{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,22]],"date-time":"2026-01-22T17:31:40Z","timestamp":1769103100625,"version":"3.49.0"},"reference-count":45,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2021,10,12]],"date-time":"2021-10-12T00:00:00Z","timestamp":1633996800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003243","name":"Ministry of Health of the Czech Republic","doi-asserted-by":"publisher","award":["NU22-01-00151"],"award-info":[{"award-number":["NU22-01-00151"]}],"id":[{"id":"10.13039\/501100003243","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003243","name":"Ministry of Health of the Czech Republic","doi-asserted-by":"publisher","award":["MH CZ - DRO IN 00023001"],"award-info":[{"award-number":["MH CZ - DRO IN 00023001"]}],"id":[{"id":"10.13039\/501100003243","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Charles University, Faculty of Medicine in Hradec Kr\u00e1lov\u00e9","award":["PROGRES Q40\/12"],"award-info":[{"award-number":["PROGRES Q40\/12"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Familial hypercholesterolemia (FH), is an autosomal dominant disorder caused by mutations in the LDLR, APOB, PCSK9, and APOE genes and is characterized by high plasma levels of total and low-density lipoprotein (LDL) cholesterol. Our study aimed to analyze the influences of two different therapies on a wide spectrum of plasma protein biomarkers of cardiovascular diseases. Plasma from FH patients under hypolipidemic therapy (N = 18; men = 8, age 55.4 \u00b1 13.1 years) and patients under combined long-term LDL apheresis\/hypolipidemic therapy (N = 14; men = 7; age 58.0 \u00b1 13.6 years) were analyzed in our study. We measured a profile of 184 cardiovascular disease (CVD) associated proteins using a proximity extension assay (PEA). Hypolipidemic therapy significantly (all p &lt; 0.01) influenced 10 plasma proteins (TM, DKK1, CCL3, CD4, PDGF subunit B, AGRP, IL18, THPO, and LOX1 decreased; ST2 increased). Under combined apheresis\/hypolipidemic treatment, 18 plasma proteins (LDLR, PCSK9, MMP-3, GDF2, CTRC, SORT1, VEGFD, IL27, CCL24, and KIM1 decreased; OPN, COL1A1, KLK6, IL4RA, PLC, TNFR1, GLO1, and PTX3 increased) were significantly affected (all p &lt; 0.006). Hypolipidemic treatment mainly affected biomarkers involved in vascular endothelial maintenance. Combined therapy influenced proteins that participate in cholesterol metabolism and inflammation.<\/jats:p>","DOI":"10.3390\/genes12101599","type":"journal-article","created":{"date-parts":[[2021,10,12]],"date-time":"2021-10-12T17:29:18Z","timestamp":1634059758000},"page":"1599","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Multiplex Protein Biomarker Profiling in Patients with Familial Hypercholesterolemia"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7167-1336","authenticated-orcid":false,"given":"Dana","family":"Dlouha","sequence":"first","affiliation":[{"name":"Center for Experimental Medicine, Institute for Clinical and Experimental Medicine, Videnska 1958\/9, 140 21 Prague, Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Milan","family":"Blaha","sequence":"additional","affiliation":[{"name":"4th Department of Internal Medicine\u2014Hematology, Faculty of Medicine in Hradec Kr\u00e1lov\u00e9, University Hospital Hradec Kr\u00e1lov\u00e9 and Charles University, 500 05 Hradec Kr\u00e1lov\u00e9, Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eva","family":"Rohlova","sequence":"additional","affiliation":[{"name":"Center for Experimental Medicine, Institute for Clinical and Experimental Medicine, Videnska 1958\/9, 140 21 Prague, Czech Republic"},{"name":"Laboratory of Gene Expression, Institute of Biotechnology CAS, BIOCEV, 252 50 Vestec, Czech Republic"},{"name":"Department of Anthropology and Human Genetics, Faculty of Science, Charles University, 120 00 Prague, Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6537-1353","authenticated-orcid":false,"given":"Jaroslav