Cardiovascular Research最新文献

{"title":"Biologically engineered valved conduits for right ventricular outflow tract repair evaluated for 52 weeks in growing lambs","authors":"Zeeshan H Syedain, Matthew Lahti, James Berry, John P Carney, Jill Schappa Faustich, Bee Haynie, Jack Maher, Richard Bianco, Gurumurthy Hiremath, John E Mayer, Robroy MacIver, Robert T Tranquillo","doi":"10.1093/cvr/cvaf038","DOIUrl":"https://doi.org/10.1093/cvr/cvaf038","url":null,"abstract":"Aims Replacement heart valves that grow with children remain an unmet need. We previously reported valves fabricated from tubes of fibroblast-derived collagenous matrix increased in size while functioning with low systolic gradients and less than moderate regurgitation over 52 weeks in most cases, when implanted as interpositional grafts in the pulmonary artery of lambs. Here, we evaluated valved conduits fabricated by including an inflow segment to the tri-tube valve allowing for myocardial anastomosis as done in a typical right ventricular outflow tract (RVOT) surgical repair, in the same growing lamb model. Methods and results In this pilot study, 19 mm valved conduits fabricated from resorbable suture were implanted into Dorset lambs (n = 3), sutured to the pulmonary annulus and distal pulmonary artery with resorbable suture after dissection of the pulmonary valve leaflets and resection of an arterial segment. Valve function and dimensions were measured with longitudinal transthoracic echocardiography. All animals exhibited an increase in valve diameter (18.2 ± 1.8 mm at 1 week to 25.1 ± 2.4 mm at 52 weeks) and leaflet free-edge length (21.1 ± 2.4 mm at 1 week to 26.2 ± 3.9 mm at 52 weeks) while functioning with at most mild regurgitation over 52 weeks. The inflow segment of the conduit grew somatically based on its unchanged thickness and increased diameter (38%) and collagen content (128%). In all three explanted conduits, the leaflets contained interstitial cells, new collagen and elastin primarily around the base, a developing endothelium on the surfaces, and they remained thin and pliable without macroscopic calcification. There was interdigitating integration of the conduit with the myocardium at the pulmonary annulus. Further, a stent was successfully placed in a valved conduit at term to evaluate feasibility of a prospective clinical intervention. Conclusion This valved conduit grows in lambs based on this pilot study and thus has clinical potential for RVOT reconstruction and long-term valve growth in children.","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"25 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143653429","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":"Upfront lipid-lowering combination therapy in high cardiovascular risk patients: a route to effective atherosclerotic cardiovascular disease prevention.","authors":"Maciej Banach, Stanisław Surma, Tomasz J Guzik, Peter E Penson, Michael J Blaha, Fausto J Pinto, Laurence S Sperling","doi":"10.1093/cvr/cvaf045","DOIUrl":"https://doi.org/10.1093/cvr/cvaf045","url":null,"abstract":"<p><p>Despite three decades of using statin therapy, 20 years of experience with ezetimbe, and availability of innovative non-statin lipid lowering therapies (LLT), there are still about 70% patients over the low-density lipoprotein cholesterol (LDL-C) goal, with every 5-6th being over the target from the group of very high and extremely high cardiovascular disease (CVD) risk patients. Adding another even every 5th patient at very high CVD risk without any LLT, makes this situation highly frustrating, especially lipid disorders are the most common CVD risk factor with the prevalence of over 60%, with the worst awareness within all cardiovascular risk factors (only about 15% people knows their LDL-C level). To answer this since 2021 there is an approach to apply upfront (immediate) lipid lowering combination therapy of statin and ezetimibe in very high and extremely high-risk patients to be on the LDL-C target as low as possible, but especially as early as possible, enabling to introduce the third line therapy (i.e., bempedoic acid and/or PCSK9 targeted therapy) already after 4-6 weeks. This review discusses the current stage of knowledge and recent data on the group of patients that might benefit the most from the upfront combination LLT, when it should be optimally implemented, and the recent data on its role on LDL-C reduction, cardiovascular and mortality outcomes as well as safety issues.