{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T03:53:16Z","timestamp":1791604396897,"version":"4.3.4"},"reference-count":36,"publisher":"Japanese Circulation Society","issue":"10","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Circ Rep"],"published-print":{"date-parts":[[2026,10,9]]},"DOI":"10.1253\/circrep.cr-26-0186","type":"journal-article","created":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T22:12:17Z","timestamp":1785276737000},"page":"1583-1589","source":"Crossref","is-referenced-by-count":0,"title":["Human Epididymis Protein 4 in Cardiovascular Disease\u3000\u2015 A Fibrosis-Driven Mediator of Tissue Remodeling and Inter-Organ Communication \u2015"],"prefix":"10.1253","volume":"8","author":[{"given":"Shinsuke","family":"Hanatani","sequence":"first","affiliation":[{"name":"Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masahiro","family":"Yamamoto","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fumihiko","family":"Ogata","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuki","family":"Okuno","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satoshi","family":"Araki","sequence":"additional","affiliation":[{"name":"Department of General Medicine and Primary Care, Kumamoto University Hospital"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuichiro","family":"Arima","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Faculty of Life Sciences, Kumamoto University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eiichiro","family":"Yamamoto","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasuhiro","family":"Izumiya","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenichi","family":"Tsujita","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"330","reference":[{"key":"1","doi-asserted-by":"publisher","unstructured":"1. Kirchhoff C, Habben I, Ivell R, Krull N. A major human epididymis-specific cDNA encodes a protein with sequence homology to extracellular proteinase inhibitors. <i>Biol Reprod<\/i> 1991; 45: 350\u2013357, doi:10.1095\/biolreprod45.2.350.","DOI":"10.1095\/biolreprod45.2.350"},{"key":"2","unstructured":"2. Hellstr\u00f6m I, Raycraft J, Hayden-Ledbetter M, Ledbetter JA, Schummer M, McIntosh M, et al. The HE4 (WFDC2) protein is a biomarker for ovarian carcinoma. <i>Cancer Res<\/i> 2003; 63: 3695\u20133700."},{"key":"3","doi-asserted-by":"publisher","unstructured":"3. Moore RG, Brown AK, Miller MC, Badgwell D, Lu Z, Allard WJ, et al. Utility of a novel serum tumor biomarker HE4 in patients with endometrioid adenocarcinoma of the uterus. <i>Gynecol Oncol<\/i> 2008; 110: 196\u2013201, doi:10.1016\/j.ygyno.2008.04.002.","DOI":"10.1016\/j.ygyno.2008.04.002"},{"key":"4","doi-asserted-by":"publisher","unstructured":"4. LeBleu VS, Teng Y, O\u2019Connell JT, Charytan D, Muller GA, Muller CA, et al. Identification of human epididymis protein-4 as a fibroblast-derived mediator of fibrosis. <i>Nat Med<\/i> 2013; 19: 227\u2013231, doi:10.1038\/nm.2989.","DOI":"10.1038\/nm.2989"},{"key":"5","doi-asserted-by":"publisher","unstructured":"5. Weber KT, Sun Y, Bhattacharya SK, Ahokas RA, Gerling IC. Myofibroblast-mediated mechanisms of pathological remodeling of the heart. <i>Nat Rev Cardiol<\/i> 2013; 10: 15\u201326, doi:10.1038\/nrcardio.2012.158.","DOI":"10.1038\/nrcardio.2012.158"},{"key":"6","doi-asserted-by":"publisher","unstructured":"6. Meyer K, Hodwin B, Ramanujam D, Engelhardt S, Sarikas A. Essential role for premature senescence of myofibroblasts in myocardial fibrosis. <i>J Am Coll Cardiol<\/i> 2016; 67: 