Nature cardiovascular research最新文献

{"title":"Alpha protein kinase 3 gene therapy restores heart function in mouse and human models of cardiomyopathy","authors":"James W. McNamara, Ellen B. Keen, Rebecca Sutton, Yinghan She, Hannah Huckstep, Lina H. H. Le, Neda R. Mehdiabadi, Madhavan S. Venkatesh, Brendan Griffen, Richard J. Mills, Christina V. Theodoris, James E. Hudson, Drew M. Titmarsh, Sean J. Humphrey, Enzo R. Porrello, David A. Elliott","doi":"10.1038/s44161-026-00843-1","DOIUrl":"10.1038/s44161-026-00843-1","url":null,"abstract":"Truncating variants in the ALPK3 gene (encoding alpha protein kinase 3) cause severe cardiomyopathy for which no curative treatment exists1–3. Here we establish an adeno-associated virus (AAV)-mediated gene replacement therapy to deliver full-length human ALPK3. AAV-ALPK3 prevented disease in neonatal Alpk3-mutant mice and reversed established pathology in adults, with proteomic analysis demonstrating reversal of more than 95% of the molecular disease signature. Beyond ALPK3 deficiency, we explored broader therapeutic potential based on ALPK3’s regulatory role in proteostasis, a pathway commonly disrupted across cardiomyopathies. ALPK3 expression is reduced in cardiomyocytes with TTN-truncating variants, the most prevalent cause of dilated cardiomyopathy, and the encoded titin protein has a protein quality control network in common with ALPK3. AAV-ALPK3 restored contractile function in human cardiac organoids with an ALPK3- or TTN-truncating variant. These findings provide proof of concept for ALPK3 gene therapy in patients with ALPK3 cardiomyopathy and reveal potential for indication expansion to cardiomyopathies associated with TTN-truncating variants, which are not amenable to gene replacement therapy due to size limitations. McNamara et al. demonstrate that adeno-associated virus-mediated delivery of full-length human ALPK3 prevents cardiomyopathy in neonatal mouse models and reverses established disease in adult mice, restoring cardiac structure, function and proteostasis, as well as contractile function in human cardiac organoids carrying ALPK3- or titin-truncating variants.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"5 9","pages":"795-806"},"PeriodicalIF":12.6,"publicationDate":"2026-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s44161-026-00843-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148802596","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Incorporating uncertainty into digital twins can improve ablation planning for ventricular tachycardia","authors":"","doi":"10.1038/s44161-026-00860-0","DOIUrl":"10.1038/s44161-026-00860-0","url":null,"abstract":"Our near real-time digital twin framework accounts for uncertainty in reconstructed scar anatomy to accurately match simulated and clinical ECG signatures in ventricular tachycardia. By integrating predictions, it generates robust, clinically actionable ablation target heatmaps to support personalized treatment.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"5 9","pages":"789-790"},"PeriodicalIF":12.6,"publicationDate":"2026-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148763895","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Accounting for uncertainty in computational models of ventricular tachycardia improves ablation guidance","authors":"Abdul Mateen Qadri, Ursula Rohrer, Fernando O. Campos, Iulia Nazarov, Ali-Razak Rashid, Pranav Bhagirath, C. Aldo Rinaldi, Ronak Rajani, Luca Azzolin, Aurel Neic, Gernot Plank, John Whitaker, Martin J. Bishop","doi":"10.1038/s44161-026-00856-w","DOIUrl":"10.1038/s44161-026-00856-w","url":null,"abstract":"Personalized ‘digital twin’ technology has the potential to revolutionize target guidance for catheter ablation therapy of ventricular tachycardia (VT); however, concerns regarding the practical implementation of these computationally intensive approaches, along with the robustness of simulation predictions given uncertainty in the interpretation and analysis of clinical imaging data used to reconstruct image-based models, are hindering clinical translation. Here we present a new technical framework that provides near-real-time guidance on VT ablation targets, inherently incorporating uncertainty in reconstructed scar anatomy. We demonstrate close agreement between simulated ECG ‘fingerprint’ signatures of VT circuits and clinical recordings in ischemic ablation patients, highlighting the need to account for variations in reconstructed scar anatomy to identify the best-matching simulated circuit. Finally, we introduce a robust method for integrating anatomical information across all viable simulated circuits from different model ‘instances’ into a simulated ablation target heatmap for practical clinical guidance. Qadri et al. develop a computational framework for near-real-time ventricular tachycardia ablation guidance that incorporates uncertainty in fibrotic scar reconstruction and simulates faithful ECG signatures of tachycardia circuits.