{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T06:37:41Z","timestamp":1785393461053,"version":"3.55.0"},"reference-count":22,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"10","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["ATVB"],"published-print":{"date-parts":[[2025,10]]},"abstract":"<jats:sec>\n            <jats:title>BACKGROUND:<\/jats:title>\n            <jats:p>Calcific aortic valve stenosis is a global clinical burden, impacting around 2% of the population over 65 years of age. No pharmacotherapeutics exist, with surgical repair and transcatheter valve replacement being the only intervention. Females are underrepresented in studies of calcific aortic valve stenosis, leading to delay in timely intervention and increased mortality. Histopathology demonstrates female calcific aortic valve stenosis presents with decreased valvular calcification but increased fibrosis and severity of symptoms. We hypothesize that the underlying molecular mechanisms contributing to disease progression and fibrocalcific burden in aortic stenosis (AS) differ between male and female patients. Our goal for this study is to use previously acquired proteomic data sets of a clinically defined human AS cohort to examine sex disparities and underlying sex-specific disease signatures.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>METHODS:<\/jats:title>\n            <jats:p>Age-matched human AS tissue samples (n=14 males, n=4 females) were each segmented into nondiseased, fibrotic, and calcified disease stages and analyzed using LC-MS\/MS (liquid chromatrophy tandem mass spectrometry) proteomics and quantitative histopathology. AS plasma samples (n=32 males, n=20 females) were analyzed for circulating sex-specific biomarkers via LC-MS\/MS.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>RESULTS:<\/jats:title>\n            <jats:p>\n              Unbiased principal component analysis shows sex- and stage-specific proteome clustering. AS pathogenesis drove sex-specific disparities in the valvular proteome: 338\/1503 total proteins were differentially enriched by sex across disease stages. Compared with sex-specific nondiseased controls, female fibrotic tissue resulted in 2.75-fold greater number of differentially enriched proteins than did male fibrotic tissue (female: 42, male: 16;\n              <jats:italic toggle=\"yes\">P<\/jats:italic>\n              &lt;0.05 threshold). In contrast, female calcific tissue identified 2.473-fold less differentially enriched proteins than male calcific tissue (female: 157, male 356;\n              <jats:italic toggle=\"yes\">P<\/jats:italic>\n              &lt;0.05 threshold). Functional Enrichment Analysis revealed specific proteins responsible for the exacerbated valvular fibrosis signature in females, implicated adenosine phosphate metabolism as a potential male-specific driver of AS, and further reinforced the shared contribution of aberrant lipid and cholesterol activity to AS progression in both sexes.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>CONCLUSIONS:<\/jats:title>\n            <jats:p>This proof-of-concept analysis allows for the identification of potential sex-specific protein drug targets implicated in AS pathobiology.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/atvbaha.125.322560","type":"journal-article","created":{"date-parts":[[2025,8,14]],"date-time":"2025-08-14T09:00:17Z","timestamp":1755162017000},"page":"1928-1934","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":8,"title":["Sexual Dimorphism of Plasma and Tissue Proteomes in Human Calcific Aortic Valve Stenosis Pathogenesis\u2014Brief Report"],"prefix":"10.1161","volume":"45","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2441-4251","authenticated-orcid":true,"given":"Cassandra L.","family":"Clift","sequence":"first","affiliation":[{"name":"Cardiovascular Division, Department of Medicine, Center for Interdisciplinary Cardiovascular Sciences (C.L.C., M.C.B., F.B.-L., F.S., H.H., S.K., T.K., M.E.T., T.P., K.A.P., M.A., S.A.S., E.A.), Harvard Medical School, Boston, MA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3923-9786","authenticated-orcid":true,"given":"Mark C.","family":"Blaser","sequence":"additional","affiliation":[{"name":"Cardiovascular Division, Department of Medicine, Center for Interdisciplinary Cardiovascular Sciences (C.L.C., M.C.B., F.B.