2018\u20132028, doi:10.1016\/j.jacc.2016.02.047.","DOI":"10.1016\/j.jacc.2016.02.047"},{"key":"7","doi-asserted-by":"publisher","unstructured":"7. Oguni T, Izumiya Y, Takashio S, Kuyama N, Tabata N, Hanatani S, et al. Non-ischemic late iodine enhancement on cardiac computed tomography: Prevalence and prognostic significance. <i>Circ J<\/i> 2026; 90: 217\u2013227, doi:10.1253\/circj.CJ-25-0599.","DOI":"10.1253\/circj.CJ-25-0599"},{"key":"8","doi-asserted-by":"publisher","unstructured":"8. de Boer RA, Cao Q, Postmus D, Damman K, Voors AA, Jaarsma T, et al. The WAP four-disulfide core domain protein HE4: A novel biomarker for heart failure. <i>JACC Heart Fail<\/i> 2013; 1: 164\u2013169, doi:10.1016\/j.jchf.2012.11.005.","DOI":"10.1016\/j.jchf.2012.11.005"},{"key":"9","doi-asserted-by":"publisher","unstructured":"9. Piek A, Meijers WC, Schroten NF, Gansevoort RT, de Boer RA, Sillje HH. HE4 serum levels are associated with heart failure severity in patients with chronic heart failure. <i>J Card Fail<\/i> 2017; 23: 12\u201319, doi:10.1016\/j.cardfail.2016.05.002.","DOI":"10.1016\/j.cardfail.2016.05.002"},{"key":"10","doi-asserted-by":"publisher","unstructured":"10. Yamamoto M, Hanatani S, Araki S, Izumiya Y, Yamada T, Nakanishi N, et al. HE4 predicts progressive fibrosis and cardiovascular events in patients with dilated cardiomyopathy. <i>J Am Heart Assoc<\/i> 2021; 10: e021069, doi:10.1161\/JAHA.120.021069.","DOI":"10.1161\/JAHA.120.021069"},{"key":"11","doi-asserted-by":"publisher","unstructured":"11. Ogata F, Hanatani S, Nakashima N, Yamamoto M, Shirahama Y, Ishii M, et al. Human epididymis protein 4 is a useful predictor of postoperative prognosis in patients with severe aortic stenosis. <i>ESC Heart Fail<\/i> 2024; 11: 2924\u20132932, doi:10.1002\/ehf2.14845.","DOI":"10.1002\/ehf2.14845"},{"key":"12","doi-asserted-by":"publisher","unstructured":"12. Okuno Y, Hanatani S, Ogata F, Yamaguchi S, Yamamoto M, Kuyama N, et al. High human epididymis protein 4 levels are associated with lower systolic function and poor prognosis in heart failure with reduced ejection fraction. <i>Circ J<\/i> 2026; 90: 581\u2013591, doi:10.1253\/circj.CJ-25-0942.","DOI":"10.1253\/circj.CJ-25-0942"},{"key":"13","doi-asserted-by":"publisher","unstructured":"13. Schuermans A, Pournamdari AB, Lee J, Bhukar R, Ganesh S, Darosa N, et al. Integrative proteomic analyses across common cardiac diseases yield mechanistic insights and enhanced prediction. <i>Nat Cardiovasc Res<\/i> 2024; 3: 1391\u20131404, doi:10.1038\/s44161-024-00567-0.","DOI":"10.1038\/s44161-024-00567-0"},{"key":"14","doi-asserted-by":"publisher","unstructured":"14. Zheng R, Bhukar R, Ganesh S, Darosa N, Small AM, Yu Z, et al. Proteomic prediction of incident cardiovascular diseases using UK Biobank data. <i>Nat Cardiovasc Res<\/i> 2024; 3: 1111\u20131123, doi:10.1038\/s44161-024-00545-6.","DOI":"10.1038\/s44161-024-00545-6"},{"key":"15","doi-asserted-by":"publisher","unstructured":"15. Huang Y, Jiang H, Zhu L. Human epididymis protein 4 as an indicator of acute heart failure in patients with chronic kidney disease. <i>Lab Med<\/i> 2020; 51: 169\u2013175, doi:10.1093\/labmed\/lmz041.","DOI":"10.1093\/labmed\/lmz041"},{"key":"16","doi-asserted-by":"crossref","unstructured":"16. Tang Y, Hu Z, Liu Z, Peng S, Liu T, Xiao Y, et al. HE4 serum levels are associated with poor prognosis in patients with acute heart failure combined with chronic kidney disease. <i>Int J Gen Med<\/i> 2023; 16: 6243\u20136251, doi:10.2147\/IJGM.S424368.","DOI":"10.2147\/IJGM.S444680"},{"key":"17","doi-asserted-by":"publisher","unstructured":"17. Bingle L, Singleton V, Bingle CD. The putative ovarian tumour