{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T02:28:25Z","timestamp":1791599305791,"version":"4.3.4"},"reference-count":52,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2025,3,4]]},"abstract":"<jats:sec xml:lang=\"en\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p xml:lang=\"en\">Calcific aortic valve disease (CAVD), and ensuing severe aortic stenosis (AS), is the foremost valvular disorder of aging, yet preventive therapies are lacking. A better understanding of the molecular underpinnings of aortic valve calcification (AVC) is necessary to develop pharmacologic interventions.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Methods and Results<\/jats:title>\n                    <jats:p xml:lang=\"en\">\n                      We undertook large\u2010scale plasma proteomics in a cohort study of adults \u226565\u2009years old, the CHS (Cardiovascular Health Study), to identify individual proteins associated with echocardiographic AVC and incident moderate\/severe AS. Proteomics measurements were performed with the aptamer\u2010based SomaLogic platform of ~5000 proteins. Significant proteins were validated in a second cohort, the AGES\u2010RS (Age, Gene\/Environment Susceptibility\u2010Reykjavik Study), which assessed AVC and AS by computed tomography. The potential causal associations of replicated proteins were tested in 2\u2010sample Mendelian randomization using identified cis protein quantitative trait loci in consortia having computed tomography\u2010quantified AVC or AS as outcomes. Six proteins showed Bonferroni\u2010corrected significant relationships with AVC in CHS. Three of these, CXCL\u201012 (C\u2010X\u2010C chemokine ligand 12), KLKB1 (kallikrein), and leptin, replicated in AGES\u2010RS, of which the former 2 are novel. Only 1 protein, CXCL6, which showed a near\u2010significant association with AS in the replication cohort, was significantly (positively) associated with incident AS. Mendelian randomization analysis was conducted for KLKB1, CXCL12, and CXCL6, which supported a causal relationship for higher KLKB1 with lower AVC (beta=\u22120.25,\n                      <jats:italic toggle=\"no\">P<\/jats:italic>\n                      =0.009).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p xml:lang=\"en\">This study of older adults newly identified and largely replicated associations of 3 circulating proteins with calcific aortic valve disease, of which the relationship of plasma KLKB1 may have a causal basis. Additional investigation is necessary to determine if KLKB1 could be harnessed for calcific aortic valve disease therapeutics.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/jaha.124.036336","type":"journal-article","created":{"date-parts":[[2025,2,26]],"date-time":"2025-02-26T06:06:12Z","timestamp":1740549972000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":8,"title":["Plasma Proteomic Assessment of Calcific Aortic Valve Disease in Older Adults"],"prefix":"10.1161","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7983-5243","authenticated-orcid":false,"given":"Anna E.","family":"Bortnick","sequence":"first","affiliation":[{"name":"Montefiore Medical Center and Albert Einstein College of Medicine","place":["Bronx"]},{"name":"Montefiore Medical Center and Albert Einstein College of Medicine","place":["Bronx"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas 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Washington","place":["Seattle"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9499-6456","authenticated-orcid":false,"given":"Daniele","family":"Massera","sequence":"additional","affiliation":[{"name":"New York University Langone Health","place":["New York"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Line","family":"Dufresne","sequence":"additional","affiliation":[{"name":"McGill University Health Centre Research Institute","place":["Montreal, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ta\u2010Yu","family":"Yang","sequence":"additional","affiliation":[{"name":"McGill University Health Centre Research Institute","place":["Montreal, Canada"]},{"name":"McGill University","place":["Montreal, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8411-4790","authenticated-orcid":false,"given":"James C.","family":"Engert","sequence":"additional","affiliation":[{"name":"McGill University Health Centre Research Institute","place":["Montreal, Canada"]},{"name":"McGill University","place":["Montreal, Canada"]},{"name":"McGill University","place":["Montreal, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George","family":"Thanassoulis","sequence":"additional","affiliation":[{"name":"McGill University Health Centre Research Institute","place":["Montreal, Canada"]},{"name":"McGill University","place":["Montreal, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0080-2420","authenticated-orcid":false,"given":"Russell P.","family":"Tracy","sequence":"additional","affiliation":[{"name":"Larner College of Medicine, University of Vermont","place":["Burlington"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6767-7687","authenticated-orcid":false,"given":"Robert 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