodeling were analyzed in MI mice and neonatal rat ventricular myocytes with cardiomyocyte-specific ANXA2 knockdown or overexpression, as well as in models with ANXA2 knockdown combined with PHB2 (prohibitin 2) silencing. Immunoprecipitation, mass spectrometry, and glutathione S-transferase pull-down assays were used to identify the interacting proteins of ANXA2.RESULTSWe showed that ANXA2 was highly expressed in murine and human ischemic failing hearts, whereas increased circulating ANXA2 positively correlated with cardiac injury in patients with acute MI. Moreover, cardiomyocyte-specific ANXA2 depletion averted cardiac mitophagy inactivation, oxidative stress, cell death, and inflammatory cell infiltration, leading to significant improvements in infarct size, heart function, and cardiac remodeling after MI. Conversely, ANXA2 overexpression in cardiomyocytes suppressed mitophagy to exacerbate cardiac injury and deteriorate heart failure after MI. Moreover, ANXA2 silencing and overexpression, respectively, in neonatal rat ventricular myocytes under hypoxia in vitro recapitulated the in vivo findings on mitochondrial function and cell death. Mechanistically, we found that ANXA2 directly interacted with the mitophagy receptor PHB2 to competitively block the binding of LC3B with PHB2 and promote PHB2 proteasomal degradation through K48-linked polyubiquitination mediated by the E3 ligase TRIM29, resulting in mitophagy inhibition under hypoxia. Consequently, PHB2 knockdown abrogated the protective effects of ANXA2 deficiency on mitochondrial function, oxidative stress, and cell viability in stressed myocytes in vitro, as well as on heart function and remodeling under MI in vivo.CONCLUSIONSThese findings highlight the significance of ANXA2 inhibition as a molecular brake on mitophagy inactivation in cardiomyocytes under MI and uncover an ANXA2-mediated posttranslational mechanism essential for maintaining mitochondrial homeostasis and alleviating heart failure after MI.
{"title":"Inhibition of Annexin A2 Facilitates PHB2-Mediated Mitophagy in Cardiomyocytes to Alleviate Cardiac Injury and Remodeling After Infarction.","authors":"Ke-Qiong Deng,Zhendong Xu,Qiong-Xin Wang,Huan-Huan Cai,Di Fan,Qingqing Wu,Xiao-Jing Zhang,Peng Zhang,Zhi-Gang She,Xingguo Liu,Xianqing Li,Zhibing Lu","doi":"10.1161/circulationaha.125.077780","DOIUrl":"https://doi.org/10.1161/circulationaha.125.077780","url":null,"abstract":"BACKGROUNDMitophagy is critically involved in cardiac injury and repair after myocardial infarction (MI), whereas the annexin A family plays an important role in mitophagy. However, the intrinsic molecular underpinnings that orchestrate the homeostasis of mitophagy in the infarcted heart remain to be fully characterized. Here, we aimed to evaluate the role of ANXA2 (annexin A2) in cardiac mitophagy in response to MI.METHODSTranscriptome analyses were conducted to identify differentially expressed genes and enriched pathways. Mitophagy, mitochondrial function, and cardiac injury and remodeling were analyzed in MI mice and neonatal rat ventricular myocytes with cardiomyocyte-specific ANXA2 knockdown or overexpression, as well as in models with ANXA2 knockdown combined with PHB2 (prohibitin 2) silencing. Immunoprecipitation, mass spectrometry, and glutathione S-transferase pull-down assays were used to identify the interacting proteins of ANXA2.RESULTSWe showed that ANXA2 was highly expressed in murine and human ischemic failing hearts, whereas increased circulating ANXA2 positively correlated with cardiac injury in patients with acute MI. Moreover, cardiomyocyte-specific ANXA2 depletion averted cardiac mitophagy inactivation, oxidative stress, cell death, and inflammatory cell infiltration, leading to significant improvements in infarct size, heart function, and cardiac remodeling after MI. Conversely, ANXA2 overexpression in cardiomyocytes suppressed mitophagy to exacerbate cardiac injury and deteriorate heart failure after MI. Moreover, ANXA2 silencing and overexpression, respectively, in