{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,2,21]],"date-time":"2025-02-21T05:33:49Z","timestamp":1740116029761,"version":"3.37.3"},"reference-count":33,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2020,10,1]],"date-time":"2020-10-01T00:00:00Z","timestamp":1601510400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"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\/100016545","name":"Roche Diagnostics","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100016545","id-type":"DOI","asserted-by":"publisher"}]},{"name":"French PIA project \u2018Lorraine Universit\u00e9 d\u2019Excellence\u2019 GEENAGE","award":["ANR-15-IDEX-04-LUE"],"award-info":[{"award-number":["ANR-15-IDEX-04-LUE"]}]},{"name":"European Research Council (ERC","award":["CoG 818715"],"award-info":[{"award-number":["CoG 818715"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,8,29]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Aims\u2003<\/jats:title>\n                  <jats:p>Elderly patients with heart failure with reduced ejection fraction (HFrEF) have worse prognosis and less often receive guideline-recommended therapies. We aim to better understand the underlying pathophysiological processes associated with ageing in HFrEF potentially leading to targeted therapies in this vulnerable population.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods and results\u2003<\/jats:title>\n                  <jats:p>From a panel of 363 cardiovascular biomarkers available in 1611 patients with HFrEF in the BIOSTAT-CHF index cohort and cross-validated in 823 patients in the BIOSTAT-CHF validation cohort, we tested which biomarkers were dysregulated in patients aged &amp;gt;75 vs. &amp;lt;65\u2009years. Second, pathway overrepresentation analyses were performed to identify biological pathways linked to higher plasma concentrations of biomarkers in elderly vs. younger patients. After adjustment, multiple test correction [false discovery rate (FDR) 1%], and cross-validation, 27\/363 biomarkers were associated with older age, 22 positively and 5 negatively. The biomarkers that were positively associated with older age were associated with tumour cell regulation, extra-cellular matrix organization, and inflammatory processes, whereas biomarkers negatively associated with older age were associated with pathways that may point to cell proliferation and tumourigenesis. Among the 27 biomarkers, WFDC2 (WAP four-disulphide core domain protein 2)\u2014that broadly functions as a protease inhibitor\u2014was associated with older age and had the strongest association with all outcomes. No protein-by-sex interaction was observed.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions\u2003<\/jats:title>\n                  <jats:p>In elderly HFrEF patients, pathways associated with extra-cellular matrix organization, inflammatory processes, and tumour cell regulation were activated, while pathways associated with tumour proliferation functions were down-regulated. These findings may help in a better understanding of the ageing processes in HFrEF and identify potential therapeutic targets.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/cvr\/cvaa279","type":"journal-article","created":{"date-parts":[[2020,9,17]],"date-time":"2020-09-17T12:23:27Z","timestamp":1600345407000},"page":"2228-2236","source":"Crossref","is-referenced-by-count":6,"title":["Differences in biomarkers and molecular pathways according to age for patients with HFrEF"],"prefix":"10.1093","volume":"117","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2304-6138","authenticated-orcid":false,"given":"Jo\u00e3o Pedro","family":"Ferreira","sequence":"first","affiliation":[{"name":"Universit\u00e9 de Lorraine, Inserm, Centre d'Investigation Clinique - Plurith\u00e9matique 14-33, Inserm U1116, CHRU, F-CRIN INI-CRCT (Cardiovascular and Renal Clinical Trialists), 4 rue du Morvan, Nancy 54500, France"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2000-9358","authenticated-orcid":false,"given":"Wouter","family":"Ouwerkerk","sequence":"additional","affiliation":[{"name":"National