{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T05:54:48Z","timestamp":1781589288502,"version":"3.54.5"},"reference-count":30,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T00:00:00Z","timestamp":1772928000000},"content-version":"vor","delay-in-days":7,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,3,1]],"date-time":"2026-03-01T00:00:00Z","timestamp":1772323200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100003196","name":"Ministero della Salute","doi-asserted-by":"publisher","award":["08072322"],"award-info":[{"award-number":["08072322"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003196","name":"Ministero della Salute","doi-asserted-by":"publisher","award":["2022 23683266"],"award-info":[{"award-number":["2022 23683266"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003196","name":"Ministero della Salute","doi-asserted-by":"publisher","award":["E03 2022 23683266 DIAGNOSTICA AVANZATA \u2010 (HLS\u2010DA)"],"award-info":[{"award-number":["E03 2022 23683266 DIAGNOSTICA AVANZATA \u2010 (HLS\u2010DA)"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Eur J Clin Investigation"],"published-print":{"date-parts":[[2026,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Calcific aortic valve disease (CAVD) is a multifactorial condition characterized by progressive leaflet calcification with a potential role for bacterial colonization in its pathogenesis. This study investigates clinical, microbiological and molecular features of calcified versus non\u2010calcified aortic regurgitation (AR) valves.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This is a prospective, observational study, whose primary objective was to compare the occurrence of bacterial detection between CAVD and AR. The secondary objectives included the evaluation of bone\u2010related calcification markers in valves from CAVD and AR patients.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We analysed 31 CAVD and 8 AR valves, yielding 111 leaflets (84 calcified, 27 non\u2010calcified). Light microscopy of CAVD leaflets revealed near\u2010complete disruption of the three\u2010layered valve architecture, with calcified masses extending through the leaflets, sparse cellularity and focal micro\u2010angiogenesis; no bacteria were detected by GRAM, PAS or TEM. Enrichment culture detected low\u2010virulence bacteria in 5.95% of CAVD and 4.16% of AR leaflets; 16S rRNA PCR was positive in 22.5% of CAVD and 12.5% of AR cases, with\n                      <jats:italic>Staphylococcus<\/jats:italic>\n                      and\n                      <jats:italic>Streptococcus<\/jats:italic>\n                      spp. predominating. Calcium content was significantly higher in CAVD leaflets (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u2009.001) and correlated with dyslipidemia (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u2009.02). Osterix expression was higher in valves with positive microbiological findings (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u2009.0001), while ALP was increased in CAVD and bicuspid valves regardless of microbial status. Valve interstitial cells from CAVD exhibited spontaneous in\u00a0vitro calcification, unlike controls.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>The early osteogenic marker osterix was found to be upregulated in patients whose valves tested positive for microbial DNA, suggesting a potential role for bacteria in driving cellular differentiation towards an osteoblastic phenotype in CAVD.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/eci.70188","type":"journal-article","created":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T19:10:47Z","timestamp":1772997047000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Infectious seeds of valve calcification: Exploring the bacterial hypothesis in the pathogenesis of calcific aortic valve disease"],"prefix":"10.1111","volume":"56","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6385-1182","authenticated-orcid":false,"given":"Antonella","family":"Forlino","sequence":"first","affiliation":[{"name":"Department of Molecular Medicine, Biochemistry Unit University of Pavia  Pavia Italy"},{"name":"Biostatistics and Clinical Epidemiology, Fondazione IRCCS Policlinico san Matteo  Pavia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-5507-3803","authenticated-orcid":false,"given":"Paola","family":"Giordani","sequence":"additional","affiliation":[{"name":"Malattie Infettive, Fondazione IRCCS Policlinico San Matteo  Pavia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2986-6644","authenticated-orcid":false,"given":"Cristina","family":"Merla","sequence":"additional","affiliation":[{"name":"Microbiologia e Virologia, Fondazione IRCCS Policlinico San Matteo  Pavia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0710-174X","authenticated-orcid":false,"given":"Silvia","family":"Roda","sequence":"additional","affiliation":[{"name":"Infectious Diseases Unit Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico  Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1430-2934","authenticated-orcid":false,"given":"Roberta","family":"Besio","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, Biochemistry Unit University of Pavia  Pavia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abeer Ahmed Qaed","family":"Ahmed","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, Biochemistry Unit University of Pavia  Pavia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-5134-5526","authenticated-orcid":false,"given":"Angela","family":"Kuka","sequence":"additional","affiliation":[{"name":"Microbiologia e Virologia, Fondazione IRCCS Policlinico San Matteo  Pavia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-5272-3138","authenticated-orcid":false,"given":"Irene","family":"Mileto","sequence":"additional","affiliation":[{"name":"Microbiologia e Virologia, Fondazione IRCCS Policlinico San Matteo  Pavia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3537-8006","authenticated-orcid":false,"given":"Greta","family":"Petazzoni","sequence":"additional","affiliation":[{"name":"Microbiologia e Virologia, Fondazione IRCCS Policlinico San Matteo  Pavia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0969-6484","authenticated-orcid":false,"given":"Marta","family":"Corbella","sequence":"additional","affiliation":[{"name":"Microbiologia