{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T12:10:49Z","timestamp":1780488649866,"version":"3.54.1"},"reference-count":17,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"21","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2025,11,4]]},"abstract":"<jats:sec xml:lang=\"en\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p xml:lang=\"en\">Clinical imaging studies of calcific aortic stenosis have suggested interleaflet pathological differences in patients. In this cross\u2010sectional study, we sought to investigate interleaflet differences in calcification, fibrous extracellular matrix remodeling, and adipocyte degeneration in explanted human aortic valves.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p xml:lang=\"en\">Diseased (n=45) and control (n=39) tricuspid aortic valve leaflets obtained from patients with aortic stenosis and normal aortic valves on echocardiography were assessed for calcification, fibrous extracellular matrix remodeling, and adipocyte degeneration using contrast\u2010enhanced microcomputed tomography in conjunction with scanning and transmission electron microscopy, with interleaflet differences analyzed by fractional response regression.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p xml:lang=\"en\">\n                      In diseased leaflets, the calcification volume fraction was significantly greater in the noncoronary cusp than the left coronary cusp (LCC; \u03b2=0.313 [95% CI, 0.048\u20130.579],\n                      <jats:italic toggle=\"no\">P<\/jats:italic>\n                      =0.021) but not than the right coronary cusp (RCC; \u03b2=0.196 [95% CI, \u22120.107 to 0.499],\n                      <jats:italic toggle=\"no\">P<\/jats:italic>\n                      =0.204), with no difference between the RCC and LCC (\u03b2=0.117 [95% CI, \u22120.150 to 0.385],\n                      <jats:italic toggle=\"no\">P<\/jats:italic>\n                      =0.390). However, the fibrous extracellular matrix volume fraction was significantly greater in the RCC and LCC than the noncoronary cusp (\u03b2=0.502 [95% CI, 0.300\u20130.704],\n                      <jats:italic toggle=\"no\">P<\/jats:italic>\n                      &lt;0.001; \u03b2=0.388 [95% CI, 0.188\u20130.589],\n                      <jats:italic toggle=\"no\">P<\/jats:italic>\n                      &lt;0.001), with the RCC also greater than the LCC (\u03b2=0.114 [95% CI, 0.065\u20130.163],\n                      <jats:italic toggle=\"no\">P<\/jats:italic>\n                      &lt;0.001). The volume fraction of osmium\u2010labeled inclusions observed on microcomputed tomography\u2014confirmed to be predominantly adipocytes (95.4 [IQR, 72.4\u201399.0]%) and occasionally membranous fat necrosis (4.6 [IQR, 1.0\u201327.6]%) on electron microscopy\u2014was significantly less in the noncoronary cusp than the LCC (\u03b2=\u22120.269 [95% CI, \u22120.441 to \u22120.096],\n                      <jats:italic toggle=\"no\">P<\/jats:italic>\n                      =0.002) but not than the RCC (\u03b2=\u22120.185 [95% CI, \u22120.409 to 0.038],\n                      <jats:italic toggle=\"no\">P<\/jats:italic>\n                      =0.104), with no difference between the RCC and LCC (\u03b2=\u22120.083 [95% CI, \u22120.348 to 0.182],\n                      <jats:italic toggle=\"no\">P<\/jats:italic>\n                      =0.538).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p xml:lang=\"en\">Valvular calcification diverges from fibrous extracellular matrix remodeling but converges with adipocyte degeneration in terms of preferential impact on the noncoronary cusp versus, in particular, the LCC. Future mechanistic studies to elucidate the intimate relationship between adipocyte degeneration and valvular calcification may provide opportunities for further therapeutic development.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/jaha.124.040616","type":"journal-article","created":{"date-parts":[[2025,11,3]],"date-time":"2025-11-03T13:17:49Z","timestamp":1762175869000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Dual Contrast\u2010Enhanced Microcomputed Tomography Uncovers Leaflet\u2010Dependent Patterns of Macrocalcification, Fibrous Extracellular Matrix Remodeling, and Adipocyte Degeneration in Calcific Aortic Stenosis"],"prefix":"10.1161","volume":"14","author":[{"given":"Mustapha","family":"El Zeini","sequence":"first","affiliation":[{"name":"Stanford University School of Medicine","place":["Stanford, USA"]},{"name":"Stanford University School of Medicine","place":["Stanford, USA"]},{"name":"Stanford Cardiovascular Institute, Stanford University","place":["Stanford, USA"]},{"name":"Veterans Affairs Palo Alto Health Care System","place":["Palo Alto, USA"]},{"name":"Veterans Affairs Palo Alto Health Care System","place":["Palo Alto, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ines Ross","family":"Tacco","sequence":"additional","affiliation":[{"name":"Stanford University School of Medicine","place":["Stanford, USA"]},{"name":"Stanford University School of Medicine","place":["Stanford, USA"]},{"name":"Stanford Cardiovascular Institute, Stanford University","place":["Stanford, USA"]},{"name":"Veterans Affairs Palo Alto Health Care System","place":["Palo Alto, USA"]},{"name":"Veterans Affairs Palo Alto Health Care System","place":["Palo