{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,6]],"date-time":"2026-02-06T00:00:50Z","timestamp":1770336050073,"version":"3.49.0"},"reference-count":33,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T00:00:00Z","timestamp":1770249600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Epigenomes"],"abstract":"<jats:p>Background\/Objectives: Atrial fibrillation (AF) is currently the most common arrhythmia worldwide, and it is linked to increased mortality and morbidity, hence the need for a better clinical stratification of AF patients. Histone complexes or nucleosomes, released into the blood circulation, are found elevated in acute conditions such as stroke, trauma, and sepsis. The aim of this pilot single-centre study was to assess whether circulating histone levels could be used for diagnostic purposes in patients with AF. Methods: A total of 40 patients, well characterised for their biochemical and clinical characteristics, were recruited from outpatient clinics. Patients were randomly recruited into two groups (n = 20 per group), i.e., persistent AF and hypertensive controls. A multi-channel flow imaging methodology based on ImageStreamX was used with a well-optimised protocol to image and quantify five individual histones (H2A, H2B, H3, H4, and macroH2A1.1) together with the dimers (H2A\/H2B, and H3\/H4). Results: In the AF groups, plasma levels of histone dimers H2A\/H2B and H3\/H4 were elevated compared to hypertensive controls, 1.8% vs. 1.06% (p-value = 0.03). H2A\/H2B dimer levels were increased in AF patients irrespective of gender, smoking status, diabetes, and pharmacological therapy. In the overall population, an inverse correlation between H2A and BMI was detected. Conclusions: Our pilot study, although limited in sample size, suggests that circulating histone complexes may be epigenetic sentinels for AF, offering mechanistic insights while addressing unmet needs in risk stratification.<\/jats:p>","DOI":"10.3390\/epigenomes10010009","type":"journal-article","created":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T11:13:01Z","timestamp":1770289981000},"page":"9","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Epigenetic Liquid Biopsy Marks Atrial Fibrillation: Evidence from the AF Big Picture Study"],"prefix":"10.3390","volume":"10","author":[{"given":"Riccardo","family":"Proietti","sequence":"first","affiliation":[{"name":"Liverpool Centre for Cardiovascular Science at the University of Liverpool, Liverpool John Moores University and Liverpool Heart and Chest Hospital (LHCH), Liverpool L14 3PE, UK"},{"name":"Department of Cardiovascular and Metabolic Medicine, Institute of Life Course and Medical Sciences, Faculty of Health and Life Sciences, University of Liverpool, Liverpool L69 7ZX, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6469-0870","authenticated-orcid":false,"given":"Nicola","family":"Tidbury","sequence":"additional","affiliation":[{"name":"Liverpool Centre for Cardiovascular Science at the University of Liverpool, Liverpool John Moores University and Liverpool Heart and Chest Hospital (LHCH), Liverpool L14 3PE, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0146-2106","authenticated-orcid":false,"given":"Joshua","family":"Preston","sequence":"additional","affiliation":[{"name":"Liverpool Centre for Cardiovascular Science at the University of Liverpool, Liverpool John Moores University and Liverpool Heart and Chest Hospital (LHCH), Liverpool L14 3PE, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2617-8133","authenticated-orcid":false,"given":"Maanya","family":"Vittal","sequence":"additional","affiliation":[{"name":"School of Pharmacy and Biomolecular Science, Faculty of Science, Liverpool John Moores University, Liverpool L3 3AF, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0464-4922","authenticated-orcid":false,"given":"Philippa","family":"McCabe","sequence":"additional","affiliation":[{"name":"School of Pharmacy and Biomolecular Science, Faculty of Science, Liverpool John Moores University, Liverpool L3 3AF, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2880-5236","authenticated-orcid":false,"given":"Garry","family":"McDowell","sequence":"additional","affiliation":[{"name":"Liverpool Centre for Cardiovascular Science at the University of Liverpool, Liverpool John Moores University and Liverpool Heart and Chest Hospital (LHCH), Liverpool L14 3PE, UK"},{"name":"School of Pharmacy and Biomolecular Science, Faculty of Science, Liverpool John Moores University, Liverpool L3 3AF, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7566-1626","authenticated-orcid":false,"given":"Gregory Y. H.","family":"Lip","sequence":"additional","affiliation":[{"name":"Liverpool Centre for Cardiovascular Science at the University of Liverpool, Liverpool John Moores University and Liverpool Heart and Chest Hospital (LHCH), Liverpool L14 3PE, UK"},{"name":"Danish Center for Health Services Research, Department of Clinical Medicine, Aalborg University, 2450 Aalborg, Denmark"},{"name":"Department of Cardiology, Lipidology and Internal Medicine with Intensive Coronary Care Unit, Medical University