{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T17:15:54Z","timestamp":1782753354280,"version":"3.54.5"},"reference-count":38,"publisher":"Oxford University Press (OUP)","issue":"11","license":[{"start":{"date-parts":[[2026,1,18]],"date-time":"2026-01-18T00:00:00Z","timestamp":1768694400000},"content-version":"vor","delay-in-days":2238,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2019,12,3]],"date-time":"2019-12-03T00:00:00Z","timestamp":1575331200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000780","name":"European Commission","doi-asserted-by":"publisher","award":["FP7-242209-BIOSTAT-CHF"],"award-info":[{"award-number":["FP7-242209-BIOSTAT-CHF"]}],"id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000780","name":"European Commission","doi-asserted-by":"publisher","award":["EudraCT 2010\u2013020808\u201329"],"award-info":[{"award-number":["EudraCT 2010\u2013020808\u201329"]}],"id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000780","name":"European Commission","doi-asserted-by":"publisher","award":["FP7\u2010242209\u2010BIOSTAT\u2010CHF"],"award-info":[{"award-number":["FP7\u2010242209\u2010BIOSTAT\u2010CHF"]}],"id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000780","name":"European Commission","doi-asserted-by":"publisher","award":["EudraCT 2010\u2013020808\u201329"],"award-info":[{"award-number":["EudraCT 2010\u2013020808\u201329"]}],"id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2020,11,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>Cathepsin D is a ubiquitous lysosomal protease that is primarily secreted due to oxidative stress. The role of circulating cathepsin D in heart failure (HF) is unknown. The aim of this study is to determine the association between circulating cathepsin D levels and clinical outcomes in patients with HF and to investigate the biological settings that induce the release of cathepsin D in HF.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and results<\/jats:title>\n                    <jats:p>Cathepsin D levels were studied in 2174 patients with HF from the BIOSTAT-CHF index study. Results were validated in 1700 HF patients from the BIOSTAT-CHF validation cohort. The primary combined outcome was all-cause mortality and\/or HF hospitalizations. Human pluripotent stem cell-derived cardiomyocytes were subjected to hypoxic, pro-inflammatory signalling and stretch conditions. Additionally, cathepsin D expression was inhibited by targeted short hairpin RNAs (shRNA). Higher levels of cathepsin D were independently associated with diabetes mellitus, renal failure and higher levels of interleukin-6 and N-terminal pro-B-type natriuretic peptide (P\u2009&amp;lt;\u20090.001 for all). Cathepsin D levels were independently associated with the primary combined outcome [hazard ratio (HR) per standard deviation (SD): 1.12; 95% confidence interval (CI) 1.02\u20131.23], which was validated in an independent cohort (HR per SD: 1.23, 95% CI 1.09\u20131.40). In vitro experiments demonstrated that human stem cell-derived cardiomyocytes released cathepsin D and troponin T in response to mechanical stretch. ShRNA-mediated silencing of cathepsin D resulted in increased necrosis, abrogated autophagy, increased stress-induced metabolism, and increased release of troponin T from human stem cell-derived cardiomyocytes under stress.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Circulating cathepsin D levels are associated with HF severity and poorer outcome, and reduced levels of cathepsin D may have detrimental effects with therapeutic potential in HF.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ejhf.1674","type":"journal-article","created":{"date-parts":[[2019,12,3]],"date-time":"2019-12-03T22:10:18Z","timestamp":1575411018000},"page":"2102-2111","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":38,"title":["The Role of Cathepsin D in the Pathophysiology of Heart Failure and its Potentially Beneficial Properties: A Translational Approach"],"prefix":"10.1093","volume":"22","author":[{"given":"Martijn F.","family":"Hoes","sequence":"first","affiliation":[{"name":"Department of Cardiology, University of Groningen , Groningen ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jasper","family":"Tromp","sequence":"additional","affiliation":[{"name":"Department of Cardiology, University of Groningen , Groningen ,","place":["The Netherlands"]},{"name":"National Heart Centre Singapore \u00a0","place":["Singapore"]},{"name":"Duke-NUS Medical School \u00a0","place":["Singapore"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wouter","family":"Ouwerkerk","sequence":"additional","affiliation":[{"name":"National Heart Centre Singapore \u00a0","place":["Singapore"]},{"name":"Department of Epidemiology, Biostatistics & Bioinformatics, Academic Medical Center , Amsterdam ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nils","family":"Bomer","sequence":"additional","affiliation":[{"name":"Department of Cardiology, University of