Cardiovascular Research最新文献

{"title":"Premature cell senescence promotes vascular smooth muscle cell phenotypic modulation and resistance to re-differentiation","authors":"Anuradha Kaistha, Sebnem Oc, Abel Martin Garrido, James C K Taylor, Maria Imaz, Matthew D Worssam, Anna Uryga, Mandy Grootaert, Kirsty Foote, Alison Finigan, Nichola Figg, Helle F Jørgensen, Martin Bennett","doi":"10.1093/cvr/cvaf102","DOIUrl":"https://doi.org/10.1093/cvr/cvaf102","url":null,"abstract":"Aims Human atherosclerotic plaque cells display DNA damage that if left unrepaired can promote premature cell senescence. Vascular smooth muscle cells (VSMCs) predisposed to senescence promote atherogenesis and features of unstable plaques and increase neointima formation after injury. However, how premature VSMC senescence promotes vascular disease and its effects on VSMC phenotype are unknown. Methods and Results Bulk RNA-seq of primary human VSMCs identified 126 significantly up- or down-regulated genes after both DNA damage-induced (D+R) or replicative senescence (RS). Upregulated genes included senescence markers CDKN2A (p16) and ICAM1 and genes expressed by phenotypically modulated de-differentiated/’fibromyocytic’ VSMCs (osteoprotegerin (TNFRSF11B), fibromodulin (FMOD)) as well as transmembrane protein 178B (TMEM178B) and secreted frizzle-related protein 4 (SFRP4). Mouse VSMCs also upregulated genes associated with de-differentiated VSMC phenotype, Tmem178b and Sfrp4 after D+R. Single-cell RNA-sequencing of lineage-traced VSMCs in mouse plaques or human plaques showed that VSMCs expressing Cdkn2a had lower contractile marker expression and higher expression of de-differentiated VSMC markers. Mice expressing a VSMC-restricted mutant telomere protein (TRF2T188A) that induces premature senescence showed increased atherosclerosis, expression of multiple de-differentiation genes in plaques and after injury, and differential regulation of pathways associated with extracellular matrix organisation, inflammation and Transforming Growth Factor-β (Tgfb). Trf2T188A VSMCs were more resistant to re-differentiation and had dysregulated Tgfb signalling at multiple levels with downregulated ligand, receptors, and coactivators and upregulated co-repressor expression. Trf2T188A VSMCs also showed cytosolic DNA and activation of the STING-TBK1-IRF3 pathway that suppressed Tgfb signalling. Silencing IRF3 restored expression of Tgfb pathway components and VSMC contractile markers after TGFb administration. Conclusions DNA damage and senescence induce genes associated with de-differentiated/fibromyocytic VSMCs, and persistence of these cells in vivo. Failure of senescent VSMCs to re-express contractile markers during re-differentiation suggests that VSMC senescence may promote atherosclerosis and neointima formation in part by inhibiting their re-differentiation.","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"25 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144260119","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":"Remodelling of supernumerary leaflet primordia leads to bicuspid aortic valve (BAV) caused by loss of primary cilia","authors":"Ahlam Alqahtani, Lorraine Eley, Jake Newton, Kimberley Macdonald, Chloe Connolly, Cindy Rodrigues-Cleto, Kristyna Neffeova, Leonor Lopez, Javier Arias, Christopher J Derrick, Mashael Alaradi, Hana Kolesova, Bill Chaudhry, Deborah J Henderson","doi":"10.1093/cvr/cvaf108","DOIUrl":"https://doi.org/10.1093/cvr/cvaf108","url":null,"abstract":"Aims Bicuspid aortic valve (BAV), where two valve leaflets are found instead of the usual three, affects 1-2% of the general population and is associated with significant morbidity and mortality. Despite its frequency, the majority of cases remain unexplained. This is, at least in part, because there are two types of valve leaflet primordia: endocardial cushions and intercalated valve swellings (ICVS). Moreover, multiple progenitors make distinct contribution to the formation of these primordia. Genomic studies in mouse and human have suggested a correlation between BAV and malfunctional primary cilia. However, the precise requirement for cilia during early embryonic valvulogenesis remains unknown. Methods and results Here, we disrupted primary cilia by deleting the ciliary gene Ift88 in the main progenitor cells forming the aortic valve using specific Cre drivers: Wnt1-Cre for neural crest cells, Isl1-Cre for second heart field cells (SHF); Tie2-Cre for endocardial-derived cells and Tnnt2-Cre for direct-differentiating SHF in the ICVS. Loss of Ift88, and thus primary cilia, from neural crest cells and endocardium did not