neonatal rat ventricular myocytes under hypoxia in vitro recapitulated the in vivo findings on mitochondrial function and cell death. Mechanistically, we found that ANXA2 directly interacted with the mitophagy receptor PHB2 to competitively block the binding of LC3B with PHB2 and promote PHB2 proteasomal degradation through K48-linked polyubiquitination mediated by the E3 ligase TRIM29, resulting in mitophagy inhibition under hypoxia. Consequently, PHB2 knockdown abrogated the protective effects of ANXA2 deficiency on mitochondrial function, oxidative stress, and cell viability in stressed myocytes in vitro, as well as on heart function and remodeling under MI in vivo.CONCLUSIONSThese findings highlight the significance of ANXA2 inhibition as a molecular brake on mitophagy inactivation in cardiomyocytes under MI and uncover an ANXA2-mediated posttranslational mechanism essential for maintaining mitochondrial homeostasis and alleviating heart failure after MI.","PeriodicalId":10331,"journal":{"name":"Circulation","volume":"84 1","pages":""},"PeriodicalIF":37.8,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145907549","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}
Pub Date : 2026-01-06Epub Date: 2025-11-08DOI: 10.1161/CIRCULATIONAHA.125.077494
Rayan A Ansari, Sabyasachi Bandyopadhyay, Rishi K Trivedi, Kelly A Brennan, Xichong Liu, Prasanth Ganesan, J Weston Hughes, Alexander C Perino, Euan A Ashley, Paul J Wang, Todd Coleman, Marco V Perez, David Ouyang, Sanjiv M Narayan, Albert J Rogers
Background: Drug-induced QT prolongation after successful inpatient loading of class III antiarrhythmics may occur during routine outpatient care. Insertable cardiac monitors offer continuous signals but are limited by single-lead configuration. We hypothesized that a spatially aware deep learning system (3DRECON-QT) can reconstruct spatial information from a single lead vector to quantify QT/QTc and identify high-risk prolongation.
Methods: We developed 3DRECON-QT using a multitask encoder-decoder that ingests a 10-s single-lead signal, reconstructs 12 leads, and predicts QT/QTc. The model was developed using 12-lead ECGs with clinician-adjudicated QT/RR from a large health system and tested in an external center with different ECG hardware. Continuous monitoring performance was assessed in a public dofetilide-loading data set with serial ECGs. In a real-world cohort of outpatients on dofetilide or sotalol presenting to the hospital or emergency room for any reason, rates of ventricular arrhythmias and QT prolongation were assessed. Device validation was tested in patients with insertable cardiac monitor recordings paired with clinical 12-lead ECGs.
Results: 3DRECON-QT classified prolonged QTc from single-lead signals with area under the receiver operating characteristics curve, 0.942 (mean absolute error, 17.5 ms) in the internal test set and 0.943 (mean absolute error, 21.1 ms) externally. During continuous dofetilide monitoring, predictions correlated with ground truth (r, 0.851; mean absolute error, 17.8 ms; area under the receiver operating characteristics curve, 0.936 for prolonged QTc, 0.816 for ≥15% QTc rise). QTc prediction from true insertable cardiac monitor recordings showed r=0.824 and mean absolute error, 17.5 ms. In outpatients on class III antiarrhythmics (n=1676), 16.5% had high-risk QTc prolongation. Ventricular arrhythmia events were 3.97% versus 0.86% without prolongation (adjusted odds ratio, 4.24 [95% CI, 1.81-9.90]). 3DRECON-QT detected these events with area under the receiver operating characteristics curve 0.94 (F1 score, 0.60).
Conclusions: A single-lead, deep-learning approach can achieve guideline-level measurement accuracy, enable continuous QTc surveillance from nonstandard ECG vectors, and identify clinically meaningful outpatient QTc prolongation associated with a >4-fold increase in serious ventricular arrhythmias. This strategy may enhance safety monitoring after class III antiarrhythmic initiation and support targeted intervention.