of Bialystok, 15-274 Bialystok, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manlio","family":"Vinciguerra","sequence":"additional","affiliation":[{"name":"Research Institute, Medical University Varna, 9002 Varna, Bulgaria"},{"name":"Department of Medicine and Surgery, LUM University, 70010 Casamassima (BA), Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"574","DOI":"10.1093\/ehjqcco\/qcaa061","article-title":"Global, regional, and national prevalence, incidence, mortality, and risk factors for atrial fibrillation, 1990\u20132017: Results from the Global Burden of Disease Study 2017","volume":"7","author":"Dai","year":"2021","journal-title":"Eur. Heart J. Qual. Care Clin. Outcomes"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"102181","DOI":"10.1016\/j.cpcardiol.2023.102181","article-title":"Atrial fibrillation and stroke: State-of-the-art and future directions","volume":"49","author":"Elsheikh","year":"2024","journal-title":"Curr. Probl. Cardiol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1080\/14779072.2023.2160319","article-title":"Atrial fibrillation and stroke","volume":"21","author":"Choi","year":"2023","journal-title":"Expert. Rev. Cardiovasc. Ther."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1093\/clinchem\/hvaa298","article-title":"Biomarkers for Risk Assessment in Atrial Fibrillation","volume":"67","author":"Berg","year":"2021","journal-title":"Clin. Chem."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Pal\u00e0, E., Bustamante, A., Pagola, J., Juega, J., Francisco-Pascual, J., Penalba, A., Rodriguez, M., De Lera Alfonso, M., Arenillas, J.F., and Cabezas, J.A. (2022). Blood-Based Biomarkers to Search for Atrial Fibrillation in High-Risk Asymptomatic Individuals and Cryptogenic Stroke Patients. Front. Cardiovasc. Med., 13.","DOI":"10.3389\/fcvm.2022.908053"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Menezes Junior Ada, S., Ferreira, L.C., Barbosa, L.J.V., Silva Dde, M.E., Saddi, V.A., and Silva, A.M.T.C. (2023). Circulating MicroRNAs as Specific Biomarkers in Atrial Fibrillation: A Meta-Analysis. Noncoding RNA, 9.","DOI":"10.3390\/ncrna9010013"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1038\/nrcardio.2014.178","article-title":"MicroRNAs and atrial fibrillation: Mechanisms and translational potential","volume":"12","author":"Luo","year":"2015","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1080\/10408360802485875","article-title":"Clinical use of circulating nucleosomes","volume":"46","author":"Holdenrieder","year":"2009","journal-title":"Crit. Rev. Clin. Lab. Sci."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"McAnena, P., Brown, J.A.L., and Kerin, M.J. (2017). Circulating Nucleosomes and Nucleosome Modifications as Biomarkers in Cancer. Cancers, 9.","DOI":"10.3390\/cancers9010005"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1186\/s13148-020-00917-2","article-title":"Circulating histone signature of human lean metabolic-associated fatty liver disease (MAFLD)","volume":"12","author":"Buzova","year":"2020","journal-title":"Clin. Epigenetics"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"3311","DOI":"10.1002\/hep4.2082","article-title":"Profiling of cell-free DNA methylation and histone signatures in pediatric NAFLD: A pilot study","volume":"6","author":"Buzova","year":"2022","journal-title":"Hepatol. Commun."},{"key":"ref_12","first-page":"2","article-title":"Obesity-induced nucleosome release predicts poor cardio-metabolic health","volume":"12","author":"Maugeri","year":"2019","journal-title":"Clin. Epigenetics"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"100784","DOI":"10.1016\/j.lanepe.2023.100784","article-title":"Atrial fibrillation: Comorbidities, lifestyle, and patient factors","volume":"37","author":"Shantsila","year":"2024","journal-title":"Lancet Reg. Health Eur."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"4343","DOI":"10.1007\/s11010-025-05254-7","article-title":"Histone H2A: A promising diagnostic marker in heart failure with reduced versus preserved ejection fraction","volume":"480","author":"Tsoneva","year":"2025","journal-title":"Mol. Cell Biochem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e13952","DOI":"10.1111\/eci.13952","article-title":"Enhanced neutrophil extracellular traps formation in AF patients with dilated left atrium","volume":"53","author":"Malinowski","year":"2023","journal-title":"Eur. J. Clin. Investig."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2746","DOI":"10.1093\/eurheartj\/eht280","article-title":"Projections on the number of individuals with atrial fibrillation in the European Union, from 2000 to 2060","volume":"34","author":"Krijthe","year":"2013","journal-title":"Eur. Heart J."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2094","DOI":"10.1097\/CCM.0000000000001162","article-title":"Circulating Histones Are Major Mediators of Cardiac Injury in Patients With Sepsis","volume":"43","author":"Alhamdi","year":"2015","journal-title":"Crit. Care Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1186\/s13072-016-0098-9","article-title":"Histone macroH2A1.2 promotes metabolic health and leanness by inhibiting adipogenesis","volume":"9","author":"Pazienza","year":"2016","journal-title":"Epigenetics Chromatin"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"824","DOI":"10.1016\/j.hrthm.2021.01.007","article-title":"Epigenetics in atrial fibrillation: A reappraisal","volume":"18","author":"Arora","year":"2021","journal-title":"Heart Rhythm."