impact aortic valve formation. However, primary cilia are essential in SHF cells for aortic valve leaflet formation, with over half of Ift88f/f;Isl1-Cre mutants presenting with BAV. As the valve leaflets are forming, 50% of the Ift88f/f;Isl1-Cre mutants have two small leaflets in the position of the usual posterior leaflet, meaning that at this stage the aortic valve is quadricuspid, which then remodels to BAV by E15.5. Mechanistic studies demonstrate premature differentiation of SHF cells as the ICVS form, leading to the formation of a broadened ICVS that forms two posterior leaflet precursors. This abnormality in the formation of the ICVS is associated with disruption of Notch-Jag1 signalling pathway, with Jag1f/f;Isl1-Cre mutants presenting with a similar phenotype. Conclusions These data show that primary cilia, via the Notch-Jag1 signalling pathway, regulate differentiation of SHF cells in the aortic valve primordia. Additionally, we identify a mechanistic link between the developmental basis of quadricuspid and bicuspid arterial valve leaflets.","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"23 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144268720","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":"Platelet-leukocyte aggregates in cardiovascular disease: prognostic significance and therapeutic potential.","authors":"Jiaying Han, Conor J Bloxham, Kilian Kirmes, Giacomo Viggiani, Leonhard P Unkelbach, Moritz von Scheidt, Stephanie G Kühne, Isabell Bernlochner, Gianluigi Condorelli, Philip W J Raake, Dario Bongiovanni","doi":"10.1093/cvr/cvaf105","DOIUrl":"https://doi.org/10.1093/cvr/cvaf105","url":null,"abstract":"<p><p>Initially recognised for their role in vascular haemostasis, platelets are now understood to be critical regulators of inflammation and immune responses through complex interactions with immune cells. Key to this role is the formation of platelet-leukocyte aggregates (PLAs), with platelet-monocyte aggregates (PMAs) representing the most thoroughly studied type in cardiovascular disease. PLAs form through the binding of platelet surface P-selectin to P-selectin glycoprotein ligand on leukocytes, an early interaction that may trigger broader inflammatory cascades. Recent studies link circulating PMAs with in vivo platelet activation and elevated PMA levels in patients with high thrombogenic risk, such as those with diabetes and acute myocardial infarction. Furthermore, PMA levels correlate with disease severity and long-term cardiovascular outcomes, highlighting their potential as prognostic biomarkers for adverse cardiovascular events. Therapeutic strategies, such as antiplatelet agents and P-selectin antagonists, have demonstrated efficacy in the inhibition of PLAs formation. However, the development of selective inhibitors that preserve the haemostatic and immune functions of platelets remains an unmet clinical need. Despite significant progress, the precise biological functions and underlying mechanisms of PLAs are not fully understood. This review integrates preclinical and clinical data to provide a comprehensive overview of platelet-leukocyte biology, with a focus on the prognostic role and therapeutic potential of PLAs in cardiovascular disease.</p>","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":""},"PeriodicalIF":10.2,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144246641","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":"Mapping human brain topography to heart rhythms: an SEEG study","authors":"Xiaopeng Wang, Haoxun Yang, Yueyang Cheng, Shujia Liu, Guangyuan Jin, Zichen Qiao, Lei Qi, Siyi Wang, Junliang Ge, Dongmei Hu, Hai Tang, Runshi Gao, Cuiping Xu, Xiaohua Zhang, Di Wang, Xiangyu Xue, Anqi Dai, Wenbo Zhao, Tao Yu, Yuping Wang, Bailu Si, Guoguang Zhao, Liankun Ren","doi":"10.1093/cvr/cvaf099","DOIUrl":"https://doi.org/10.1093/cvr/cvaf099","url":null,"abstract":"Aims The interplay between the heart and brain has been a subject of interest for centuries, as dysfunction in this interaction is implicated in various cardiovascular diseases and neurological disorders. Despite this advancement, there is currently a limited understanding of the mechanisms that the human brain communicates with heart rhythms. Here, we aim to characterize the human brain processing of heart rhythms and map human brain topography to heart rhythms. Methods and Results We investigated how the human brain processes heart rhythms in a cohort of 54 drug-resistant epilepsy patients who simultaneously recorded electrocardiography and stereoelectroencephalography (SEEG) during pre-surgical evaluation. Intracranial heartbeat-evoked