{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T11:32:28Z","timestamp":1783423948505,"version":"3.54.6"},"reference-count":29,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2018,10,1]],"date-time":"2018-10-01T00:00:00Z","timestamp":1538352000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2018,10,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>BACKGROUND<\/jats:title>\n                  <jats:p>Several plasma proteins have been suggested as markers for a variety of cardiovascular conditions but fail to qualify in independent patient cohorts. This may relate to interference of medication on plasma protein concentrations. We used proteomics to identify plasma proteins that changed in concentration with heparin administration and therefore potentially may confound their evaluation as biomarkers in situations in which heparin is used.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>METHODS<\/jats:title>\n                  <jats:p>We used a proteomic approach based on isobaric tagging and nano-LC-MS\/MS analysis to quantify several hundred proteins in a discovery study in which individual plasma samples from 9 patients at intravascular ultrasound follow-up 12 months after an acute myocardial infarction before heparin administration and 2, 15, and 60 min after heparin administration; we validated our findings in 500 individual plasma samples obtained at admission from patients with suspected ST segment elevation myocardial infarction (STEMI), of whom 363 were treated with heparin before admission.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>RESULTS<\/jats:title>\n                  <jats:p>In the discovery study, 25 of 653 identified plasma proteins displayed a changed concentration after heparin administration (Bonferroni-corrected P value at P &amp;lt; 7.66 \u00d7 10\u22125). Fourteen of the proteins changed significantly among heparin-treated patients in the validation study (nominal significance level of P &amp;lt; 6.92 \u00d7 10\u22125). Among heparin-affected proteins in both the discovery study and the validation study were midkine, spondin 1, secreted frizzled-like protein 1, lipoprotein lipase, and follistatin, all previously associated with STEMI.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>CONCLUSIONS<\/jats:title>\n                  <jats:p>Medications such as heparin administration given before blood sampling may confound biomarker discovery and should be carefully considered in such studies.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1373\/clinchem.2017.282665","type":"journal-article","created":{"date-parts":[[2018,8,16]],"date-time":"2018-08-16T09:34:36Z","timestamp":1534412076000},"page":"1474-1484","source":"Crossref","is-referenced-by-count":25,"title":["Proteomic Discovery and Validation of the Confounding Effect of Heparin Administration on the Analysis of Candidate Cardiovascular Biomarkers"],"prefix":"10.1093","volume":"64","author":[{"given":"Hans C","family":"Beck","sequence":"first","affiliation":[{"name":"Department of Clinical Biochemistry and Pharmacology"},{"name":"Centre for Clinical Proteomics"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisette O","family":"Jensen","sequence":"first","affiliation":[{"name":"Department of Cardiology"},{"name":"Center for Individualized Medicine in Arterial Diseases, Odense University Hospital, University of Southern Denmark, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charlotte","family":"Gils","sequence":"first","affiliation":[{"name":"Department of Clinical Biochemistry and Pharmacology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Albertine M M","family":"Ilondo","sequence":"first","affiliation":[{"name":"Department of Clinical Biochemistry and Pharmacology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Frydland","sequence":"first","affiliation":[{"name":"Heart Center, Copenhagen University Hospital, Rigshospitalet, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Hassager","sequence":"first","affiliation":[{"name":"Heart Center, Copenhagen University Hospital, Rigshospitalet, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ole K","family":"M\u00f8ller-Helgestad","sequence":"first","affiliation":[{"name":"Department of Cardiology"},{"name":"Center for Individualized Medicine in Arterial Diseases, Odense University Hospital, University of Southern Denmark, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacob E","family":"M\u00f8ller","sequence":"first","affiliation":[{"name":"Department of Cardiology"},{"name":"Center for Individualized Medicine in Arterial Diseases, Odense University Hospital, University of Southern Denmark, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lars M","family":"Rasmussen","sequence":"first","affiliation":[{"name":"Department of Clinical Biochemistry and Pharmacology"},{"name":"Centre for Clinical Proteomics"},{"name":"Center for Individualized Medicine in Arterial Diseases, Odense University Hospital, University of Southern Denmark, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2018,10,1]]},"reference":[{"key":"2020022606053775500_B1","doi-asserted-by":"crossref","first-page":"S48","DOI":"10.5301\/jva.5000376","article-title":"New