{"title":"Deep Learning-Based Continuous QT Monitoring to Identify High-Risk Prolongation Events After Class III Antiarrhythmic Initiation.","authors":"Rayan A Ansari, Sabyasachi Bandyopadhyay, Rishi K Trivedi, Kelly A Brennan, Xichong Liu, Prasanth Ganesan, J Weston Hughes, Alexander C Perino, Euan A Ashley, Paul J Wang, Todd Coleman, Marco V Perez, David Ouyang, Sanjiv M Narayan, Albert J Rogers","doi":"10.1161/CIRCULATIONAHA.125.077494","DOIUrl":"https://doi.org/10.1161/CIRCULATIONAHA.125.077494","url":null,"abstract":"<p><strong>Background: </strong>Drug-induced QT prolongation after successful inpatient loading of class III antiarrhythmics may occur during routine outpatient care. Insertable cardiac monitors offer continuous signals but are limited by single-lead configuration. We hypothesized that a spatially aware deep learning system (3DRECON-QT) can reconstruct spatial information from a single lead vector to quantify QT/QTc and identify high-risk prolongation.</p><p><strong>Methods: </strong>We developed 3DRECON-QT using a multitask encoder-decoder that ingests a 10-s single-lead signal, reconstructs 12 leads, and predicts QT/QTc. The model was developed using 12-lead ECGs with clinician-adjudicated QT/RR from a large health system and tested in an external center with different ECG hardware. Continuous monitoring performance was assessed in a public dofetilide-loading data set with serial ECGs. In a real-world cohort of outpatients on dofetilide or sotalol presenting to the hospital or emergency room for any reason, rates of ventricular arrhythmias and QT prolongation were assessed. Device validation was tested in patients with insertable cardiac monitor recordings paired with clinical 12-lead ECGs.</p><p><strong>Results: </strong>3DRECON-QT classified prolonged QTc from single-lead signals with area under the receiver operating characteristics curve, 0.942 (mean absolute error, 17.5 ms) in the internal test set and 0.943 (mean absolute error, 21.1 ms) externally. During continuous dofetilide monitoring, predictions correlated with ground truth (<i>r</i>, 0.851; mean absolute error, 17.8 ms; area under the receiver operating characteristics curve, 0.936 for prolonged QTc, 0.816 for ≥15% QTc rise). QTc prediction from true insertable cardiac monitor recordings showed <i>r</i>=0.824 and mean absolute error, 17.5 ms. In outpatients on class III antiarrhythmics (n=1676), 16.5% had high-risk QTc prolongation. Ventricular arrhythmia events were 3.97% versus 0.86% without prolongation (adjusted odds ratio, 4.24 [95% CI, 1.81-9.90]). 3DRECON-QT detected these events with area under the receiver operating characteristics curve 0.94 (F1 score, 0.60).</p><p><strong>Conclusions: </strong>A single-lead, deep-learning approach can achieve guideline-level measurement accuracy, enable continuous QTc surveillance from nonstandard ECG vectors, and identify clinically meaningful outpatient QTc prolongation associated with a >4-fold increase in serious ventricular arrhythmias. This strategy may enhance safety monitoring after class III antiarrhythmic initiation and support targeted intervention.</p>","PeriodicalId":10331,"journal":{"name":"Circulation","volume":"153 1","pages":"35-46"},"PeriodicalIF":38.6,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145854728","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}
Pub Date : 2026-01-06Epub Date: 2025-12-29DOI: 10.1161/CIRCULATIONAHA.125.078640
{"title":"Highlights From the Circulation Family of Journals.","authors":"","doi":"10.1161/CIRCULATIONAHA.125.078640","DOIUrl":"https://doi.org/10.1161/CIRCULATIONAHA.125.078640","url":null,"abstract":"","PeriodicalId":10331,"journal":{"name":"Circulation","volume":"153 1","pages":"59-63"},"PeriodicalIF":38.6,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145854722","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}
Pub Date : 2026-01-06Epub Date: 2025-12-29DOI: 10.1161/CIRCULATIONAHA.125.077507
Varsha K Tanguturi, Sammy Elmariah