A.","family":"Hubacek","sequence":"additional","affiliation":[{"name":"Center for Experimental Medicine, Institute for Clinical and Experimental Medicine, Videnska 1958\/9, 140 21 Prague, Czech Republic"},{"name":"First Faculty of Medicine, Charles University, 128 00 Prague, Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vera","family":"Lanska","sequence":"additional","affiliation":[{"name":"Statistical Unit, Institute for Clinical and Experimental Medicine, 140 21 Prague, Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jakub","family":"Visek","sequence":"additional","affiliation":[{"name":"3rd Department of Internal Medicine\u2014Metabolism and Gerontology, Faculty of Medicine in Hradec Kr\u00e1lov\u00e9, University Hospital Hradec Kr\u00e1lov\u00e9 and Charles University, 500 05 Hradec Kr\u00e1lov\u00e9, Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8088-9919","authenticated-orcid":false,"given":"Vladimir","family":"Blaha","sequence":"additional","affiliation":[{"name":"3rd Department of Internal Medicine\u2014Metabolism and Gerontology, Faculty of Medicine in Hradec Kr\u00e1lov\u00e9, University Hospital Hradec Kr\u00e1lov\u00e9 and Charles University, 500 05 Hradec Kr\u00e1lov\u00e9, Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,10,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"574474","DOI":"10.3389\/fgene.2020.574474","article-title":"Genetics of Familial Hypercholesterolemia: New Insights","volume":"11","author":"Vrablik","year":"2020","journal-title":"Front. Genet."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"3478","DOI":"10.1093\/eurheartj\/eht273","article-title":"Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: Guidance for clinicians to prevent coronary heart disease","volume":"34","author":"Nordestgaard","year":"2013","journal-title":"Eur. Heart J."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2113","DOI":"10.1210\/jc.2015-3874","article-title":"The p.Leu167del Mutation in APOE Gene Causes Autosomal Dominant Hypercholesterolemia by Down-regulation of LDL Receptor Expression in Hepatocytes","volume":"101","author":"Cenarro","year":"2016","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_4","unstructured":"Ballantyne, C.M. (2015). Clinical evaluation for genetic and secondary causes of dyslipidemia. Clinical Lipidology: A Companion to Braunwald\u2019s Heart Disease, Elsevier. [2nd ed.]."},{"key":"ref_5","unstructured":"Jameson, J.L., Kasper, D.L., Longo, D.L., Fauci, A.S., Hauser, S.L., and Loscalzo, J. (2018). Disorders of lipoprotein metabolism. Harrison\u2019s Principles of Internal Medicine, McGraw Hill. [20th ed.]."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"818","DOI":"10.1253\/circj.CJ-10-0110","article-title":"Pleiotropic Effects of Statins-Basic Research and Clinical Perspectives","volume":"74","author":"Zhou","year":"2010","journal-title":"Circ. J."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"314283","DOI":"10.1100\/2012\/314283","article-title":"LDL-Apheresis: Technical and Clinical Aspects","volume":"2012","author":"Bambauer","year":"2012","journal-title":"Sci. World J."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"S91","DOI":"10.33549\/physiolres.933584","article-title":"Lipoprotein Apheresis in the Treatment of Dyslipidemia\u2013the Czech Republic Experience","volume":"66","author":"Blaha","year":"2017","journal-title":"Physiol. Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"3634","DOI":"10.2174\/1381612824666181025115658","article-title":"Lipoprotein Apheresis and PCSK9-Inhibitors. Impact on Atherogenic Lipoproteins and Anti-Inflammatory Mediators in Familial Hypercholesterolaemia","volume":"24","author":"Stefanutti","year":"2019","journal-title":"Curr. Pharm. Des."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1016\/j.atherosclerosissup.2017.05.037","article-title":"Analysis of circulating miRNAs in patients with familial hypercholesterolaemia treated by LDL\/Lp(a) apheresis","volume":"30","author":"Dlouha","year":"2017","journal-title":"Atheroscler. Suppl."