{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T16:14:56Z","timestamp":1785428096423,"version":"3.56.0"},"posted":{"date-parts":[[2026,5,19]]},"group-title":"Molecular Biology","reference-count":56,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T00:00:00Z","timestamp":1779148800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"name":"BONFOR-Forschungsf\u00f6rderungsprogramm of the Medical Faculty of the University of Bonn","award":["O-117.0059"],"award-info":[{"award-number":["O-117.0059"]}]},{"award":["SFB TRR259"],"award-info":[{"award-number":["SFB TRR259"]}],"id":[{"id":"https:\/\/ror.org\/018mejw64","id-type":"ROR","asserted-by":"publisher"}]},{"award":["GM74897"],"award-info":[{"award-number":["GM74897"]}],"id":[{"id":"https:\/\/ror.org\/001d55x84","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,5,19]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Calcific aortic valve stenosis (AVS) is the most prevalent valvular heart disease in Western adults, yet no disease-modifying therapy exists. High shear stress (HSS) generated by progressive valvular obstruction drives endothelial injury and immune-mediated inflammation, but the contribution of circulating T cells to AVS pathogenesis remains poorly defined.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Objectives<\/jats:title>\n                  <jats:p>We tested whether chronic HSS corresponds with epigenomic reprogramming of peripheral T cells proportionate with hemodynamic severity to yield a clinically informative proxy of disease.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>\n                    A prospective cohort of 70 participants was recruited for peripheral blood sampling, including 34 with severe symptomatic AVS (aortic valve area &lt;1.0 cm\n                    <jats:sup>2<\/jats:sup>\n                    , mean gradient \u226540 mmHg) scheduled for transcatheter aortic valve implantation and 36 age- and sex-matched controls. Peripheral T cells were isolated and profiled by genome-wide CpG methylation (Illumina MethylationEPIC) and RNA-sequencing. To test whether HSS directly activates inflammatory signaling, Jurkat T cells were exposed to 20 dyn\/cm\n                    <jats:sup>2<\/jats:sup>\n                    HSS via parallel-plate microfluidic chamber and concomitant CD3\/CD28 stimulation, followed by assessment of NFAT nuclear translocation and NFAT target gene expression.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    Unsupervised clustering of the 5,000 most-variable CpG loci resolved an epigenomic axis segregating AVS from control T cells (PC1, 15.8% variance explained;\n                    <jats:italic>P<\/jats:italic>\n                    = 3.9\u00d710\n                    <jats:sup>-6<\/jats:sup>\n                    ). Multivariable-adjusted analysis identified 3,950 differentially methylated positions (1,889 hyper-, 2,061 hypo-methylated), enriched in promoter-associated CpG islands implicating aortic valve morphogenesis (P = 6.0 x 10\n                    <jats:sup>-10<\/jats:sup>\n                    ) and cell-cell adhesion pathways (P = 9.5 x 10\n                    <jats:sup>-5<\/jats:sup>\n                    ). Multi-omics factor analysis isolated a latent factor that independently associated with AVS (adjusted P = 1.8\u00d710\n                    <jats:sup>-3<\/jats:sup>\n                    ; AUC = 0.79), enriched for chemokine receptor binding and TNF-family signaling, and correlated with canonical HSS-responsive transcripts, consistent with a T cell-mediated shear stress activation. An 18-CpG elastic-net methylation risk score discriminated AVS from controls (AUC = 0.89) and independently predicted hemodynamic severity (\u03b2 = 7.05 mmHg\/SD, 95% CI 2.31-11.79). HSS augmented NFAT nuclear translocation in CD3\/CD28-activated Jurkat T cells and induced NFAT-responsive inflammatory transcripts.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Severe AVS is associated with promoter-enriched epigenomic remodeling of circulating T cells that converges on hemodynamic stress-dependent inflammatory programs. An 18-CpG methylation risk score outperforms clinical covariates and tracks hemodynamic severity, establishing peripheral T cell DNA methylation as a molecular corollary of AVS.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.05.17.722103","type":"posted-content","created":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T12:05:17Z","timestamp":1779192317000},"source":"Crossref","is-referenced-by-count":0,"title":["Aortic valve stenosis promotes pathological shear stress-dependent epigenomic dysregulation in circulating T cells"],"prefix":"10.64898","author":[{"given":"Yunyang","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Anaesthesiology and Intensive Care Medicine, University Hospital Bonn, University of Bonn, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan Lucas","family":"Kleiner","sequence":"additional","affiliation":[{"name":"Department of Anaesthesiology and Intensive Care Medicine, University Hospital Bonn, University of Bonn, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2009-2059","authenticated-orcid":false,"given":"Jimmy","family":"Zheng","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Department of Medicine, Stanford University Hospital, Stanford, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-3924-3438","authenticated-orcid":false,"given":"Frank","family":"Splettstoesser","sequence":"additional","affiliation":[{"name":"Department of Anaesthesiology and Intensive Care Medicine, University Hospital Bonn, University of Bonn, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1531-2088","authenticated-orcid":false,"given":"Sebastian","family":"Zimmer","sequence":"additional","affiliation":[{"name":"Heart Center Bonn, Clinic for Internal Medicine II, University Hospital Bonn, Bonn, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7930-0270","authenticated-orcid":false,"given":"Mark","family":"Coburn","sequence":"additional","affiliation":[{"name":"Department of Anaesthesiology and Intensive Care Medicine, University Hospital Bonn, University of Bonn, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7647-1613","authenticated-orcid":false,"given":"Christina","family":"Weisheit","sequence":"additional","affiliation":[{"name":"Department of Anaesthesiology and Intensive Care Medicine, University Hospital Bonn, University of Bonn, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1460-9442","authenticated-orcid":false,"given":"Stilla","family":"Frede","sequence":"additional","affiliation":[{"name":"Department of Anaesthesiology and Intensive Care Medicine, University Hospital Bonn, University of Bonn, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0114-560X","authenticated-orcid":false,"given":"Mark E.","family":"Pepin","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Department of Medicine, Stanford University Hospital, Stanford, CA, USA"},{"name":"The Broad Institute of Harvard and MIT, Cambridge, MA, USA"},{"name":"Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026052111151426000_2026.05.17.722103v1.1","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehab395"},{"key":"2026052111151426000_2026.05.17.722103v1.2","doi-asserted-by":"publisher","DOI":"10.1038\/s41569-021-00570-z"},{"key":"2026052111151426000_2026.05.17.722103v1.3","doi-asserted-by":"publisher","DOI":"10.1016\/j.pcad.2014.02.006"},{"key":"2026052111151426000_2026.05.17.722103v1.4","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.114.302523"},{"key":"2026052111151426000_2026.05.17.722103v1.5","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehab757"},{"key":"2026052111151426000_2026.05.17.722103v1.6","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2003.12.041"},{"key":"2026052111151426000_2026.05.17.722103v1.7","doi-asserted-by":"crossref","first-page":"26","DOI":"10.4110\/in.2016.16.1.26","article-title":"Involvement of immune cell network in aortic valve stenosis: Communication between valvular interstitial cells and immune cells","volume":"16","year":"2016","journal-title":"Immune Netw"},{"key":"2026052111151426000_2026.05.17.722103v1.8","doi-asserted-by":"crossref","unstructured":"Hulin A , Hortells L , Gomez-Stallons MV , et al. 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