potentials (HEPs) derived from averaging brain responses time-locked to R peaks of heartbeats in consecutive resting-state SEEG epochs, were characterized in terms of their morphology and spatiotemporal distribution across the brain. The analysis revealed a complex brain topography to heart rhythms that includes the anticipated bilateral thalamus, insula, amygdala, and anterior cingulate cortex, while also extending to the dorsolateral prefrontal cortex, supramarginal gyrus, and superior temporal gyrus. Employing an eigen microstates approach, we disentangled two prominent components of the HEPs network in the time window from 100 to 400 ms post R-peak, reflecting early (100-250 ms) and delayed (250-400 ms) processing pathways. Furthermore, we mapped human brain neurotransmitter receptor signatures onto the HEPs topography, providing the first evidence that serotonin receptor 5HT2a serves as a dominant signature of this organization at the cortical level. Additionally, brain regions exhibiting stronger HEPs showed more pronounced heart rate changes following direct electrical stimulation (DES) via SEEG. Conclusions We generated a spatiotemporal dynamic map of HEPs across cortical and subcortical regions. Our characterization of HEPs revealed various dominant components and established a direct association between its topographic organization and distribution of neurotransmitter receptors. This study provides a foundational framework for understanding the brain processing of heart signals and paves the way for novel therapeutic interventions and cardiovascular diseases.","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"38 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144218812","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":"Single-cell epigenomic and transcriptomic analysis unveils the pivotal role of GATA5/ISL1+ fibroblasts in cardiac repair post-myocardial infarction","authors":"Shuchen Zhang, Boyang Xiang, Yiheng Zhao, Wenjing Wang, Lili Chen, Xiang Zhou","doi":"10.1093/cvr/cvaf101","DOIUrl":"https://doi.org/10.1093/cvr/cvaf101","url":null,"abstract":"Aims A comprehensive understanding of the genome-wide regulatory landscape of the cardiac tissues post-myocardial infarction (MI) is still lacking. We therefore integrated single-cell RNA sequencing (scRNA-seq) and single-cell for transposase-accessible chromatin sequencing (scATAC-seq) to elucidate the epigenetic landscape of the heart post-MI. Methods and results We established MI mice through ligation of the left anterior descending coronary artery, and obtained cardiac tissues from mice at 1,3,7 and 14-day post-MI. Integrative analyses of the scRNA-seq and scATAC-seq data revealed the presence of two novel fibroblast subpopulations in the MI cardiac tissues, termed GATA-binding protein 5/ISL LIM Homeobox 1 (GATA5/ISL1) + fibroblasts and GLI family zinc finger 3 (Gli3) high fibroblasts. The GATA5/ISL1+ fibroblasts were characterized by fibroblast and cardiomyocyte signatures and were found to play a crucial role in cardiac repair post-MI. Moreover, adenoviral-mediated overexpression of GATA5 and ISL1 ameliorated cardiac function and attenuated myocardial fibrosis in the MI mice. RNA sequencing confirmed that GATA5 and ISL1 co-regulate Wnt signaling pathway to promote the transformation of fibroblasts into functional cardiomyocytes. Furthermore, analysis of the human cardiac tissues of MI patients also revealed the presence of GATA5/ISL1+ fibroblasts in the scar tissues, suggesting their crucial role in cardiac tissue repair post-MI. In addition, proteomic analyses revealed enhanced cardiac repair and development signaling in the GATA5/ISL1-overexpressing human cardiac fibroblasts. Conclusions The study provides novel perspectives on the mechanisms of myocardial injury and repair at the single-cell level and indicates the potential role of GATA5 and ISL1 as therapeutic targets for MI treatment.","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"38 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144210796","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":"Obesity and heart failure: exploring the cardiometabolic axis.","authors":"Jennifer J Rayner, Ines Abdesselam, Jiliu Pan, Andrew J M Lewis, Oliver J Rider","doi":"10.1093/cvr/cvaf090","DOIUrl":"https://doi.org/10.1093/cvr/cvaf090","url":null,"abstract":"<p><p>Obesity is one of the biggest risks to public health in both developed and developing countries, and yet incidence continues to skyrocket. Being the main risk factor for a large number of life-limiting conditions, obesity has the potential to cause enormous damage unless