marker gene HE4 (WFDC2), is expressed in normal tissues and undergoes complex alternative splicing to yield multiple protein isoforms. <i>Oncogene<\/i> 2002; 21: 2768\u20132773, doi:10.1038\/sj.onc.1205360.","DOI":"10.1038\/sj.onc.1205360"},{"key":"18","doi-asserted-by":"publisher","unstructured":"18. Drapkin R, von Horsten HH, Lin Y, Mok SC, Crum CP, Welch WR, et al. Human epididymis protein 4 (HE4) is a secreted glycoprotein that is overexpressed by serous and endometrioid ovarian carcinomas. <i>Cancer Res<\/i> 2005; 65: 2162\u20132169, doi:10.1158\/0008-5472.CAN-04-3924.","DOI":"10.1158\/0008-5472.CAN-04-3924"},{"key":"19","doi-asserted-by":"publisher","unstructured":"19. Bingle CD, Vyakarnam A. Novel innate immune functions of the whey acidic protein family. <i>Trends Immunol<\/i> 2008; 29: 444\u2013453, doi:10.1016\/j.it.2008.07.001.","DOI":"10.1016\/j.it.2008.07.001"},{"key":"20","doi-asserted-by":"publisher","unstructured":"20. Galgano MT, Hampton GM, Frierson HF Jr. Comprehensive analysis of HE4 expression in normal and malignant human tissues. <i>Mod Pathol<\/i> 2006; 19: 847\u2013853, doi:10.1038\/modpathol.3800568.","DOI":"10.1038\/modpathol.3800568"},{"key":"21","doi-asserted-by":"publisher","unstructured":"21. Nakajima K, Ono M, Radovi\u0107 U, Dizdarevi\u0107 S, Tomizawa SI, Kuroha K, et al. Lack of whey acidic protein (WAP) four-disulfide core domain protease inhibitor 2 (WFDC2) causes neonatal death from respiratory failure in mice. <i>Dis Model Mech<\/i> 2019; 12: dmm040139, doi:10.1242\/dmm.040139.","DOI":"10.1242\/dmm.040139"},{"key":"22","doi-asserted-by":"publisher","unstructured":"22. Chhikara N, Saraswat M, Tomar AK, Dey S, Singh S, Yadav S. Human epididymis protein-4 (HE-4): A novel cross-class protease inhibitor. <i>PLoS One<\/i> 2012; 7: e47672, doi:10.1371\/journal.pone.0047672.","DOI":"10.1371\/journal.pone.0047672"},{"key":"23","doi-asserted-by":"publisher","unstructured":"23. Ribeiro JR, Gaudet HM, Khan M, Schorl C, James NE, Oliver MT, et al. Human epididymis protein 4 promotes events associated with metastatic ovarian cancer via regulation of the extracellular matrix. <i>Front Oncol<\/i> 2018; 7: 332, doi:10.3389\/fonc.2017.00332.","DOI":"10.3389\/fonc.2017.00332"},{"key":"24","doi-asserted-by":"publisher","unstructured":"24. Jeong H, Lee B, Kim KH, Cho SY, Cho Y, Park J, et al. WFDC2 promotes M2 macrophage polarization by up-regulating IL33 expression. <i>Gastroenterology<\/i> 2021; 161: 953\u2013967.e15, doi:10.1053\/j.gastro.2021.05.058.","DOI":"10.1053\/j.gastro.2021.05.058"},{"key":"25","doi-asserted-by":"crossref","unstructured":"25. Hara T, Sata M. Association between chronic inflammation and cardiovascular disease: Focus on high-sensitivity C-reactive protein. <i>Circ J<\/i> 2026, doi:10.1253\/circj.CJ-26-0173.","DOI":"10.1253\/circj.CJ-26-0173"},{"key":"26","doi-asserted-by":"publisher","unstructured":"26. Hu C, Francisco J, Del Re DP, Sadoshima J. Decoding the impact of the hippo pathway on different cell types in heart failure. <i>Circ J<\/i> 2024; 89: 6\u201315, doi:10.1253\/circj.CJ-24-0171.","DOI":"10.1253\/circj.CJ-24-0171"},{"key":"27","doi-asserted-by":"publisher","unstructured":"27. Nagai T, Katsuki M, Amemiya K, Takahashi A, Oyama-Manabe N, Ohta-Ogo K, et al. Chronic active myocarditis and inflammatory cardiomyopathy: Challenges in diagnosis and treatment. <i>Circ J<\/i> 2026; 90: 152\u2013161, doi:10.1253\/circj.CJ-25-0246.","DOI":"10.1253\/circj.CJ-25-0246"},{"key":"28","doi-asserted-by":"publisher","unstructured":"28. Kitai T, Kohsaka S, Kato T, Kato E, Sato K, Teramoto K, et al. JCS\/JHFS 