Alto, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John I.","family":"Jimenez","sequence":"additional","affiliation":[{"name":"Stanford University School of Medicine","place":["Stanford, USA"]},{"name":"Stanford Cardiovascular Institute, Stanford University","place":["Stanford, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela","family":"Kabiri","sequence":"additional","affiliation":[{"name":"Stanford University School of Medicine","place":["Stanford, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5878-1864","authenticated-orcid":false,"given":"Arturas","family":"Vailionis","sequence":"additional","affiliation":[{"name":"Stanford University","place":["Stanford, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0825-3160","authenticated-orcid":false,"given":"John","family":"Perrino","sequence":"additional","affiliation":[{"name":"Stanford University","place":["Stanford, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6062-6230","authenticated-orcid":false,"given":"Dale","family":"Burns","sequence":"additional","affiliation":[{"name":"Stanford University","place":["Stanford, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristin C.","family":"Jensen","sequence":"additional","affiliation":[{"name":"Stanford University School of Medicine","place":["Stanford, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas A.","family":"Burdon","sequence":"additional","affiliation":[{"name":"Stanford University School of Medicine","place":["Stanford, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4545-1273","authenticated-orcid":false,"given":"Yasuhiro","family":"Shudo","sequence":"additional","affiliation":[{"name":"Stanford University School of Medicine","place":["Stanford, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2506-492X","authenticated-orcid":false,"given":"Y. Joseph","family":"Woo","sequence":"additional","affiliation":[{"name":"Stanford University School of Medicine","place":["Stanford, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tie","family":"Liang","sequence":"additional","affiliation":[{"name":"Stanford University School of Medicine","place":["Stanford, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4024-3691","authenticated-orcid":false,"given":"Kevin M.","family":"Alexander","sequence":"additional","affiliation":[{"name":"Stanford University School of Medicine","place":["Stanford, USA"]},{"name":"Stanford Cardiovascular Institute, Stanford University","place":["Stanford, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4709-007X","authenticated-orcid":false,"given":"Lydia\u2010Marie","family":"Joubert","sequence":"additional","affiliation":[{"name":"Stanford University","place":["Menlo Park, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9694-5468","authenticated-orcid":false,"given":"Ian Y.","family":"Chen","sequence":"additional","affiliation":[{"name":"Stanford University School of Medicine","place":["Stanford, USA"]},{"name":"Stanford University School of Medicine","place":["Stanford, USA"]},{"name":"Stanford Cardiovascular Institute, Stanford University","place":["Stanford, USA"]},{"name":"Veterans Affairs Palo Alto Health Care System","place":["Palo Alto, USA"]},{"name":"Veterans Affairs Palo Alto Health Care System","place":["Palo Alto, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehab757"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2021.09.1367"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCIMAGING.121.012884"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10439-020-02677-9"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcmg.2016.11.020"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.21037\/qims-23-778"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.3390\/jcm9010029"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1136\/heartjnl-2019-314879"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.carpath.2020.107276"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1136\/heartjnl-2020-318556"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10753-012-9565-z"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.119.015610"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.4081\/monaldi.2019.1022"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1136\/hrt.74.1.34"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijcard.2007.12.086"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.athoracsur.2012.12.061"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1111\/pin.12074"}],"container-title":["Journal of the American Heart Association"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/JAHA.124.040616","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T11:21:03Z","timestamp":1780485663000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/JAHA.124.040616"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,4]]},"references-count":17,"journal-issue":{"issue":"21","published-print":{"date-parts":[[2025,11,4]]}},"alternative-id":["10.1161\/JAHA.124.040616"],"URL":"https:\/\/doi.org\/10.1161\/jaha.124.040616","relation":{},"ISSN":["2047-9980"],"issn-type":[{"value":"2047-9980","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,4]]},"assertion":[{"value":"2025-04-28","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-09-26","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-11-03","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e040616"}}