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"5 9","pages":"807-818"},"PeriodicalIF":12.6,"publicationDate":"2026-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s44161-026-00856-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148765065","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Spatial transcriptomics reveals heterogeneity in rejection and recovery after heart transplantation","authors":"","doi":"10.1038/s44161-026-00855-x","DOIUrl":"10.1038/s44161-026-00855-x","url":null,"abstract":"Subcellular-resolution spatial transcriptomics exposes cell-specific molecular states that underlie acute rejection and recovery in heart transplantation, helping to explain why biopsies with similar histological appearances can present differently in the clinic.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"5 9","pages":"791-792"},"PeriodicalIF":12.6,"publicationDate":"2026-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148763610","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rethinking the selection of in vivo thrombosis models in the hybrid era","authors":"Kellie R. Machlus, Alisa S. Wolberg, Jessica C. Cardenas","doi":"10.1038/s44161-026-00850-2","DOIUrl":"10.1038/s44161-026-00850-2","url":null,"abstract":"Microfluidic, organoid, and in silico platforms have transformed our ability to investigate thrombosis-related biology, but preclinical in vivo models remain uniquely able to capture the interactions that shape thrombotic disease. Nevertheless, these models are not interchangeable and need to be carefully selected.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"5 8","pages":"661-664"},"PeriodicalIF":12.6,"publicationDate":"2026-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148704550","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Established and emerging roles of lysosomal dysfunction in cardiac aging","authors":"Yohan Santin, Ilias Simon, Angelo Parini, Frank Lezoualc’h, Elena Sommariva","doi":"10.1038/s44161-026-00853-z","DOIUrl":"10.1038/s44161-026-00853-z","url":null,"abstract":"Cardiac aging is a central biological process underlying most cardiovascular diseases. Lysosomes, once regarded as terminal degradative compartments, are now recognized as dynamic metabolic and signaling hubs whose dysfunction has profound consequences for the aging heart. Human lysosomal storage disorders provide compelling evidence that isolated lysosomal defects are sufficient to cause early cardiomyopathy, underscoring the myocardium’s exceptional dependence on sustained lysosomal competence. In physiological aging, impaired autophagy is the most apparent manifestation of lysosomal decline but represents only one facet of a broader network regulating nutrient sensing, ion and lipid homeostasis, receptor trafficking, exocytosis/secretion and inter-organelle communication. Here, we review established and emerging lysosome-dependent mechanisms across the hallmarks of cardiac aging, highlighting lysosomes as potential upstream drivers of this process. We discuss key knowledge gaps and therapeutic strategies aimed at restoring lysosomal function, positioning lysosomes as central and actionable targets for preserving cardiac resilience with age. Santin et al. review the emerging role of lysosomes as central regulators of cardiac aging, highlighting their functions in coordinating metabolism, signaling and cellular homeostasis. They discuss how lysosomal dysfunction contributes to age-related decline and outline lysosome-targeted strategies as promising approaches to preserve cardiac function and resilience.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"5 8","pages":"675-692"},"PeriodicalIF":12.6,"publicationDate":"2026-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148704551","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dynamic cellular programs of human cardiac allograft rejection revealed by spatial transcriptomics","authors":"Kaushik Amancherla, Angela M. Taravella Oill, Xavier Bledsoe, Arianna L. Williams, Nelson Chow, Anna J. Smith, Melissa A. Farrow, Shilin Zhao, Quanhu Sheng, David W. Bearl, Alexander N. Perez, Robert D. Hoffman, Jonathan N. Menachem, Hasan K. Siddiqi, Douglas M. Brinkley, Evan D. Mee, Niran Hadad, Vineet Agrawal, Jeffrey Schmeckpepper, Aniket Rali, Stacy Tsai, Eric Farber-Eger, Quinn S. Wells, Jane E. Freedman, Nathan R. Tucker, Jeffrey M. Spraggins, Kelly H. Schlendorf, Eric R. Gamazon, Nicholas Banovich, Ravi V. Shah","doi":"10.1038/s44161-026-00849-9","DOIUrl":"10.1038/s44161-026-00849-9","url":null,"abstract":"Allograft rejection following solid-organ transplantation is a major cause of graft dysfunction and mortality. Current diagnostic approaches rely on histology, which exhibits wide diagnostic variability and lacks clinically relevant molecular phenotyping. Here we