Heart Centre Singapore, Hospital Drive, Singapore 169659, Singapore"},{"name":"Department of Dermatology, Amsterdam UMC, University of Amsterdam, Amsterdam Infection & Immunity Institute, Amsterdam, the Netherlands"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4663-7213","authenticated-orcid":false,"given":"Bernadet T","family":"Santema","sequence":"additional","affiliation":[{"name":"Department of Cardiology, University of Groningen, University Medical Centre Groningen, Hanzeplein 1, 9713 GZ Groningen, the Netherlands"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1611-7935","authenticated-orcid":false,"given":"Dirk J","family":"van Veldhuisen","sequence":"additional","affiliation":[{"name":"Department of Cardiology, University of Groningen, University Medical Centre Groningen, Hanzeplein 1, 9713 GZ Groningen, the Netherlands"}]},{"given":"Chim C","family":"Lang","sequence":"additional","affiliation":[{"name":"Division of Molecular and Clinical Medicine, School of Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee, UK"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6553-5749","authenticated-orcid":false,"given":"Leong L","family":"Ng","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, NIHR Leicester Biomedical Research Centre, Leicester, UK"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3331-7314","authenticated-orcid":false,"given":"Stefan D","family":"Anker","sequence":"additional","affiliation":[{"name":"Department of Cardiology (CVK) and Berlin-Brandenburg Center for Regenerative Therapies (BCRT), German Centre for Cardiovascular Research (DZHK) partner site Berlin, Charit\u00e9 - Universit\u00e4tsmedizin Berlin, Berlin, Germany"}]},{"given":"Kenneth","family":"Dickstein","sequence":"additional","affiliation":[{"name":"Cardiology Division, Stavanger University Hospital, Postboks 8100, 4068 Stavanger, Norway"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6691-8568","authenticated-orcid":false,"given":"Marco","family":"Metra","sequence":"additional","affiliation":[{"name":"Cardiology, ASST Spedali Civili and Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia, Italy"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1471-7016","authenticated-orcid":false,"given":"John G F","family":"Cleland","sequence":"additional","affiliation":[{"name":"Robertson Centre for Biostatistics, Institute of Health and Wellbeing, University of Glasgow, Glasgow Royal Infirmary, Glasgow, UK"}]},{"given":"Samani J","family":"Nilesh","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, NIHR Leicester Biomedical Research Centre, Leicester, UK"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5640-0332","authenticated-orcid":false,"given":"Gerasimos","family":"Filippatos","sequence":"additional","affiliation":[{"name":"National and Kapodistrian University of Athens, School of Medicine, Attikon University Hospital, Athens, Greece"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8186-6620","authenticated-orcid":false,"given":"Joseph-Pierre","family":"Aboumsallem","sequence":"additional","affiliation":[{"name":"Department of Cardiology, University of Groningen, University Medical Centre Groningen, Hanzeplein 1, 9713 GZ Groningen, the Netherlands"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4775-9140","authenticated-orcid":false,"given":"Rudolf A","family":"de Boer","sequence":"additional","affiliation":[{"name":"Department of Cardiology, University of Groningen, University Medical Centre Groningen, Hanzeplein 1, 9713 GZ Groningen, the Netherlands"}]},{"given":"Sylwia","family":"Figarska","sequence":"additional","affiliation":[{"name":"Department of Cardiology, University of Groningen, University Medical Centre Groningen, Hanzeplein 1, 9713 GZ Groningen, the Netherlands"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9056-7152","authenticated-orcid":false,"given":"Iziah E","family":"Sama","sequence":"additional","affiliation":[{"name":"Department of Cardiology, University of