</p>","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":""},"PeriodicalIF":10.2,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143647477","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":"Protective functions of liver X receptor α on calcified aortic valve: involvement of regulating endoplasmic reticulum-mediated osteogenic differentiation","authors":"Lishan Zeng, Xin Chen, Kai Kang, Yifei Lin, Zhongxing Zhou, Shuaijie Chen, Chunkai Huang, Qingqing Lin, Hongzhuang Wang, Longqing Chen, Liangliang Yan, HanFan Qiu, Jinxiu Lin, Xiaoyan Lin, Dajun Chai","doi":"10.1093/cvr/cvaf044","DOIUrl":"https://doi.org/10.1093/cvr/cvaf044","url":null,"abstract":"Aims Effective therapeutic drugs for calcific aortic valve disease (CAVD) are lacking, although its incidence has been increasing over the past decade, and is predicted to continue rising in the future. This study aimed to explore the role and potential mechanisms of liver X receptor α (LXRα) in CAVD, which offers a promising approach for treating CAVD. Methods and results Osteogenic stimulation was performed following which a substantial downregulation of LXRα was observed in human calcific aortic valves and in valvular interstitial cells. Further functional investigations revealed that silencing LXRα exacerbated calcification both in vitro and in vivo. We showed that LXRα suppressed the protein kinase R-like ER kinase (PERK)/eukaryotic initiation factor 2 (elF2α)/activating transcription factor 4 (ATF4) pathway, which controls endoplasmic reticulum stress (ERS) and promotes osteogenic differentiation thereby slowing the course of CAVD. Conclusion Our research offers fresh perspectives on how LXRα controls the pathophysiology of CAVD via regulating ERS. The findings suggest that targeting LXRα is a potential treatment strategy for treating aortic valve calcification.","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"19 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143631474","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":"Opportunities and challenges for the use of human samples in translational cardiovascular research: a scientific statement of the ESC Working Group on Cellular Biology of the Heart, the ESC Working Group on Cardiovascular Surgery, the ESC Council on Basic Cardiovascular Science, the ESC Scientists of Tomorrow, the European Association of Percutaneous Cardiovascular Interventions of the ESC, and the Heart Failure Association of the ESC","authors":"Sean M Davidson, Ioanna Andreadou, Charalambos Antoniades, Jozef Bartunek, Cristina Basso, Bianca J J M Brundel, Robert A Byrne, Gemma Chiva-Blanch, Paula da Costa Martins, Paul C Evans, Henrique Girão, Zoltan Giricz, Can Gollmann-Tepeköylü, Tomasz Guzik, Mariann Gyöngyösi, Norbert Hübner, Michael Joner, Petra Kleinbongard, Thomas Krieg, Elisa Liehn, Rosalinda Madonna, Ange Maguy, Melanie Paillard, Maurizio Pesce, Steffen E Petersen, Gabriele G Schiattarella, Joost P G Sluijter, Sabine Steffens, Katrin Streckfuss-Bömeke, Matthias Thielmann, Art Tucker, Sophie Van Linthout, William Wijns, Johann Wojta, Joseph C Wu, Cinzia Perrino","doi":"10.1093/cvr/cvaf023","DOIUrl":"https://doi.org/10.1093/cvr/cvaf023","url":null,"abstract":"Animal models offer invaluable insights into disease mechanisms but cannot entirely mimic the variability and heterogeneity of human populations, nor the increasing prevalence of multi-morbidity. Consequently, employing human samples—such as whole blood or fractions, valvular and vascular tissues, myocardium, pericardium, or human-derived cells—is essential for enhancing the translational relevance of cardiovascular research. For instance, myocardial tissue slices, which preserve crucial structural and functional characteristics of the human heart, can be used in vitro to examine drug responses. Human blood serves as a rich source of biomarkers, including extracellular vesicles, various types of RNA (miRNA, lncRNA, and circRNAs), circulating inflammatory cells, and endothelial colony-forming cells, facilitating detailed studies of cardiovascular diseases. Primary cardiomyocytes and vascular cells isolated from human tissues are invaluable for mechanistic investigations in vitro. In cases where these are unavailable, human induced pluripotent stem cells serve as effective substitutes, albeit with specific limitations. However, the use of human samples presents challenges such as ethical approvals, tissue procurement and storage, variability in patient genetics and treatment regimens, and the selection of appropriate control