technology: heparin and antimicrobial-coated catheters","volume":"16","author":"Ibeas-Lopez","year":"2015","journal-title":"J Vasc Access"},{"key":"2020022606053775500_B2","doi-asserted-by":"crossref","first-page":"526","DOI":"10.1373\/clinchem.2010.152702","article-title":"Profile of serum pregnancy-associated plasma protein A after sustained subcutaneous low molecular weight heparin administration in patients with cerebrovascular diseases","volume":"57","author":"Wang","year":"2011","journal-title":"Clin Chem"},{"key":"2020022606053775500_B3","doi-asserted-by":"crossref","first-page":"1214","DOI":"10.1373\/clinchem.2008.108738","article-title":"Intravenous administration of low molecular weight and unfractionated heparin elicits a rapid increase in serum pregnancy-associated plasma protein A","volume":"55","author":"Tertti","year":"2009","journal-title":"Clin Chem"},{"key":"2020022606053775500_B4","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1016\/j.clinbiochem.2004.10.015","article-title":"Circulating pregnancy-associated plasma protein A is not an early marker of acute myocardial infarction","volume":"38","author":"Dominguez-Rodriguez","year":"2005","journal-title":"Clin Biochem"},{"key":"2020022606053775500_B5","doi-asserted-by":"crossref","first-page":"1022","DOI":"10.1056\/NEJMoa003147","article-title":"Pregnancy-associated plasma protein A as a marker of acute coronary syndromes","volume":"345","author":"Bayes-Genis","year":"2001","journal-title":"N Engl J Med"},{"key":"2020022606053775500_B6","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1067\/mlc.2001.117666","article-title":"Lipoprotein lipase during continuous heparin infusion: tissue stores become partially depleted","volume":"138","author":"Nasstrom","year":"2001","journal-title":"J Lab Clin Med"},{"key":"2020022606053775500_B7","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.atherosclerosis.2008.03.026","article-title":"Osteoprotegerin released from the vascular wall by heparin mainly derives from vascular smooth muscle cells","volume":"201","author":"Nybo","year":"2008","journal-title":"Atherosclerosis"},{"key":"2020022606053775500_B8","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1161\/CIRCULATIONAHA.116.021803","article-title":"Aptamer-based proteomic profiling reveals novel candidate biomarkers and pathways in cardiovascular disease","volume":"134","author":"Ngo","year":"2016","journal-title":"Circulation"},{"key":"2020022606053775500_B9","doi-asserted-by":"crossref","first-page":"M110","DOI":"10.1074\/mcp.M110.004978","article-title":"Multiplexed homogeneous proximity ligation assays for high-throughput protein biomarker research in serological material","volume":"10","author":"Lundberg","year":"2011","journal-title":"Mol Cell Proteomics"},{"key":"2020022606053775500_B10","doi-asserted-by":"crossref","first-page":"14882","DOI":"10.1038\/srep14882","article-title":"The 82-plex plasma protein signature that predicts increasing inflammation","volume":"5","author":"Tepel","year":"2015","journal-title":"Sci Rep"},{"key":"2020022606053775500_B11","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/j.cels.2016.02.015","article-title":"Plasma proteome profiling to assess human health and disease","volume":"2","author":"Geyer","year":"2016","journal-title":"Cell Syst"},{"key":"2020022606053775500_B12","article-title":"Risk factors of late cardiogenic shock and mortality in ST-segment elevation myocardial infarction patients","author":"Obling","year":"2017","journal-title":"Eur Heart J Acute Cardiovasc Care"},{"key":"2020022606053775500_B13","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1016\/j.chroma.2006.08.097","article-title":"Biological fingerprinting analysis of the interactome of a kinase inhibitor in human plasma by a chemiproteomic approach","volume":"1134","author":"Tian","year":"2006","journal-title":"J Chromatogr A"},{"key":"2020022606053775500_B14","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1016\/j.carrev.2016.11.010","article-title":"Influence of ezetimibe in addition to high-dose atorvastatin therapy on plaque composition in patients with ST-segment elevation myocardial infarction assessed by serial: intravascular ultrasound with iMap: the OCTIVUS trial","volume":"18","author":"Hougaard","year":"2017","journal-title":"Cardiovasc Revasc Med"},{"key":"2020022606053775500_B15","doi-asserted-by":"crossref","first-page":"1147","DOI":"10.1016\/j.jacc.2016.12.021","article-title":"A clinical and biomarker scoring system to predict the presence of obstructive coronary artery disease","volume":"69","author":"Ibrahim","year":"2017","journal-title":"J Am Coll Cardiol"},{"key":"2020022606053775500_B16","doi-asserted-by":"crossref","first-page":"2925","DOI":"10.1111\/bph.12601","article-title":"Measuring midkine: the utility of midkine as a biomarker in cancer and other diseases","volume":"171","author":"Jones","year":"2014","journal-title":"Br J Pharmacol"},{"key":"2020022606053775500_B17","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1016\/S0022-2143(03)00059-3","article-title":"Lower