e Virologia, Fondazione IRCCS Policlinico San Matteo  Pavia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrizia","family":"Cambieri","sequence":"additional","affiliation":[{"name":"Microbiologia e Virologia, Fondazione IRCCS Policlinico San Matteo  Pavia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6899-3462","authenticated-orcid":false,"given":"Baldanti","family":"Fausto","sequence":"additional","affiliation":[{"name":"Microbiologia e Virologia, Fondazione IRCCS Policlinico San Matteo  Pavia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3128-8441","authenticated-orcid":false,"given":"Annalisa","family":"De Silvestri","sequence":"additional","affiliation":[{"name":"Biostatistics and Clinical Epidemiology, Fondazione IRCCS Policlinico san Matteo  Pavia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5403-6274","authenticated-orcid":false,"given":"Totaro","family":"Pasquale","sequence":"additional","affiliation":[{"name":"Cardiac Surgery Unit Fondazione IRCCS Policlinico san Matteo  Pavia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-5552-8116","authenticated-orcid":false,"given":"Filippo","family":"Amoroso","sequence":"additional","affiliation":[{"name":"Cardiac Surgery Unit Fondazione IRCCS Policlinico san Matteo  Pavia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pelenghi","family":"Stefano","sequence":"additional","affiliation":[{"name":"Cardiac Surgery Unit Fondazione IRCCS Policlinico san Matteo  Pavia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7895-5291","authenticated-orcid":false,"given":"Maraschi","family":"Federica","sequence":"additional","affiliation":[{"name":"Department of Chemistry University of Pavia  Pavia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2948-7994","authenticated-orcid":false,"given":"Eloisa","family":"Arbustini","sequence":"additional","affiliation":[{"name":"Department of Research, Centre for Inherited Cardiovascular Diseases Fondazione IRCCS Policlinico San Matteo  Pavia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-0493-0938","authenticated-orcid":false,"given":"Viviana","family":"Vilardo","sequence":"additional","affiliation":[{"name":"Department of Research, Centre for Inherited Cardiovascular Diseases Fondazione IRCCS Policlinico San Matteo  Pavia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8911-8827","authenticated-orcid":false,"given":"Alexandra","family":"Smirnova","sequence":"additional","affiliation":[{"name":"Department of Research, Centre for Inherited Cardiovascular Diseases Fondazione IRCCS Policlinico San Matteo  Pavia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0235-9207","authenticated-orcid":false,"given":"Raffaele","family":"Bruno","sequence":"additional","affiliation":[{"name":"Malattie Infettive, Fondazione IRCCS Policlinico San Matteo  Pavia Italy"},{"name":"Department of Medicine, Surgical, Diagnostic and Pediatric Science University of Pavia  Pavia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5246-928X","authenticated-orcid":false,"given":"Elena","family":"Seminari","sequence":"additional","affiliation":[{"name":"Malattie Infettive, Fondazione IRCCS Policlinico San Matteo  Pavia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,3,8]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehab757"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21165620"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.119.313067"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1313875"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.104.486738"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000070591.21548.69"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtcvs.2019.02.019"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.semtcvs.2019.10.003"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22115805"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtcvs.2021.04.002"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciad271"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/0002-9149(86)90067-6"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0003-4975(03)01454-1"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-31029-w"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1093\/icvts\/ivaa285"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms232415476"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1002\/ccr3.5591"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2024.1480961"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.15698\/mic2023.02.791"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijcard.2008.10.014"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/ni.2635"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/0020-711X(93)90522-G"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11914-014-0195-2"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00223-017-0331-y"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.archoralbio.2012.07.012"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.4061\/2011\/721419"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.113.300155"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-49016-0"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2018.01635"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-025-85909-z"}],"container-title":["European Journal of Clinical Investigation"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/eci.70188","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/eci.70188","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/eci.70188","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T05:49:51Z","timestamp":1781588991000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/eci.70188"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3]]},"references-count":30,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2026,3]]}},"alternative-id":["10.1111\/eci.70188"],"URL":"https:\/\/doi.org\/10.1111\/eci.70188","archive":["Portico"],"relation":{},"ISSN":["0014-2972","1365-2362"],"issn-type":[{"value":"0014-2972","type":"print"},{"value":"1365-2362","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3]]},"assertion":[{"value":"2025-09-20","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-02-09","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-03-08","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70188"}}