samples. Biobanks are central to the efficient use of these scarce and valuable resources. This scientific statement discusses opportunities to implement the use of human samples for cardiovascular research within specific clinical contexts, offers a practical framework for acquiring and utilizing different human materials, and presents examples of human sample applications for specific cardiovascular diseases, providing a valuable resource for clinicians, translational and basic scientists engaged in cardiovascular research.","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"8 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143618382","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":"Blood pressure and the brain: the conundrum of hypertension and dementia.","authors":"Rebecca F Gottesman, Marco Egle, Renee C Groechel, Amreen Mughal","doi":"10.1093/cvr/cvaf010","DOIUrl":"https://doi.org/10.1093/cvr/cvaf010","url":null,"abstract":"<p><p>As the population ages, the anticipated rates of dementia worldwide are likely to increase dramatically, especially in low- and middle-income countries; thus, any opportunity to modify dementia risk is especially critical. Hypertension is one risk factor that is highly prevalent, consistently important for late-life brain health, and which could represent a target for prevention of dementia. Furthermore, hypertension is the most significant modifiable risk factor for stroke. This review will summarize existing literature linking hypertension with dementia and brain health more broadly, will discuss potential mechanisms linking hypertension with brain health, and will consider specific factors that may impact not only the relationship between hypertension and the brain but also the importance of treatment, including different associations over the life course.</p>","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":""},"PeriodicalIF":10.2,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143623593","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":"Cardiac ischemia/reperfusion increases cardiomyocyte KLF5 in pigs and mice that aggravates tissue injury and remodeling","authors":"Nikolaos Mylonas, Georgios Siokatas, Effimia Zacharia, Christine Pol, Tyler Rolland, Ioannis D Kyriazis, Matthew Hoffman, Alycia Hildebrand, Thomas Bannister, Erhe Gao, Ira J Goldberg, Vincent W Yang, Agnieszka B Bialkowska, John Elrod, John M Canty, Ioanna Andreadou, Brian Weil, Konstantinos Drosatos","doi":"10.1093/cvr/cvaf040","DOIUrl":"https://doi.org/10.1093/cvr/cvaf040","url":null,"abstract":"Aims Activation of the transcriptional factor Krüppel-like factor 5 (KLF5) is detrimental to chronic heart failure. We explored the involvement of KLF5 in myocardial ischemia/reperfusion injury. Methods and results Yorkshire pigs underwent 75΄ of ischemia, followed by 3h or 24h of reperfusion. C57BL/6J mice underwent 30΄ of ischemia, followed by 10’, 2h, 12h, 24h, or 4 weeks of reperfusion. Hearts and isolated cardiomyocytes were analyzed for gene expression. We assessed cardiac function, infarct size (IS), oxidative stress, and fibrosis in mice subjected to pharmacologic or genetic KLF5 inhibition, as well as pharmacologic inhibition of NADPH oxidases or Glucose Transporter (GLUT)1 and GLUT4. Bulk RNA sequencing, untargeted 1H-NMR metabolomics and LC-MS lipidomics were performed. Isolated primary murine cardiomyocytes were infected with recombinant adenovirus expressing KLF5. During reperfusion, cardiοmyocyte KLF5 expression was increased in porcine and murine hearts. Pharmacologic or cardiomyocyte-specific genetic inhibition of KLF5 reduced IS and improved cardiac function in mice. Importantly, acute KLF5 inhibition during early reperfusion suppressed fibrosis and preserved systolic cardiac function 4 weeks post-ischemia/reperfusion. This improvement was associated with lower NOX4 expression, less oxidative stress, and suppressed inflammation and cell apoptosis. Pharmacologic inhibition of NOX4 conferred the same benefit. Metabolomic analysis indicated that KLF5 inhibition lowered glucose-derived metabolites (UDP-Glucose and Lactate) at early reperfusion. Accordingly, cardiac GLUT1 and GLUT4 levels were increased with ischemia/reperfusion, which was reverted by KLF5 inhibition. Pharmacologic inhibition of both GLUT1/4 reduced IS. Finally, myocardial KLF5 overexpression increased GLUT1 mRNA levels and mouse mortality. Conclusions Ischemia/reperfusion increases cardiomyocyte KLF5 expression in pigs and mice. This constitutes a