plasma levels of lipoprotein lipase after infusion of low molecular weight heparin than after administration of conventional heparin indicate more rapid catabolism of the enzyme","volume":"142","author":"Nasstrom","year":"2003","journal-title":"J Lab Clin Med"},{"key":"2020022606053775500_B18","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1038\/nbt.1899","article-title":"A pipeline that integrates the discovery and verification of plasma protein biomarkers reveals candidate markers for cardiovascular disease","volume":"29","author":"Addona","year":"2011","journal-title":"Nat Biotechnol"},{"key":"2020022606053775500_B19","doi-asserted-by":"crossref","first-page":"840","DOI":"10.1038\/hr.2016.66","article-title":"A minimally invasive endovascular rabbit model for experimental induction of progressive myocardial hypertrophy","volume":"39","author":"Tsigkas","year":"2016","journal-title":"Hypertens Res"},{"key":"2020022606053775500_B20","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1016\/j.jchf.2017.01.008","article-title":"Limited added value of circulating inflammatory biomarkers in chronic heart failure","volume":"5","author":"Nymo","year":"2017","journal-title":"JACC Heart Fail"},{"key":"2020022606053775500_B21","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1002\/ejhf.980","article-title":"Circulating proteins as predictors of incident heart failure in the elderly","volume":"20","author":"Stenemo","year":"2018","journal-title":"Eur J Heart Fail"},{"key":"2020022606053775500_B22","doi-asserted-by":"crossref","first-page":"e0133970","DOI":"10.1371\/journal.pone.0133970","article-title":"Secreted frizzled related protein 3 in chronic heart failure: analysis from the controlled rosuvastatin multinational trial in heart failure (CORONA)","volume":"10","author":"Askevold","year":"2015","journal-title":"PLoS One"},{"key":"2020022606053775500_B23","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1111\/joim.12175","article-title":"The cardiokine secreted frizzled-related protein 3, a modulator of Wnt signalling, in clinical and experimental heart failure","volume":"275","author":"Askevold","year":"2014","journal-title":"J Intern Med"},{"key":"2020022606053775500_B24","doi-asserted-by":"crossref","first-page":"1462","DOI":"10.1373\/clinchem.2009.126029","article-title":"Myeloperoxidase: a useful biomarker for cardiovascular disease risk stratification?","volume":"55","author":"Schindhelm","year":"2009","journal-title":"Clin Chem"},{"key":"2020022606053775500_B25","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1016\/j.arcmed.2011.07.004","article-title":"Long-term prognostic value of myeloperoxidase on acute coronary syndrome: a meta-analysis","volume":"42","author":"Chen","year":"2011","journal-title":"Arch Med Res"},{"key":"2020022606053775500_B26","doi-asserted-by":"crossref","first-page":"1871","DOI":"10.1161\/CIRCULATIONAHA.105.590083","article-title":"Heparins increase endothelial nitric oxide bioavailability by liberating vessel-immobilized myeloperoxidase","volume":"113","author":"Baldus","year":"2006","journal-title":"Circulation"},{"key":"2020022606053775500_B27","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/j.ijcard.2008.10.035","article-title":"Liberation of vessel adherent myeloperoxidase by enoxaparin improves endothelial function","volume":"140","author":"Rudolph","year":"2010","journal-title":"Int J Cardiol"},{"key":"2020022606053775500_B28","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/j.freeradbiomed.2009.04.004","article-title":"Neutrophil activation precedes myocardial injury in patients with acute myocardial infarction","volume":"47","author":"Goldmann","year":"2009","journal-title":"Free Radic Biol Med"},{"key":"2020022606053775500_B29","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1093\/eurheartj\/ehv320","article-title":"2015 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: Task Force for the Management of Acute Coronary Syndromes in Patients Presenting without Persistent ST-Segment Elevation of the European Society of Cardiology (ESC)","volume":"37","author":"Roffi","year":"2016","journal-title":"Eur Heart J"}],"container-title":["Clinical Chemistry"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/clinchem\/article-pdf\/64\/10\/1474\/32642945\/clinchem1474.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/clinchem\/article-pdf\/64\/10\/1474\/32642945\/clinchem1474.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,2,26]],"date-time":"2020-02-26T06:14:46Z","timestamp":1582697686000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/clinchem\/article\/64\/10\/1474\/5608616"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,10,1]]},"references-count":29,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2018,10,1]]},"published-print":{"date-parts":[[2018,10,1]]}},"URL":"https:\/\/doi.org\/10.1373\/clinchem.2017.282665","relation":{},"ISSN":["0009-9147","1530-8561"],"issn-type":[{"value":"0009-9147","type":"print"},{"value":"1530-8561","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2018,10,1]]},"published":{"date-parts":[[2018,10,1]]}}}