Groningen, University Medical Centre Groningen, Hanzeplein 1, 9713 GZ Groningen, the Netherlands"}]},{"given":"Adriaan A","family":"Voors","sequence":"additional","affiliation":[{"name":"Department of Cardiology, University of Groningen, University Medical Centre Groningen, Hanzeplein 1, 9713 GZ Groningen, the Netherlands"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7456-1570","authenticated-orcid":false,"given":"Faiez","family":"Zannad","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Lorraine, Inserm, Centre d'Investigation Clinique - Plurith\u00e9matique 14-33, Inserm U1116, CHRU, F-CRIN INI-CRCT (Cardiovascular and Renal Clinical Trialists), 4 rue du Morvan, Nancy 54500, France"}]}],"member":"286","published-online":{"date-parts":[[2020,10,1]]},"reference":[{"key":"2021120106391187900_cvaa279-B1","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1146\/annurev-physiol-021317-121454","article-title":"Aging in the cardiovascular system: lessons from Hutchinson-Gilford Progeria syndrome","volume":"80","author":"Hamczyk","year":"2018","journal-title":"Annu Rev Physiol"},{"key":"2021120106391187900_cvaa279-B2","doi-asserted-by":"crossref","first-page":"1614","DOI":"10.1016\/j.ehj.2004.06.038","article-title":"Quantifying the heart failure epidemic: prevalence, incidence rate, lifetime risk and prognosis of heart failure. The Rotterdam Study","volume":"25","author":"Bleumink","year":"2004","journal-title":"Eur Heart J"},{"key":"2021120106391187900_cvaa279-B3","doi-asserted-by":"crossref","first-page":"P572","DOI":"10.1016\/S0140-6736(17)32520-5","article-title":"Temporal trends and patterns in heart failure incidence: a population-based study of 4 million individuals","volume":"391","author":"Conrad","year":"2018","journal-title":"Lancet"},{"key":"2021120106391187900_cvaa279-B4","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1093\/eurjhf\/hft028","article-title":"Heart failure in elderly patients: distinctive features and unresolved issues","volume":"15","author":"Lazzarini","year":"2013","journal-title":"Eur J Heart Fail"},{"key":"2021120106391187900_cvaa279-B5","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1161\/HYPERTENSIONAHA.119.12655","article-title":"Concept of extremes in vascular aging","volume":"74","author":"Laurent","year":"2019","journal-title":"Hypertension"},{"key":"2021120106391187900_cvaa279-B6","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.ebiom.2017.03.046","article-title":"Biological age predictors","volume":"21","author":"Jylhava","year":"2017","journal-title":"EBioMedicine"},{"key":"2021120106391187900_cvaa279-B7","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1002\/ejhf.785","article-title":"Development and validation of multivariable models to predict mortality and hospitalization in patients with heart failure","volume":"19","author":"Voors","year":"2017","journal-title":"Eur J Heart Fail"},{"key":"2021120106391187900_cvaa279-B8","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1016\/j.jacc.2019.11.062","article-title":"Biological versus chronological aging: JACC focus seminar","volume":"75","author":"Hamczyk","year":"2020","journal-title":"J Am Coll Cardiol"},{"key":"2021120106391187900_cvaa279-B9","doi-asserted-by":"crossref","first-page":"716","DOI":"10.1002\/ejhf.531","article-title":"A systems BIOlogy Study to TAilored Treatment in Chronic Heart Failure: rationale, design, and baseline characteristics of BIOSTAT-CHF","volume":"18","author":"Voors","year":"2016","journal-title":"Eur J Heart Fail"},{"key":"2021120106391187900_cvaa279-B10","doi-asserted-by":"crossref","first-page":"803","DOI":"10.1093\/eurjhf\/hfs105","article-title":"ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC","volume":"14","author":"McMurray","year":"2012","journal-title":"Eur J Heart Fail"},{"key":"2021120106391187900_cvaa279-B11","doi-asserted-by":"crossref","first-page":"27","DOI":"10.2202\/1544-6115.1302","article-title":"On the operational characteristics of the Benjamini and Hochberg False Discovery Rate