-L., F.S., H.H., S.K., T.K., M.E.T., T.P., K.A.P., M.A., S.A.S., E.A.), Harvard Medical School, Boston, MA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7436-3873","authenticated-orcid":true,"given":"Francesca","family":"Bartoli-Leonard","sequence":"additional","affiliation":[{"name":"Cardiovascular Division, Department of Medicine, Center for Interdisciplinary Cardiovascular Sciences (C.L.C., M.C.B., F.B.-L., F.S., H.H., S.K., T.K., M.E.T., T.P., K.A.P., M.A., S.A.S., E.A.), Harvard Medical School, Boston, MA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4840-1172","authenticated-orcid":true,"given":"Florian","family":"Schlotter","sequence":"additional","affiliation":[{"name":"Cardiovascular Division, Department of Medicine, Center for Interdisciplinary Cardiovascular Sciences (C.L.C., M.C.B., F.B.-L., F.S., H.H., S.K., T.K., M.E.T., T.P., K.A.P., M.A., S.A.S., E.A.), Harvard Medical School, Boston, MA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideyuki","family":"Higashi","sequence":"additional","affiliation":[{"name":"Cardiovascular Division, Department of Medicine, Center for Interdisciplinary Cardiovascular Sciences (C.L.C., M.C.B., F.B.-L., F.S., H.H., S.K., T.K., M.E.T., T.P., K.A.P., M.A., S.A.S., E.A.), Harvard Medical School, Boston, MA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiori","family":"Kuraoka","sequence":"additional","affiliation":[{"name":"Cardiovascular Division, Department of Medicine, Center for Interdisciplinary Cardiovascular Sciences (C.L.C., M.C.B., F.B.-L., F.S., H.H., S.K., T.K., M.E.T., T.P., K.A.P., M.A., S.A.S., E.A.), Harvard Medical School, Boston, MA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8075-6099","authenticated-orcid":true,"given":"Taku","family":"Kasai","sequence":"additional","affiliation":[{"name":"Cardiovascular Division, Department of Medicine, Center for Interdisciplinary Cardiovascular Sciences (C.L.C., M.C.B., F.B.-L., F.S., H.H., S.K., T.K., M.E.T., T.P., K.A.P., M.A., S.A.S., E.A.), Harvard Medical School, Boston, MA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6431-5077","authenticated-orcid":true,"given":"Mandy E.","family":"Turner","sequence":"additional","affiliation":[{"name":"Cardiovascular Division, Department of Medicine, Center for Interdisciplinary Cardiovascular Sciences (C.L.C., M.C.B., F.B.-L., F.S., H.H., S.K., T.K., M.E.T., T.P., K.A.P., M.A., S.A.S., E.A.), Harvard Medical School, Boston, MA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tan","family":"Pham","sequence":"additional","affiliation":[{"name":"Cardiovascular Division, Department of Medicine, Center for Interdisciplinary Cardiovascular Sciences (C.L.C., M.C.B., F.B.-L., F.S., H.H., S.K., T.K., M.E.T., T.P., K.A.P., M.A., S.A.S., E.A.), Harvard Medical School, Boston, MA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3685-8212","authenticated-orcid":true,"given":"Katelyn A.","family":"Perez","sequence":"additional","affiliation":[{"name":"Cardiovascular Division, Department of Medicine, Center for Interdisciplinary Cardiovascular Sciences (C.L.C., M.C.B., F.B.-L., F.S., H.H., S.K., T.K., M.E.T., T.P., K.A.P., M.A., S.A.S., E.A.), Harvard Medical School, Boston, MA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon C.","family":"Robson","sequence":"additional","affiliation":[{"name":"Brigham and Women\u2019s Hospital, and Department of Anesthesia, Critical Care and Pain Medicine, Center for Inflammation Research, Beth Israel Deaconess Medical Center (S.C.R.), Harvard Medical School, Boston, MA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6721-7050","authenticated-orcid":true,"given":"Simon C.","family":"Body","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Boston University School of Medicine, MA (S.C.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6209-7253","authenticated-orcid":true,"given":"Jochen D.","family":"Muehlschlegel","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD (J.D.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9275-2079","authenticated-orcid":true,"given":"Masanori","family":"Aikawa","sequence":"additional","affiliation":[{"name":"Cardiovascular Division, Department of Medicine, Center for Interdisciplinary Cardiovascular Sciences (C.L.C., M.C.B., F.B.-L., F.S., H.H., S.K., T.K., M.E.T., T.P., K.A.P., M.A., S.A.S., E.A.), Harvard Medical School, Boston, MA."},{"name":"Channing Division of Network 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