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2335","DOI":"10.1016\/j.jacc.2014.02.555","article-title":"Atrial remodeling and atrial fibrillation: Recent advances and translational perspectives","volume":"63","author":"Nattel","year":"2014","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"19123","DOI":"10.1038\/s41598-023-46304-8","article-title":"Deficiency of histone variant macroH2A1.1 is associated with sexually dimorphic obesity in mice","volume":"13","author":"Chiodi","year":"2023","journal-title":"Sci. Rep."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1676","DOI":"10.1096\/fj.14-262717","article-title":"MacroH2A1 isoforms are associated with epigenetic markers for activation of lipogenic genes in fat-induced steatosis","volume":"29","author":"Podrini","year":"2015","journal-title":"FASEB J."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1038\/ijo.2014.91","article-title":"Genetic ablation of macrohistone H2A1 leads to increased leanness, glucose tolerance and energy expenditure in mice fed a high-fat diet","volume":"39","author":"Sheedfar","year":"2015","journal-title":"Int. J. Obes."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"35","DOI":"10.18632\/aging.100632","article-title":"SIRT1-metabolite binding histone macroH2A1.1 protects hepatocytes against lipid accumulation","volume":"6","author":"Pazienza","year":"2014","journal-title":"Aging"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Rappa, F., Greco, A., Podrini, C., Cappello, F., Foti, M., Bourgoin, L., Peyrou, M., Marino, A., Scibetta, N., and Williams, R. (2013). Immunopositivity for Histone MacroH2A1 Isoforms Marks Steatosis-Associated Hepatocellular Carcinoma. PLoS ONE, 8.","DOI":"10.1371\/annotation\/b456329c-02fa-4055-afb8-2090cec17da6"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1115","DOI":"10.1093\/cvr\/cvab139","article-title":"Extracellular histones are a target in myocardial ischaemia-reperfusion injury","volume":"118","author":"Shah","year":"2022","journal-title":"Cardiovasc. Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"631","DOI":"10.3109\/1354750X.2014.954001","article-title":"miRNAs as biomarkers of atrial fibrillation","volume":"19","author":"Silbiger","year":"2014","journal-title":"Biomarkers"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1040","DOI":"10.1161\/CIRCEP.114.003057","article-title":"Atrial Fibrillation Burden and Short-Term Risk of Stroke: Case-Crossover Analysis of Continuously Recorded Heart Rhythm from Cardiac Electronic Implanted Devices","volume":"8","author":"Turakhia","year":"2015","journal-title":"Circ. Arrhythm. Electrophysiol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e007071","DOI":"10.1161\/CIRCEP.118.007071","article-title":"HDAC (Histone Deacetylase) Inhibitor Valproic Acid Attenuates Atrial Remodeling and Delays the Onset of Atrial Fibrillation in Mice","volume":"12","author":"Scholz","year":"2019","journal-title":"Circ. Arrhythm. Electrophysiol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1124\/jpet.116.234591","article-title":"Class I Histone Deacetylase Inhibition for the Treatment of Sustained Atrial Fibrillation","volume":"358","author":"Seki","year":"2016","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1093\/eurheartj\/ehu359","article-title":"Higher risk of death and stroke in patients with persistent vs. paroxysmal atrial fibrillation: Results from the ROCKET-AF Trial","volume":"36","author":"Steinberg","year":"2015","journal-title":"Eur. Heart J."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1007\/s40291-024-00754-6","article-title":"Extracellular Histones Profiles of Pediatric H3K27-Altered Diffuse Midline Glioma","volume":"29","author":"Buzova","year":"2025","journal-title":"Mol. Diagn. Ther."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Buzova, D., Frohlich, J., Zapletalova, D., Raffaele, M., Lo Re, O., Tsoneva, D.K., Sterba, J., Cerveny, J., and Vinciguerra, M. (2023). Detection of cell-free histones in the cerebrospinal fluid of pediatric central nervous system malignancies by imaging flow cytometry. Front. Mol. Biosci., 10.","DOI":"10.3389\/fmolb.2023.1254699"}],"container-title":["Epigenomes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-4655\/10\/1\/9\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T11:40:44Z","timestamp":1770291644000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-4655\/10\/1\/9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,5]]},"references-count":33,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,3]]}},"alternative-id":["epigenomes10010009"],"URL":"https:\/\/doi.org\/10.3390\/epigenomes10010009","relation":{},"ISSN":["2075-4655"],"issn-type":[{"value":"2075-4655","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,5]]}}}