procedure","volume":"6","author":"Green","year":"2007","journal-title":"Stat Appl Genet Mol Biol"},{"key":"2021120106391187900_cvaa279-B12","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1002\/ejhf.1811","article-title":"A network analysis to identify pathophysiological pathways distinguishing ischaemic from non-ischaemic heart failure","volume":"22","author":"Sama","year":"2020","journal-title":"Eur J Heart Fail"},{"key":"2021120106391187900_cvaa279-B13","doi-asserted-by":"crossref","first-page":"2498","DOI":"10.1101\/gr.1239303","article-title":"Cytoscape: a software environment for integrated models of biomolecular interaction networks","volume":"13","author":"Shannon","year":"2003","journal-title":"Genome Res"},{"key":"2021120106391187900_cvaa279-B14","doi-asserted-by":"crossref","first-page":"1194","DOI":"10.1016\/j.cell.2013.05.039","article-title":"The hallmarks of aging","volume":"153","author":"Lopez-Otin","year":"2013","journal-title":"Cell"},{"key":"2021120106391187900_cvaa279-B15","doi-asserted-by":"crossref","first-page":"804","DOI":"10.1016\/j.jacc.2019.06.053","article-title":"Cardiovascular aging and heart failure: JACC review topic of the week","volume":"74","author":"Triposkiadis","year":"2019","journal-title":"J Am Coll Cardiol"},{"key":"2021120106391187900_cvaa279-B16","doi-asserted-by":"crossref","first-page":"e013754","DOI":"10.1161\/JAHA.119.013754","article-title":"Reverse cardio-oncology: cancer development in patients with cardiovascular disease","volume":"9","author":"Aboumsallem","year":"2020","journal-title":"J Am Heart Assoc"},{"key":"2021120106391187900_cvaa279-B17","doi-asserted-by":"crossref","first-page":"1515","DOI":"10.1002\/ejhf.1539","article-title":"Cancer and heart disease: associations and relations","volume":"21","author":"Boer","year":"2019","journal-title":"Eur J Heart Fail"},{"key":"2021120106391187900_cvaa279-B18","doi-asserted-by":"crossref","first-page":"844","DOI":"10.1093\/cvr\/cvz035","article-title":"Common risk factors for heart failure and cancer","volume":"115","author":"Meijers","year":"2019","journal-title":"Cardiovasc Res"},{"key":"2021120106391187900_cvaa279-B19","doi-asserted-by":"crossref","first-page":"678","DOI":"10.1161\/CIRCULATIONAHA.117.030816","article-title":"Heart failure stimulates tumor growth by circulating factors","volume":"138","author":"Meijers","year":"2018","journal-title":"Circulation"},{"key":"2021120106391187900_cvaa279-B20","first-page":"165","article-title":"The biology of erbB-2\/neu\/HER-2 and its role in cancer","volume":"1198","author":"Hynes","year":"1994","journal-title":"Biochim Biophys Acta"},{"key":"2021120106391187900_cvaa279-B21","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1007\/s00395-016-0576-z","article-title":"ErbB2 signaling at the crossing between heart failure and cancer","volume":"111","author":"Vermeulen","year":"2016","journal-title":"Basic Res Cardiol"},{"key":"2021120106391187900_cvaa279-B22","doi-asserted-by":"crossref","first-page":"2242","DOI":"10.1038\/leu.2016.173","article-title":"A germline ERBB3 variant is a candidate for predisposition to erythroid MDS\/erythroleukemia","volume":"30","author":"Braunstein","year":"2016","journal-title":"Leukemia"},{"key":"2021120106391187900_cvaa279-B23","doi-asserted-by":"crossref","first-page":"18748","DOI":"10.1074\/jbc.M311227200","article-title":"Characterization of a novel C-type lectin-like gene, LSECtin: demonstration of carbohydrate binding and expression in sinusoidal endothelial cells of liver and lymph node","volume":"279","author":"Liu","year":"2004","journal-title":"J Biol Chem"},{"key":"2021120106391187900_cvaa279-B24","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1161\/01.CIR.0000048894.99865.02","article-title":"Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises: part III: cellular and molecular clues to heart and arterial aging","volume":"107","author":"Lakatta","year":"2003","journal-title":"Circulation"},{"key":"2021120106391187900_cvaa279-B25","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1186\/s13048-017-0329-0","article-title":"WAP