{"title":"Response by Tanguturi and Elmariah to Letter Regarding Article, \"Electronic Provider Notification to Facilitate the Recognition and Management of Severe Aortic Stenosis: A Randomized Clinical Trial\".","authors":"Varsha K Tanguturi, Sammy Elmariah","doi":"10.1161/CIRCULATIONAHA.125.077507","DOIUrl":"https://doi.org/10.1161/CIRCULATIONAHA.125.077507","url":null,"abstract":"","PeriodicalId":10331,"journal":{"name":"Circulation","volume":"153 1","pages":"e2-e3"},"PeriodicalIF":38.6,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145854731","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}
Pub Date : 2026-01-06Epub Date: 2025-12-29DOI: 10.1161/CIRCULATIONAHA.125.077852
Lauren K Truby, Michael D Shapiro
{"title":"When the Target Is Not the Driver: Rethinking LDL in Cardiac Allograft Vasculopathy.","authors":"Lauren K Truby, Michael D Shapiro","doi":"10.1161/CIRCULATIONAHA.125.077852","DOIUrl":"10.1161/CIRCULATIONAHA.125.077852","url":null,"abstract":"","PeriodicalId":10331,"journal":{"name":"Circulation","volume":"153 1","pages":"18-20"},"PeriodicalIF":38.6,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12752930/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145854692","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}
Pub Date : 2026-01-06Epub Date: 2025-12-29DOI: 10.1161/CIRCULATIONAHA.125.076105
Qing Huang, Xiangyu Jian, Feng Wu
{"title":"Letter by Huang et al Regarding Article, \"Electronic Provider Notification to Facilitate the Recognition and Management of Severe Aortic Stenosis: A Randomized Clinical Trial\".","authors":"Qing Huang, Xiangyu Jian, Feng Wu","doi":"10.1161/CIRCULATIONAHA.125.076105","DOIUrl":"https://doi.org/10.1161/CIRCULATIONAHA.125.076105","url":null,"abstract":"","PeriodicalId":10331,"journal":{"name":"Circulation","volume":"153 1","pages":"e1"},"PeriodicalIF":38.6,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145854667","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}
BACKGROUNDImbalances in cardiac branched-chain amino acid (BCAA) metabolism and mitochondrial homeostasis are implicated in the onset and development of heart failure. However, the mechanisms triggering the downregulation of cardiac BCAA metabolism in heart failure remain unclear. Here, we identify a novel role of the RNA-binding protein GRSF1 (guanine-rich RNA sequence binding factor 1) in post-transcriptionally regulating cell-intrinsic BCAA metabolic pathways, ultimately contributing to the pathogenesis of heart failure.METHODSWe examined GRSF1 expression in the heart tissues of patients with dilated cardiomyopathy and generated mice with cardiomyocyte-specific deletion or overexpression of GRSF1 in vivo to investigate its role in heart failure. The effect of GRSF1 on BCAA homeostasis was assessed through untargeted and targeted metabolomics and mitochondrial function analysis. To elucidate the mechanisms underlying GRSF1-mediated metabolic regulation, we employed mice with cardiomyocyte-specific deletion of BCKDHB (branched-chain keto acid dehydrogenase E1 subunit β) and mice with cardiomyocyte-specific expression of GRSF1 lacking a quasi-RNA recognition motif.RESULTSGRSF1 expression was significantly decreased in the hearts of patients with heart failure and failing murine hearts. Cardiomyocyte-specific GRSF1 deletion resulted in cardiac dysfunction, spontaneous progression to dilated cardiomyopathy, and heart failure, accompanied by increased cardiac hypertrophy and fibrosis. Conversely, GRSF1 overexpression attenuated cardiac remodeling and heart failure induced by transverse aortic constriction. Mechanistically, GRSF1 maintained BCAA homeostasis and mitochondrial function by directly interacting with the G-tracts in the coding region of BCKDHB mRNA through a quasi-RNA recognition motif to promote the stability of BCKDHB mRNA at the post-transcriptional level, thereby increasing its protein expression. Functional recovery mediated by GRSF1 overexpression in cardiomyocytes was partially blocked upon cardiac-specific deletion of BCKDHB.CONCLUSIONSOur study identified GRSF1 as a cell-intrinsic metabolic checkpoint that maintains cardiac BCAA homeostasis by regulating BCKDHB mRNA turnover. Targeting GRSF1 may offer therapeutic benefits for heart failure and other cardiometabolic diseases requiring BCAA manipulation.