central element of myocardial injury pathophysiology and is associated with stimulation of GLUT1 and GLUT4 expression, activation of NOX4, oxidative stress, inflammation and apoptosis. Acute KLF5 inhibition during reperfusion constitutes a novel therapeutic approach against myocardial ischemia/reperfusion injury.","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"42 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143607947","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":"Unveiling the role of tyrosine kinases in doxorubicin-induced cardiotoxicity and beyond.","authors":"Edoardo Lazzarini, Claudia Altomare, Lucio Barile","doi":"10.1093/cvr/cvaf035","DOIUrl":"https://doi.org/10.1093/cvr/cvaf035","url":null,"abstract":"","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":""},"PeriodicalIF":10.2,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143623594","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":"Targeted delivery of TAPI-1 via biomimetic nanoparticles ameliorates post-infarct left ventricle function and remodeling.","authors":"Qing Chen, Yang Yu, Lei Tong, Robert M Weiss, Shun-Guang Wei","doi":"10.1093/cvr/cvaf039","DOIUrl":"10.1093/cvr/cvaf039","url":null,"abstract":"<p><strong>Aims: </strong>The potential of nanoparticles as effective drug delivery tools for treating failing hearts in heart failure remains a challenge. Leveraging the rapid infiltration of neutrophils into infarcted hearts after myocardial infarction (MI), we developed a nanoparticle platform engineered with neutrophil-membrane proteins for the targeted delivery of TAPI-1, a TACE/ADAM17 inhibitor, to the inflamed myocardium, aiming to treat cardiac dysfunction and remodeling in rats with MI.</p><p><strong>Methods and results: </strong>Neutrophil-mimic liposomal nanoparticles (Neu-LNPs) were constructed by integrating synthesized liposomal nanoparticles with LPS-stimulated neutrophil membrane fragments and then loaded with TAPI-1. MI rats were treated with TAPI-1 delivered via Neu-LNPs for 4 weeks. Left ventricular function was assessed by echocardiography and cardiac fibrosis was evaluated post-treatment. The novel Neu-LNPs maintained typical nanoparticle features, but with increased biocompatibility. Neu-LNPs demonstrated improved targeting ability and cellular internalization, facilitated by LFA1/Mac1/ICAM-1 interaction. Neu-LNPs displayed higher accumulation and cellular uptake by macrophages and cardiomyocytes in infarcted hearts post-MI, with a sustained duration. Treatments with TAPI-1-Neu-LNPs demonstrated greater protection against myocardial injury and cardiac dysfunction in MI rats compared to untargeted TAPI-1, along with reduced cardiac collagen deposition and expression of fibrosis biomarkers as well as altered immune cell compositions within the hearts.</p><p><strong>Conclusions: </strong>Targeted treatment with TACE/ADAM17 inhibitor delivered via biomimetic nanoparticles exhibited pronounced advantages in improving left ventricle function, mitigating cardiac remodeling, and reducing inflammatory responses within the infarcted hearts. This study underscores the effectiveness of Neu-LNPs as a drug delivery strategy to enhance therapeutic efficacy in clinical settings.</p>","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":""},"PeriodicalIF":10.2,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143555990","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":"Targeting the PDK/PDH axis modulates neutrophil and smooth muscle cell pathological responses and prevents abdominal aortic aneurysm formation","authors":"S Griepke, A Grentzmann, G L Tripodi, J Hansen, M P Fonseca, M D Nilsson, Y Tallouzi, E Grupe, P S Jensen, H C Beck, G Temprano-Sagrera, M Sabater-Lleal, M Burton, M Dembic, M Thomassen, M J Forteza, M G Terp, J S Lindholt, L M Rasmussen, L B Steffensen, J Stubbe, D F J Ketelhuth","doi":"10.1093/cvr/cvaf032","DOIUrl":"https://doi.org/10.1093/cvr/cvaf032","url":null,"abstract":"Aims Abdominal aortic aneurysm (AAA) is a life-threatening condition where inflammation plays a key role. Currently, AAA treatment relies exclusively on surgical interventions, and no guideline drug therapy to prevent aneurysm growth or rupture is available. Pharmacological reprogramming of immune cell metabolism, through the modulation of the pyruvate dehydrogenase kinase/pyruvate dehydrogenase (PDK/PDH) axis, has been identified as an attractive strategy to combat inflammation. Here we aimed, for the first time, to investigate the role of the PDK/PDH