2025 Guideline on diagnosis and treatment of heart failure. <i>Circ J<\/i> 2025; 89: 1278\u20131444, doi:10.1253\/circj.CJ-25-0002.","DOI":"10.1253\/circj.CJ-25-0002"},{"key":"29","doi-asserted-by":"publisher","unstructured":"29. Tahara T, Hada M, Kanaji Y, Usui E, Nagamine T, Ueno H, et al. Serial extracellular volume by coronary computed tomography after acute myocardial infarction with left-main vasospasm. <i>Circ Rep<\/i> 2024; 6: 600\u2013601, doi:10.1253\/circrep.CR-24-0094.","DOI":"10.1253\/circrep.CR-24-0094"},{"key":"30","doi-asserted-by":"publisher","unstructured":"30. Giuliani C, Zanuttini A, Nuche J, Farjat Pasos JI, Bernard J, Lionel T, et al. Human epididymis protein 4 in transcatheter aortic valve implantation: Diagnostic and prognostic value. <i>JACC Adv<\/i> 2025; 4: 101722, doi:10.1016\/j.jacadv.2025.101722.","DOI":"10.1016\/j.jacadv.2025.101722"},{"key":"31","doi-asserted-by":"publisher","unstructured":"31. Tang Y, Zhu WY, Peng SL, Huang S, Zhao QN, Tan SY, et al. Prognostic value of human epididymis protein 4 in acute myocardial infarction. <i>Int J Gen Med<\/i> 2024; 17: 6243\u20136251, doi:10.2147\/IJGM.S470399. eCollection 2024.","DOI":"10.2147\/IJGM.S470399"},{"key":"32","doi-asserted-by":"publisher","unstructured":"32. Amemiya K, Nakashima J, Ohta-Ogo K, Ishibashi-Ueda H, Matsumoto M, Ikeda Y, et al. Tenascin-C and fibrosis as prognostic predictors of peripartum cardiomyopathy: A histopathological study. <i>Circ J<\/i> 2026; 90: 569\u2013578, doi:10.1253\/circj.CJ-25-0768.","DOI":"10.1253\/circj.CJ-25-0768"},{"key":"33","doi-asserted-by":"publisher","unstructured":"33. Wan J, Wang Y, Cai G, Liang J, Yue C, Wang F, et al. Elevated serum concentrations of HE4 as a novel biomarker of disease severity and renal fibrosis in kidney disease. <i>Oncotarget<\/i> 2016; 7: 67748\u201367759, doi:10.18632\/oncotarget.11682.","DOI":"10.18632\/oncotarget.11682"},{"key":"34","doi-asserted-by":"publisher","unstructured":"34. Izawa KP, Ogura A. Unraveling the Cardiorenal Nexus: Emerging frameworks and the role of exercise therapy. <i>Circ Rep<\/i> 2025; 8: 381\u2013390, doi:10.1253\/circrep.CR-25-0198.","DOI":"10.1253\/circrep.CR-25-0198"},{"key":"35","doi-asserted-by":"publisher","unstructured":"35. Liu SF, Nambiar Veetil N, Li Q, Kucherenko MM, Knosalla C, Kuebler WM. Pulmonary hypertension: Linking inflammation and pulmonary arterial stiffening. <i>Front Immunol<\/i> 2022; 13: 959209, doi:10.3389\/fimmu.2022.959209. eCollection 2022.","DOI":"10.3389\/fimmu.2022.959209"},{"key":"36","doi-asserted-by":"publisher","unstructured":"36. Jin Q, Tang Y, Liu Z, Xie W, Luo Q, Zhao Z, et al. Serum human epididymis protein 4 level as a predictor of clinical worsening in idiopathic pulmonary arterial hypertension: A pilot study. <i>BMC Cardiovasc Disord<\/i> 2020; 20: 175, doi:10.1186\/s12872-020-01461-w.","DOI":"10.1186\/s12872-020-01461-w"}],"container-title":["Circulation Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.jstage.jst.go.jp\/article\/circrep\/8\/10\/8_CR-26-0186\/_pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T03:29:56Z","timestamp":1791602996000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.jstage.jst.go.jp\/article\/circrep\/8\/10\/8_CR-26-0186\/_article"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,9]]},"references-count":36,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2026]]}},"URL":"https:\/\/doi.org\/10.1253\/circrep.cr-26-0186","relation":{},"ISSN":["2434-0790"],"issn-type":[{"value":"2434-0790","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,9]]},"article-number":"CR-26-0186"}}