addressed urgently. Heart failure (HF) is the most common cardiovascular disease associated with obesity. The incidence of HF overall continues to rise and mortality rates remain high, despite the rapid and significant advances in pharmacotherapy which have recently transformed the landscape of HF treatment. Both obesity and heart failure are multisystem disorders which are closely interlinked. Obesity poses the body a number of challenges, ranging from haemodynamic, to neuroendocrine, to inflammatory, to intracellular physiology. This narrative review describes the pathophysiological 'vicious cycle' caused by the combination of obesity and HF. Management of obesity in established heart failure has for years been a controversial topic, and yet an increasing body of evidence suggests that there are numerous benefits to managing obesity and insulin resistance in heart failure. Here we review the existing evidence base, as well as exciting new developments, suggesting that we may finally be on the brink of a revolution in managing obesity in heart failure.</p>","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":""},"PeriodicalIF":10.2,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144207762","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":"A rare gain of function variant of hepatic lipase attenuates hypercholesterolemia and atherosclerosis in mice via an LDL receptor-independent mechanism","authors":"Thibaud Sotin, Xiaoke Ge, Milena Schönke, Lucie Vince, Amélie Thouzeau, Samuel Frey, Victoria Lorant, Lisa Krul, Amanda C M Pronk, Reshma Lalai, Trea C M Streefland, Salwa Afkir, Wieneke Dijk, Sarra Smati, Marieke Heijink, Niek Blomberg, Martin Giera, Mathilde Di Filippo, Philippe Moulin, Sander Kooijman, Bertrand Cariou, Patrick C N Rensen, Cédric Le May","doi":"10.1093/cvr/cvaf097","DOIUrl":"https://doi.org/10.1093/cvr/cvaf097","url":null,"abstract":"Aims LIPC encodes hepatic lipase (HL), a liver-bound protein with both phospholipase and triglyceride lipase activity, and involved in the catabolism of circulating lipoproteins. We recently identified the gain-of-function variant HL-E97G, with selectively increased phospholipase activity, as a new genetic cause of familial combined hypocholesterolemia in humans. The role of HL in the development of atherosclerosis remains controversial. In this context, the action of HL-E97G on the development of atherosclerosis remains unknown. Methods and Results To evaluate the lipid-lowering and anti-atherogenic properties of HL-E97G versus wild-type HL (HL-WT) in hypercholesterolemic APOE*3-Leiden.CETP mice, a well-established model for human-like lipoprotein metabolism, and to assess dependence of these effects on the LDL receptor (LDLR) pathway in LDLR-deficient (Ldlr-/-) mice. APOE*3.Leiden.CETP mice or Ldlr-/- mice received an intravenous injection of AAV8 expressing either eGFP (control), HL-WT or HL-E97G (3×1011 GC/mouse) while being fed pro-atherogenic diets. Plasma cholesterol levels were measured monthly, and aortic atherosclerotic lesion sizes were assessed at termination. HL-E97G largely decreased plasma total cholesterol exposure in APOE*3-Leiden.CETP mice (-63% vs control; -58% vs HL-WT), resulting at least in part from increased uptake of (V)LDL by the liver, accompanied by a marked decrease in atherosclerotic lesion size (-98% vs control; -97% vs HL-WT) in the aortic root. Importantly, HL-E97G also strongly reduced plasma cholesterol exposure in Ldlr-/- mice (-80% vs control; -77% vs HL-WT), and decreased atherosclerotic lesion size in the aortic root (-54% vs control; -41% vs HL-WT) and the aortic arch (-73% vs control; -70% vs HL-WT). Conclusions HL-E97G strongly reduces plasma cholesterol levels, by increasing the uptake of (V)LDL, to decrease atherosclerosis development in mice independently of the LDLR pathway. These data suggest that modulating HL function is a promising tool in patients with familial hypercholesterolemia.","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"70 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144210791","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 regeneration beyond stem cells: harnessing sarcomere dynamics and endogenous repair mechanisms.","authors":"Xiaoke Yin, Manuel Mayr","doi":"10.1093/cvr/cvaf103","DOIUrl":"https://doi.org/10.1093/cvr/cvaf103","url":null,"abstract":"","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":""},"PeriodicalIF":10.2,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144207761","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":"Ceramides in cardiovascular disease – emerging role as independent risk predictors