{"title":"GRSF1 Protects Against Heart Failure by Maintaining BCAA Homeostasis.","authors":"Hu Wang,Jiaxing Wang,Min Zhu,Ling Jin,Hao Cui,Cihang Liu,Chenyu Fan,Hui Li,Jichun Yang,Ming Cui,Jiangping Song,Wengong Wang,Ming Xu","doi":"10.1161/circulationaha.125.074700","DOIUrl":"https://doi.org/10.1161/circulationaha.125.074700","url":null,"abstract":"BACKGROUNDImbalances in cardiac branched-chain amino acid (BCAA) metabolism and mitochondrial homeostasis are implicated in the onset and development of heart failure. However, the mechanisms triggering the downregulation of cardiac BCAA metabolism in heart failure remain unclear. Here, we identify a novel role of the RNA-binding protein GRSF1 (guanine-rich RNA sequence binding factor 1) in post-transcriptionally regulating cell-intrinsic BCAA metabolic pathways, ultimately contributing to the pathogenesis of heart failure.METHODSWe examined GRSF1 expression in the heart tissues of patients with dilated cardiomyopathy and generated mice with cardiomyocyte-specific deletion or overexpression of GRSF1 in vivo to investigate its role in heart failure. The effect of GRSF1 on BCAA homeostasis was assessed through untargeted and targeted metabolomics and mitochondrial function analysis. To elucidate the mechanisms underlying GRSF1-mediated metabolic regulation, we employed mice with cardiomyocyte-specific deletion of BCKDHB (branched-chain keto acid dehydrogenase E1 subunit β) and mice with cardiomyocyte-specific expression of GRSF1 lacking a quasi-RNA recognition motif.RESULTSGRSF1 expression was significantly decreased in the hearts of patients with heart failure and failing murine hearts. Cardiomyocyte-specific GRSF1 deletion resulted in cardiac dysfunction, spontaneous progression to dilated cardiomyopathy, and heart failure, accompanied by increased cardiac hypertrophy and fibrosis. Conversely, GRSF1 overexpression attenuated cardiac remodeling and heart failure induced by transverse aortic constriction. Mechanistically, GRSF1 maintained BCAA homeostasis and mitochondrial function by directly interacting with the G-tracts in the coding region of BCKDHB mRNA through a quasi-RNA recognition motif to promote the stability of BCKDHB mRNA at the post-transcriptional level, thereby increasing its protein expression. Functional recovery mediated by GRSF1 overexpression in cardiomyocytes was partially blocked upon cardiac-specific deletion of BCKDHB.CONCLUSIONSOur study identified GRSF1 as a cell-intrinsic metabolic checkpoint that maintains cardiac BCAA homeostasis by regulating BCKDHB mRNA turnover. Targeting GRSF1 may offer therapeutic benefits for heart failure and other cardiometabolic diseases requiring BCAA manipulation.","PeriodicalId":10331,"journal":{"name":"Circulation","volume":"23 1","pages":""},"PeriodicalIF":37.8,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145897449","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}
Pub Date : 2026-01-05DOI: 10.1161/circulationaha.125.075789
Thomas G Martin,Dakota R Hunt,Christopher C Ebmeier,Abhishek P Dhand,Christina Alamana,Joseph C Cleveland,Sharon L Graw,Sarah Bruner,Michael R Bristow,Luisa Mestroni,Matthew R G Taylor,Jason A Burdick,Amrut V Ambardekar,Peter M Buttrick,Leslie A Leinwand
BACKGROUNDCardiac reverse remodeling occurs in a small subset of patients with heart failure treated with guideline-directed therapies. This phenomenon, which is defined by reduced ventricular dilatation and improved systolic function, is most common in patients receiving left ventricular assist device (LVAD) therapy. Identifying therapeutic targets for initiating reverse remodeling is an area of great clinical interest, because these patients experience improved outcomes and quality of life. Targets may be discovered among the unique molecular changes associated with LVAD-induced partial myocardial functional recovery; however, the mechanisms underlying this favorable response are incompletely understood.METHODSTo identify molecular signatures of recovery, we studied paired pre-LVAD