four-disulfide core domain protein 2 promotes metastasis of human ovarian cancer by regulation of metastasis-associated genes","volume":"10","author":"Chen","year":"2017","journal-title":"J Ovarian Res"},{"key":"2021120106391187900_cvaa279-B26","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1038\/s41586-019-0992-y","article-title":"Colonic epithelial cell diversity in health and inflammatory bowel disease","volume":"567","author":"Parikh","year":"2019","journal-title":"Nature"},{"key":"2021120106391187900_cvaa279-B27","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1515\/med-2016-0024","article-title":"The diagnosis and pathological value of combined detection of HE4 and CA125 for patients with ovarian cancer","volume":"11","author":"Zheng","year":"2016","journal-title":"Open Med (Wars)"},{"key":"2021120106391187900_cvaa279-B28","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1016\/j.jchf.2012.11.005","article-title":"The WAP four-disulfide core domain protein HE4: a novel biomarker for heart failure","volume":"1","author":"de Boer","year":"2013","journal-title":"JACC Heart Fail"},{"key":"2021120106391187900_cvaa279-B29","doi-asserted-by":"crossref","first-page":"4991","DOI":"10.4049\/jimmunol.164.10.4991","article-title":"Cutting edge: inflammatory responses can be triggered by TREM-1, a novel receptor expressed on neutrophils and monocytes","volume":"164","author":"Bouchon","year":"2000","journal-title":"J Immunol"},{"key":"2021120106391187900_cvaa279-B30","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1055\/s-0039-3400746","article-title":"Interruption of the CXCL13\/CXCR5 chemokine axis enhances plasma IgM levels and attenuates atherosclerosis development","volume":"120","author":"van der Vorst","year":"2020","journal-title":"Thromb Haemost"},{"key":"2021120106391187900_cvaa279-B31","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1016\/j.atherosclerosis.2012.06.071","article-title":"Increased levels of the homeostatic chemokine CXCL13 in human atherosclerosis\u2014potential role in plaque stabilization","volume":"224","author":"Smedbakken","year":"2012","journal-title":"Atherosclerosis"},{"key":"2021120106391187900_cvaa279-B32","doi-asserted-by":"crossref","first-page":"2761","DOI":"10.1038\/s41598-017-03062-8","article-title":"Identification of 15 novel risk loci for coronary artery disease and genetic risk of recurrent events, atrial fibrillation and heart failure","volume":"7","author":"Verweij","year":"2017","journal-title":"Sci Rep"},{"key":"2021120106391187900_cvaa279-B33","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1007\/s12015-014-9571-7","article-title":"Transmyocardial revascularization enhances bone marrow stem cell engraftment in infarcted hearts through SCF-C-kit and SDF-1-CXCR4 signaling axes","volume":"11","author":"Shahzad","year":"2015","journal-title":"Stem Cell Rev and Rep"}],"container-title":["Cardiovascular Research"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/cardiovascres\/advance-article-pdf\/doi\/10.1093\/cvr\/cvaa279\/34160667\/cvaa279.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/cardiovascres\/article-pdf\/117\/10\/2228\/41325721\/cvaa279.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/cardiovascres\/article-pdf\/117\/10\/2228\/41325721\/cvaa279.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,12,1]],"date-time":"2021-12-01T10:16:41Z","timestamp":1638353801000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/cardiovascres\/article\/117\/10\/2228\/5917017"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,10,1]]},"references-count":33,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2020,10,1]]},"published-print":{"date-parts":[[2021,8,29]]}},"URL":"https:\/\/doi.org\/10.1093\/cvr\/cvaa279","relation":{},"ISSN":["0008-6363","1755-3245"],"issn-type":[{"type":"print","value":"0008-6363"},{"type":"electronic","value":"1755-3245"}],"subject":[],"published-other":{"date-parts":[[2021,9,1]]},"published":{"date-parts":[[2020,10,1]]}}}