leverage image-based spatial transcriptomics at subcellular resolution in longitudinal human cardiac biopsies to characterize transcriptional heterogeneity in 62 adult and pediatric heart transplant recipients during and following histologically diagnosed rejection. Across 28 cell types, we identified significant differences in abundance in immune and parenchymal cells across different classes of rejection. We observed broad overlap in transcriptional states across rejection severity and significant heterogeneity within rejection grades. Responders and nonresponders to augmented therapies had distinct transcriptomic profiles, with nonresponders exhibiting baseline T cell hyperactivation and tissue remodeling genes. We also identified cell-specific genes linked to long-term outcomes after heart transplant. These results underscore the importance of subtyping cellular states during rejection to stratify immune–cardiac interactions relevant to short- and long-term outcomes. Using spatial transcriptomics on longitudinal human cardiac biopsies, Amancherla, Oill and colleagues reveal marked cellular and molecular heterogeneity in transplanted hearts undergoing rejection, identify gene expression profiles linked to therapy response and outcomes, and show that acute rejection signatures are associated with chronic rejection development.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"5 9","pages":"819-834"},"PeriodicalIF":12.6,"publicationDate":"2026-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s44161-026-00849-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148708840","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reducing the mechanical load reawakens adult cardiomyocyte proliferation","authors":"","doi":"10.1038/s44161-026-00845-z","DOIUrl":"10.1038/s44161-026-00845-z","url":null,"abstract":"In a mouse model, reducing ventricular workload promotes adult cardiomyocyte proliferation through NRG1–ERBB4 signaling between epicardial cells and cardiomyocytes; this signaling activates the pentose phosphate pathway to provide metabolic support.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"5 8","pages":"673-674"},"PeriodicalIF":12.6,"publicationDate":"2026-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148686748","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanical unloading promotes adult cardiomyocyte proliferation through epicardial NRG1–ERBB4 signaling","authors":"Chenyu Jiang, Tianyu Liu, Zihao Dai, Li Xiang, Yifan Zhu, Xingliang Zhou, Xu Huang, Yi Shen, Jian Liu, Yuxi Ji, Lin Cheng, Fang Yu, Yi Yan, Bei Feng, Tuo Pan, Jinhai Chen, Yu Nie, Hao Zhang, Yiwei Liu","doi":"10.1038/s44161-026-00841-3","DOIUrl":"10.1038/s44161-026-00841-3","url":null,"abstract":"In mammals, the postnatal increase in cardiac workload coincides with the loss of cardiomyocyte proliferative capacity, rendering adult cardiomyocytes permanently post-mitotic. Whether reducing load can restore regenerative potential in the adult heart remains unknown. Here we use a heterotopic heart transplantation model, in which the donor heart is vascularized but nonpumping, to show that mechanical unloading induces adult cardiomyocyte proliferation, revealed by Ki67-based and MADM (mosaic analysis with double markers) lineage tracing. Applying heterotopic transplantation to infarcted hearts to achieve mechanical unloading similarly promoted regeneration within peri-infarct regions. Single-nucleus RNA sequencing of unloaded hearts identified enhanced epicardial–cardiomyocyte communication via the NRG1–ERBB4–STAT3 axis. Epicardial Nrg1 deletion blocked STAT3 activation and cardiomyocyte proliferation. CUT&Tag revealed STAT3 directly upregulates H6pd in cardiomyocytes, boosting pentose phosphate pathway activity to supply nucleotides and reducing equivalents for proliferation. These findings delineate a mechanotransductive pathway linking epicardial signals to cardiomyocyte cell-cycle re-entry, providing a framework for leveraging unloading to promote cardiac regeneration. Jiang et al. show that mechanical unloading promotes cardiomyocyte proliferation by enhancing epicardial–cardiomyocyte communication through the NRG1–ERBB4 axis and STAT3 activation.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"5 8","pages":"705-724"},"PeriodicalIF":12.6,"publicationDate":"2026-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148681280","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cannabis use is associated with pro-atherogenic immune cell activation in young and healthy users","authors":"Andrea Tavosanis","doi":"10.1038/s44161-026-00859-7","DOIUrl":"10.1038/s44161-026-00859-7","url":null,"abstract":"","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"5 8","pages":"666-666"},"PeriodicalIF":12.6,"publicationDate":"2026-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148674781","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}