and post-LVAD myocardial samples from patients with heart failure who received LVAD as a bridge to transplant (10 responders and 9 nonresponders) and controls without heart failure. We performed bulk RNA sequencing, tandem mass tag quantitative proteomics, and tandem mass tag quantitative phosphoproteomics with follow-up mechanistic and functional investigations in primary rat cardiomyocytes and human engineered heart tissues.RESULTSAlternative RNA splicing was the leading pathway associated with a favorable response to LVAD. Responders had increased RNA splicing factor expression and unique gene splice variant expression compared with nonresponders. Alternative splicing of CAMK2D (calcium/calmodulin-dependent protein kinase 2δ) was a particularly strong predictor of recovery; increased inclusion of exon 14, which encodes the nuclear splice variant CAMK2D-B, was inversely correlated with functional recovery. Nonresponders also displayed hyperphosphorylation near the nuclear localization signal in CAMK2D-B. Investigations in primary cardiomyocytes and subcellular organelle fractions from the human hearts revealed that nuclear localization signal phosphorylation prevented adrenergic stress-dependent nuclear targeting of CAMK2D-B. Expression of a cytoplasm-restricted CAMK2D-B uniquely remodeled the phosphoproteome of primary rat cardiomyocytes compared with a nuclear-competent version and blunted calcium transients in engineered heart tissues.CONCLUSIONSThis is the first study to integrate transcriptome, alternative transcriptome, proteome, and phosphoproteome analyses of heart samples from LVAD-supported patients to investigate myocardial recovery. We identified that increased expression and phosphorylation of the nuclear CAMK2D splice variant predicted poor outcomes. This phosphorylation restricted CAMK2D-B to the cytosol, leading to impaired cardiomyocyte calcium handling. These findings suggest that LVAD nonresponder patients may benefit from therapies that modulate subcellular localization of CAMK2D or inhibit its activity.
{"title":"Myocardial Recovery With Mechanical Circulatory Support Is Linked to Alternative Splicing and Subcellular Localization of CAMK2D.","authors":"Thomas G Martin,Dakota R Hunt,Christopher C Ebmeier,Abhishek P Dhand,Christina Alamana,Joseph C Cleveland,Sharon L Graw,Sarah Bruner,Michael R Bristow,Luisa Mestroni,Matthew R G Taylor,Jason A Burdick,Amrut V Ambardekar,Peter M Buttrick,Leslie A Leinwand","doi":"10.1161/circulationaha.125.075789","DOIUrl":"https://doi.org/10.1161/circulationaha.125.075789","url":null,"abstract":"BACKGROUNDCardiac reverse remodeling occurs in a small subset of patients with heart failure treated with guideline-directed therapies. This phenomenon, which is defined by reduced ventricular dilatation and improved systolic function, is most common in patients receiving left ventricular assist device (LVAD) therapy. Identifying therapeutic targets for initiating reverse remodeling is an area of great clinical interest, because these patients experience improved outcomes and quality of life. Targets may be discovered among the unique molecular changes associated with LVAD-induced partial myocardial functional recovery; however, the mechanisms underlying this favorable response are incompletely understood.METHODSTo identify molecular signatures of recovery, we studied paired pre-LVAD and post-LVAD myocardial samples from patients with heart failure who received LVAD as a bridge to transplant (10 responders and 9 nonresponders) and controls without heart failure. We performed bulk RNA sequencing, tandem mass tag quantitative proteomics, and tandem mass tag quantitative phosphoproteomics with follow-up mechanistic and functional investigations in primary rat cardiomyocytes and human engineered heart tissues.RESULTSAlternative RNA splicing was the leading pathway associated with a favorable response to LVAD. Responders had increased RNA splicing factor expression and unique gene splice variant expression compared with