{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T15:54:05Z","timestamp":1791388445130,"version":"4.3.3"},"reference-count":24,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"15","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2021,8,3]]},"abstract":"<jats:sec xml:lang=\"en\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p xml:lang=\"en\">Cardiac fibrosis plays a crucial role in the pathogenesis of dilated cardiomyopathy (DCM). HE4 (human epididymis protein 4) is a secretory protein expressed in activated fibroblasts that exacerbates tissue fibrosis. In the present study, we investigated the clinical utility of HE4 measurement in patients with DCM and its pathophysiological role in preclinical experiments in vivo and in vitro.<\/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 measured serum HE4 levels of 87 patients with DCM. Endomyocardial biopsy expressed severe fibrosis only in the high HE4 group (\n                      <jats:italic>P<\/jats:italic>\n                      &lt;0.0001). Echocardiography showed that left ventricular end\u2010diastolic diameter tends to decrease over time (58\u00b17.3 to 51\u00b16.6\u00a0mm;\n                      <jats:italic>P<\/jats:italic>\n                      &lt;0.0001) in the low HE4 group (&lt;59.65\u00a0pmol\/L [median value]). HE4 was significantly associated with risk reduction of mortality and cardiovascular hospitalization in multivariate Cox model. In vivo, HE4 was highly expressed in kidney and lung tissue of mouse, and scarcely expressed in heart. In genetically induced DCM mouse model, HE4 expression increased in kidney but not in heart and lung. In vitro, supernatant from HE4\u2010transfected human embryonic kidney 293T cells enhanced transdifferentiation of rat neonatal fibroblasts and increased expression of fibrosis\u2010related genes, and this was accompanied by the activation of extracellular signal\u2010regulated kinase signaling in cardiac fibroblasts. Treatment with an inhibitor of upstream signal of extracellular signal\u2010regulated kinase or a neutralizing HE4 antibody canceled the profibrotic properties of HE4.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p xml:lang=\"en\">HE4 functions as a secretory factor, activating cardiac fibroblasts, thereby inducing cardiac interstitial fibrosis. HE4 could be a promising biomarker for assessing ongoing fibrosis and a novel therapeutic target in DCM.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Registration<\/jats:title>\n                    <jats:p xml:lang=\"en\">\n                      URL:\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/upload.umin.ac.jp\/cgi-open-bin\/ctr\">https:\/\/upload.umin.ac.jp\/cgi\u2010open\u2010bin\/ctr<\/jats:ext-link>\n                      ; Unique identifier: UMIN000043062.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/jaha.120.021069","type":"journal-article","created":{"date-parts":[[2021,7,29]],"date-time":"2021-07-29T05:02:11Z","timestamp":1627534931000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":42,"title":["HE4 Predicts Progressive Fibrosis and Cardiovascular Events in Patients With Dilated Cardiomyopathy"],"prefix":"10.1161","volume":"10","author":[{"given":"Masahiro","family":"Yamamoto","sequence":"first","affiliation":[{"name":"Department of Cardiovascular Medicine Faculty of Life Sciences Kumamoto University Kumamoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9627-9373","authenticated-orcid":false,"given":"Shinsuke","family":"Hanatani","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine Faculty of Life Sciences Kumamoto University Kumamoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satoshi","family":"Araki","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine Faculty of Life Sciences Kumamoto University Kumamoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasuhiro","family":"Izumiya","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine Faculty of Life Sciences Kumamoto University Kumamoto Japan"},{"name":"Department of Cardiovascular Medicine Osaka City University Graduate School of Medicine Osaka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshihiro","family":"Yamada","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine Faculty of Life Sciences Kumamoto University Kumamoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nobuhiro","family":"Nakanishi","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine Faculty of Life Sciences Kumamoto University Kumamoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshifumi","family":"Ishida","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine Faculty of Life Sciences Kumamoto University Kumamoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satoru","family":"Yamamura","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine Faculty of Life Sciences Kumamoto University Kumamoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuichi","family":"Kimura","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine Faculty of Life Sciences Kumamoto University Kumamoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuichiro","family":"Arima","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine Faculty of Life Sciences Kumamoto University Kumamoto Japan"},{"name":"International Research Center for Medical Sciences Kumamoto University Kumamoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1205-3252","authenticated-orcid":false,"given":"Taishi","family":"Nakamura","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine Faculty of Life Sciences Kumamoto University Kumamoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seiji","family":"Takashio","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine Faculty of Life Sciences Kumamoto University Kumamoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eiichiro","family":"Yamamoto","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine Faculty of Life Sciences Kumamoto University Kumamoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenji","family":"Sakamoto","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine Faculty of Life Sciences Kumamoto University Kumamoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2962-8056","authenticated-orcid":false,"given":"Koichi","family":"Kaikita","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine Faculty of Life Sciences Kumamoto University Kumamoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenichi","family":"Matsushita","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine Faculty of Life Sciences Kumamoto University Kumamoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9171-3636","authenticated-orcid":false,"given":"Sachio","family":"Morimoto","sequence":"additional","affiliation":[{"name":"Department of Health Sciences Fukuoka International University of Health and Welfare Fukuoka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takaaki","family":"Ito","sequence":"additional","affiliation":[{"name":"Department of Pathology and Experimental Medicine Faculty of Life Sciences Kumamoto University Kumamoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenichi","family":"Tsujita","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine Faculty of Life Sciences Kumamoto University Kumamoto Japan"},{"name":"Center for Metabolic Regulation of Healthy Aging Kumamoto University Kumamoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIR.0000000000000757"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2018.09.035"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2010.11.030"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1136\/heartjnl-2016-311017"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.86898"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2019.02.049"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2016.02.047"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcmg.2018.08.021"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2989"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2013.05.019"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.echo.2005.10.005"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCHEARTFAILURE.118.005220"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.114.014821"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.119.13357"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1111\/bph.13062"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M204572200"},{"key":"e_1_3_2_18_2","unstructured":"National Center for Biotechnology Information . WFDC2 WAP four\u2010disulfide core domain 2 [Homo sapiens (human)]. Gene ID: 10406 updated on June 11 2021. www.ncbi.nlm.nih.gov\/gene\/10406. Accessed June 17 2021."},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature24676"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1096\/fj.201901950R"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.athoracsur.2017.04.046"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jchf.2012.11.005"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cardfail.2016.05.002"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.128722"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00380-017-1069-1"}],"container-title":["Journal of the American Heart Association"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/JAHA.120.021069","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,13]],"date-time":"2024-05-13T07:50:35Z","timestamp":1715586635000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/JAHA.120.021069"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,3]]},"references-count":24,"journal-issue":{"issue":"15","published-print":{"date-parts":[[2021,8,3]]}},"alternative-id":["10.1161\/JAHA.120.021069"],"URL":"https:\/\/doi.org\/10.1161\/jaha.120.021069","relation":{},"ISSN":["2047-9980"],"issn-type":[{"value":"2047-9980","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,8,3]]},"assertion":[{"value":"2021-03-07","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-06-14","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-07-29","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e021069"}}