Groningen , Groningen ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silke U.","family":"Oberdorf-Maass","sequence":"additional","affiliation":[{"name":"Department of Cardiology, University of Groningen , Groningen ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nilesh J.","family":"Samani","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Sciences, University of Leicester, and NIHR Leicester Biomedical Research Centre, Glenfield Hospital , Leicester ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leong L.","family":"Ng","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Sciences, University of Leicester, and NIHR Leicester Biomedical Research Centre, Glenfield Hospital , Leicester ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chim C.","family":"Lang","sequence":"additional","affiliation":[{"name":"Division of Molecular & Clinical Medicine, University of Dundee , Dundee ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pim","family":"van der Harst","sequence":"additional","affiliation":[{"name":"Department of Cardiology, University of Groningen , Groningen ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hans","family":"Hillege","sequence":"additional","affiliation":[{"name":"Department of Cardiology, University of Groningen , Groningen ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan D.","family":"Anker","sequence":"additional","affiliation":[{"name":"Division of Cardiology and Metabolism \u2013 Heart Failure, Cachexia & Sarcopenia; Department of Cardiology (CVK); and Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charit\u00e9 University Medicine , Berlin ,","place":["Germany"]},{"name":"Department of Cardiology and Pneumology, University Medicine G\u00f6ttingen (UMG) , G\u00f6ttingen ,","place":["Germany"]},{"name":"DZHK (German Center for Cardiovascular Research) , Berlin ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Metra","sequence":"additional","affiliation":[{"name":"Institute of Cardiology, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia , Brescia ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dirk J.","family":"van Veldhuisen","sequence":"additional","affiliation":[{"name":"Department of Cardiology, University of Groningen , Groningen ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adriaan A.","family":"Voors","sequence":"additional","affiliation":[{"name":"Department of Cardiology, University of Groningen , Groningen ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"van der Meer","sequence":"additional","affiliation":[{"name":"Department of Cardiology, University of Groningen , Groningen ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2019,12,3]]},"reference":[{"key":"2026011721380950800_ejhf1674-bib-0001","doi-asserted-by":"crossref","DOI":"10.1002\/ejhf.1320","article-title":"Treating oxidative stress in heart failure: past, present and future","author":"van der Pol","year":"2019","journal-title":"Eur J Heart Fail"},{"key":"2026011721380950800_ejhf1674-bib-0002","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1161\/CIRCHEARTFAILURE.109.864785","article-title":"Cardiac-specific overexpression of catalase identifies hydrogen peroxide-dependent and -independent phases of myocardial remodeling and prevents the progression to overt heart failure in G(alpha)q-overexpressing transgenic mice","volume":"3","author":"Qin","year":"2010","journal-title":"Circ Heart Fail"},{"key":"2026011721380950800_ejhf1674-bib-0003","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1161\/CIRCULATIONAHA.115.019790","article-title":"Novel biomarker of oxidative stress is associated with risk of death in patients with coronary artery disease","volume":"133","author":"Patel","year":"2016","journal-title":"Circulation"},{"key":"2026011721380950800_ejhf1674-bib-0004","doi-asserted-by":"crossref","first-page":"1474","DOI":"10.1161\/CIRCULATIONAHA.109.906818","article-title":"Oxidative stress regulates left ventricular PDE5 expression in the failing heart","volume":"121","author":"Lu","year":"2010","journal-title":"Circulation"},{"key":"2026011721380950800_ejhf1674-bib-0005","doi-asserted-by":"crossref","first-page":"1154","DOI":"10.1161\/01.CIR.0000026820.87824.6A","article-title":"Heterozygous cellular glutathione peroxidase deficiency in the mouse: abnormalities in vascular and cardiac function and structure","volume":"106","author":"Forgione","year":"2002","journal-title":"Circulation"},{"key":"2026011721380950800_ejhf1674-bib-0006","doi-asserted-by":"crossref","first-page":"13403","DOI":"10.1016\/S0021-9258(18)80010-2","article-title":"Cleavage of parathyroid hormone in macrophage endosomes illustrates a novel pathway for intracellular processing of proteins","volume":"264","author":"Diment","year":"1989","journal-title":"J Biol Chem"},{"key":"2026011721380950800_ejhf1674-bib-0007","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1042\/bj1170601","article-title":"Cathepsin D. 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