nonresponders. Alternative splicing of CAMK2D (calcium/calmodulin-dependent protein kinase 2δ) was a particularly strong predictor of recovery; increased inclusion of exon 14, which encodes the nuclear splice variant CAMK2D-B, was inversely correlated with functional recovery. Nonresponders also displayed hyperphosphorylation near the nuclear localization signal in CAMK2D-B. Investigations in primary cardiomyocytes and subcellular organelle fractions from the human hearts revealed that nuclear localization signal phosphorylation prevented adrenergic stress-dependent nuclear targeting of CAMK2D-B. Expression of a cytoplasm-restricted CAMK2D-B uniquely remodeled the phosphoproteome of primary rat cardiomyocytes compared with a nuclear-competent version and blunted calcium transients in engineered heart tissues.CONCLUSIONSThis is the first study to integrate transcriptome, alternative transcriptome, proteome, and phosphoproteome analyses of heart samples from LVAD-supported patients to investigate myocardial recovery. We identified that increased expression and phosphorylation of the nuclear CAMK2D splice variant predicted poor outcomes. This phosphorylation restricted CAMK2D-B to the cytosol, leading to impaired cardiomyocyte calcium handling. These findings suggest that LVAD nonresponder patients may benefit from therapies that modulate subcellular localization of CAMK2D or inhibit its activity.","PeriodicalId":10331,"journal":{"name":"Circulation","volume":"1191 1","pages":""},"PeriodicalIF":37.8,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145897633","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}
BACKGROUNDParvovirus B19 is a DNA virus transmitted via respiratory droplets, commonly causing erythema infectiosum in children but also implicated in acute myocarditis. In 2024, an outbreak of parvovirus B19 infections was reported across Europe and the United States. Despite growing awareness, data on the clinical features and outcomes of children with parvovirus B19-associated acute myocarditis remain limited.METHODSThis multicenter retrospective observational study reviewed medical records of pediatric patients (<18 years of age) admitted with acute myocarditis to 11 Italian tertiary pediatric cardiac centers between January 1, 2022, and October 31, 2024. Of 217 cases, 66 had confirmed parvovirus B19 DNA in plasma (PVB19+), whereas 82 with negative parvovirus B19 testing served as a comparator group (PVB19-). Population-based incidence trends of pediatric myocarditis were also evaluated in the Lombardy region from 2004 through 2024.RESULTSAmong PVB19+ acute myocarditis cases, 58 of 66 (87.9%) were admitted in 2024. The median age was 32 months, with 51 of 66 (77.2%) ≤7 years of age, and 36 of 66 (54.5%) were boys. Median plasma viral load was 34 411 copies/mL, whereas only 30 of 56 (53.6%) had immunoglobulin M (IgM) positivity. Among 26 of 66 (39.4%) with available histology, 23 (88.4%) had lymphocytic myocarditis, and parvovirus B19 DNA was identified in 84.0% of myocardial specimens. Among 25 of 65 (38.4%) who underwent genetic testing, none had pathogenic or likely pathogenic variants. Overall, 13 of 66 (19.7%) died, underwent heart transplantation, or received a durable left ventricular assist device (in total, there were 6 deaths, 5 durable left ventricular assist devices, and 5 transplantations) compared with 1 of 82 (1.2%) among PVB19- acute myocarditis (one patient who received a durable left ventricular assist device and later underwent transplantation; P<0.001). A marked increase in regional and institutional myocarditis incidence in pediatric acute myocarditis was observed in 2024, predominantly in children ≤7 years of age, driven by PVB19+ cases.CONCLUSIONSDuring the 2024 parvovirus B19 outbreak, pediatric PVB19+ acute myocarditis cases surged in Italy and were associated with severe outcomes. A high index of suspicion is required for diagnosis, and early virological testing is essential to guide management and potentially improve outcomes.