axis in AAA and its potential as a therapeutic target. Methods and results Analysis of three separate transcriptome datasets revealed that the expression of PDK isoenzymes is skewed in human AAA. Thus, human AAA homogenates showed increased levels of phosphorylated PDH-Ser293 and lactate compared to controls, confirming a metabolic deviation. In mice subjected to porcine pancreatic elastase (PPE)-induced AAA, treatment with dichloroacetate (DCA), a pan inhibitor of PDK isoenzymes, prevented aortic dilation, reducing the increase in inner aortic diameter by approximately 58% compared to controls. Further analysis showed that DCA treatment upregulated contractile VSMC-related genes and downregulated neutrophil-related genes in the mice. In line with the previous, PDK-inhibition prevented elastin breakdown, preserved aortic alpha-smooth muscle actin and collagen expression, and decreased neutrophil infiltration and neutrophil extracellular traps (NET) release. Thus, treating VSMC with DCA or PDK1-siRNA revealed that the PDK/PDH axis regulates their dedifferentiation, influencing contractile gene expression and proliferation. Moreover, we found that DCA-induced PDK inhibition inhibited neutrophil NET release in vivo and in vitro. Conclusion We show that the PDK/PDH axis is skewed in human AAA. Through the inhibition of PDK, in vitro and in vivo, we demonstrated that the PDK/PDH axis is a key regulator of vascular- and neutrophil-associated pathological responses with AAA formation. Our study pinpoints immunometabolic reprogramming using PDK inhibitors as an attractive strategy to fight AAA disease.","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"59 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143546537","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":"Antisense-mediated regulation of exon usage in the elastic spring region of Titin modulates sarcomere function.","authors":"Selvi Celik, Ludvig Hyrefelt, Tomasz Czuba, Yuan Li, Juliana Assis, Julia Martinez, Markus Johansson, Oscar André, Jane Synnergren, Joakim Sandstedt, Pontus Nordenfelt, Kristina Vukusic, J Gustav Smith, Olof Gidlöf","doi":"10.1093/cvr/cvaf037","DOIUrl":"https://doi.org/10.1093/cvr/cvaf037","url":null,"abstract":"<p><strong>Background: </strong>Alternative splicing of Titin (TTN) I-band exons produce protein isoforms with variable size and elasticity, but the mechanisms whereby TTN splice factors regulate exon usage and thereby determining cardiomyocyte passive stiffness and diastolic function, is not well understood. Non-coding RNA transcripts from the antisense strand of protein-coding genes have been shown to regulate alternative splicing of the sense gene. The TTN gene locus harbours >80 natural antisense transcripts (NATs) with unknown function in the human heart. The aim of this study was to determine if TTN antisense transcripts play a role in alternative splicing of TTN.</p><p><strong>Methods and results: </strong>RNA-sequencing and RNA in situ hybridization (ISH) of cardiac tissue from heart failure patients (HF), unused donor hearts and human iPS-derived cardiomyocytes (iPS-CMs) were used to determine the expression and localization of TTN NATs. Live cell imaging was used to analyze the effect of NATs on sarcomere properties. RNA ISH, immunofluorescence was performed in iPS-CMs to study the interaction between NATs, TTN mRNA and splice factor protein RBM20.We found that TTN-AS1-276 was the predominant TTN NAT in the human heart and that it was upregulated in HF. Knock down of TTN-AS1-276 in human iPS-CMs resulted in decreased interaction between the splicing factor RBM20 and TTN pre-mRNA, decreased TTN I-band exon skipping, and markedly lower expression of the less compliant TTN isoform N2B. The effect on TTN exon usage was independent of sense-antisense exon overlap and polymerase II elongation rate. Furthermore, knockdown resulted in longer sarcomeres with preserved alignment, improved fractional shortening and relaxation times.</p><p><strong>Conclusions: </strong>We demonstrate a role for TTN-AS1-276 in facilitating alternative splicing of TTN and regulating sarcomere properties. This transcript could constitute a target for improving cardiac passive stiffness and diastolic function in conditions such as heart failure with preserved ejection fraction.</p>","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":""},"PeriodicalIF":10.2,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143555986","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}