and novel therapeutic targets","authors":"Roland Klingenberg, Andreas Leiherer, Dobromir Dobrev, Juan C Kaski, Bodo Levkau, Winfried März, Samuel Sossalla, Arnold von Eckardstein, Heinz Drexel","doi":"10.1093/cvr/cvaf093","DOIUrl":"https://doi.org/10.1093/cvr/cvaf093","url":null,"abstract":"Ceramides are bioactive lipid mediators involved in apoptosis, inflammation, and fibrosis. This narrative review provides a concise overview of the emerging role of ceramides in cardiovascular disease with emphasis on atherosclerotic vascular disease and heart failure, suggesting a potential use of ceramides in risk stratification and as putative therapeutic targets. Recent developments based on observational evidence and genetic associations, including Mendelian randomization studies in humans, are summarized and put into context with experimental evidence for the role of ceramides in human and animal models of disease. Emerging scores composed of ceramides and phosphatidylcholines that are based on the length and desaturation of the N-acyl chains are discussed in the light of novel data demonstrating age- and sex-specific differences. Also reviewed is the structural heterogeneity of the sphingoid bases, including non-conventional sphingolipids that are increasingly recognized for their importance in health and disease. Lastly, novel targets and potential modalities for tissue-specific transfer of drugs are discussed.","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"36 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144210855","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":"Platelets and inflammation - insights from platelet non-coding RNA content and release in the Bruneck Study and the PACMAN-AMI trial","authors":"Clemens Gutmann, Temo Barwari, Christian Schulte, Konstantinos Theofilatos, Bhawana Singh, Kaloyan Takov, Gonca Suna, Melissa V Chan, Paul C Armstrong, Christian Cassel, Yasushi Ueki, Jonas D Häner, Peter Santer, Peter Willeit, Christian Hengstenberg, Lorenz Räber, Stefan Kiechl, Johann Willeit, Timothy D Warner, Manuel Mayr","doi":"10.1093/cvr/cvaf100","DOIUrl":"https://doi.org/10.1093/cvr/cvaf100","url":null,"abstract":"Aims Platelets contain non-coding RNAs (ncRNAs), and their measurement may complement platelet aggregometry. Methods and results In the community-based Bruneck Study (n = 338), we generated platelet-rich plasma (PRP), platelet-poor plasma (PPP) and platelets. PRP was subjected to aggregometry using various agonists and processed to platelet releasates thereafter. Releasates, PPP and platelets underwent real-time polymerase chain reactions to measure ncRNAs. Platelet ncRNA release appeared agonist-specific, dose-dependent, and inhibited by aspirin. Collagen triggered the strongest release for most ncRNAs, whereas miR-150 was hyperresponsive to ADP, and miR-21 was hyperresponsive to arachidonic acid. Comparing the dynamic range of ncRNA release to aggregation, aggregation reached a maximum at high agonist concentrations, while ncRNAs continued to rise. Cohort-wide associations showed that inflammation parameters like neutrophil counts and C-reactive protein correlated inversely with platelet aggregation and ncRNA release. Similarly, a high leukocyte-derived RNA content in isolated platelets correlated inversely with aggregation. Inverse correlations were absent in aspirin users. Through experiments on plasma-free platelet releasates and platelets, including size-exclusion chromatography, ultracentrifugation and degradation assays, we discovered that microRNAs and YRNAs are carried by proteins and readily released, while circular-, long non-coding- and messenger RNAs are carried by vesicles and preferentially retained. Finally, we assessed ncRNA responses to short- and long-term dual antiplatelet therapy (DAPT) in plasma from 265 patients with acute myocardial infarction (AMI) of the PACMAN-AMI trial. Most of the DAPT effect was already achieved by 4 weeks, with a further reduction at 52 weeks, revealing a short- and long-term DAPT effect not captured by aggregometry. Conclusions Inflammation and leukocyte-derived RNAs in isolated platelets are associated with reduced platelet responses ex vivo, potentially reflecting exhaustion through pre-activation in vivo. We show that protein-bound ncRNAs are readily released from platelets, whereas vesicle-bound ncRNAs are preferentially retained. We highlight the potential of ncRNAs as biomarkers complementing aggregometry.","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"15 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144210823","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}