{"title":"Clinical Spectrum of Children With Parvovirus B19-Associated Acute Myocarditis.","authors":"Enrico Ammirati,Giacomo Veronese,Francesca Raimondi,Giuseppe Alberto Annoni,Domenico Sirico,Francesco Bianco,Alessio Franceschini,Gessica Ingrasciotta,Giovanni Meliota,Guglielmo Capponi,Isabella Pellicioli,Gaia Biancamaria Chiesa,Carlo Beretta,Giada Colombo,Giovanni Di Salvo,Sandra Nonini,Francesca Aresta,Luca Ragni,Tammam Hasan,Maurizio Brighenti,Giovanna Travi,Olivia Leoni,Paul Stefan Vrabie,Michele Ercolanoni,Giuseppe Limongelli,Emanuele Monda,Maria Giovanna Russo,Alessandra Corato,Elena Reffo,Valentina Bucciarelli,Sergio Filippelli,Susanna Breviario,Carlo Pace Napoleone,Ugo Vairo,Maristella Lombardi,Nadia Assanta,Pietro Marchese,Paolo Ferrero,Flavio Luciano Ribichini,Andrea Garascia,Michele Giovanni Mondino,Antonio Amodeo,Rachele Adorisio,Ezio Bonanomi","doi":"10.1161/circulationaha.125.075943","DOIUrl":"https://doi.org/10.1161/circulationaha.125.075943","url":null,"abstract":"BACKGROUNDParvovirus B19 is a DNA virus transmitted via respiratory droplets, commonly causing erythema infectiosum in children but also implicated in acute myocarditis. In 2024, an outbreak of parvovirus B19 infections was reported across Europe and the United States. Despite growing awareness, data on the clinical features and outcomes of children with parvovirus B19-associated acute myocarditis remain limited.METHODSThis multicenter retrospective observational study reviewed medical records of pediatric patients (<18 years of age) admitted with acute myocarditis to 11 Italian tertiary pediatric cardiac centers between January 1, 2022, and October 31, 2024. Of 217 cases, 66 had confirmed parvovirus B19 DNA in plasma (PVB19+), whereas 82 with negative parvovirus B19 testing served as a comparator group (PVB19-). Population-based incidence trends of pediatric myocarditis were also evaluated in the Lombardy region from 2004 through 2024.RESULTSAmong PVB19+ acute myocarditis cases, 58 of 66 (87.9%) were admitted in 2024. The median age was 32 months, with 51 of 66 (77.2%) ≤7 years of age, and 36 of 66 (54.5%) were boys. Median plasma viral load was 34 411 copies/mL, whereas only 30 of 56 (53.6%) had immunoglobulin M (IgM) positivity. Among 26 of 66 (39.4%) with available histology, 23 (88.4%) had lymphocytic myocarditis, and parvovirus B19 DNA was identified in 84.0% of myocardial specimens. Among 25 of 65 (38.4%) who underwent genetic testing, none had pathogenic or likely pathogenic variants. Overall, 13 of 66 (19.7%) died, underwent heart transplantation, or received a durable left ventricular assist device (in total, there were 6 deaths, 5 durable left ventricular assist devices, and 5 transplantations) compared with 1 of 82 (1.2%) among PVB19- acute myocarditis (one patient who received a durable left ventricular assist device and later underwent transplantation; P<0.001). A marked increase in regional and institutional myocarditis incidence in pediatric acute myocarditis was observed in 2024, predominantly in children ≤7 years of age, driven by PVB19+ cases.CONCLUSIONSDuring the 2024 parvovirus B19 outbreak, pediatric PVB19+ acute myocarditis cases surged in Italy and were associated with severe outcomes. A high index of suspicion is required for diagnosis, and early virological testing is essential to guide management and potentially improve outcomes.","PeriodicalId":10331,"journal":{"name":"Circulation","volume":"43 1","pages":""},"PeriodicalIF":37.8,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145897450","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}
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