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/j.atherosclerosissup.2017.05.002","article-title":"Antioxidant defense system in familial hypercholesterolemia and the effects of lipoprotein apheresis","volume":"30","author":"Blaha","year":"2017","journal-title":"Atheroscler. Suppl."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.transci.2005.09.001","article-title":"Rheohaemapheresis of ophthalmological diseases and diseases of the microcirculation","volume":"34","author":"Borberg","year":"2006","journal-title":"Transfus. Apher. Sci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1111\/1744-9987.12056","article-title":"Proteomic Analysis of Proteins Eliminated by Low-Density Lipoprotein Apheresis","volume":"18","author":"Yuasa","year":"2013","journal-title":"Ther. Apher. Dial."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1093\/clinchem\/18.6.499","article-title":"Estimation of the Concentration of Low-Density Lipoprotein Cholesterol in Plasma, Without Use of the Preparative Ultracentrifuge","volume":"18","author":"Friedewald","year":"1972","journal-title":"Clin. Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1016\/S0009-9120(01)00261-2","article-title":"Biochemical profile and survival in nonagenarians","volume":"34","author":"Solichova","year":"2001","journal-title":"Clin. Biochem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1016\/S0021-9150(00)00371-3","article-title":"The rebound of lipoproteins after LDL-apheresis. Kinetics and estimation of mean lipoprotein levels","volume":"152","author":"Kroon","year":"2000","journal-title":"Atherosclerosis"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Assarsson, E., Lundberg, M., Holmquist, G., Bj\u00f6rkesten, J., Thorsen, S.B., Ekman, D., Eriksson, A., Dickens, E.R., Ohlsson, S., and Edfeldt, G. (2014). Homogenous 96-Plex PEA Immunoassay Exhibiting High Sensitivity, Specificity, and Excellent Scalability. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0095192"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e102","DOI":"10.1093\/nar\/gkr424","article-title":"Homogeneous antibody-based proximity extension assays provide sensitive and specific detection of low-abundant proteins in human blood","volume":"39","author":"Lundberg","year":"2011","journal-title":"Nucleic Acids Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1155\/2018\/8598054","article-title":"Cardiovascular Outcomes of PCSK9 Inhibitors: With Special Emphasis on Its Effect beyond LDL-Cholesterol Lowering","volume":"2018","author":"Bandyopadhyay","year":"2018","journal-title":"J. Lipids"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1124\/mol.112.078915","article-title":"Cholesterol-Lowering Drugs Inhibit Lectin-Like Oxidized Low-Density Lipoprotein-1 Receptor Function by Membrane Raft Disruption","volume":"82","author":"Matarazzo","year":"2012","journal-title":"Mol. Pharmacol."},{"key":"ref_21","first-page":"955","article-title":"Vascular endothelial growth factor-D is overexpressed in human cardiac allograft vasculopathy and diabetic atherosclerosis and induces endothelial permeability to low-density lipoproteins in vitro","volume":"30","author":"Wong","year":"2011","journal-title":"J. Hear. Lung Transplant."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s11883-015-0496-7","article-title":"Sortilin, Encoded by the Cardiovascular Risk Gene SORT1, and Its Suggested Functions in Cardiovascular Disease","volume":"17","author":"Kjolby","year":"2015","journal-title":"Curr. Atheroscler. Rep."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1016\/j.gendis.2019.08.003","article-title":"Highly expressed BMP9\/GDF2 in postnatal mouse liver and lungs may account for its pleiotropic effects on stem cell differentiation, angiogenesis, tumor growth and metabolism","volume":"7","author":"Liu","year":"2020","journal-title":"Genes Dis."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"742","DOI":"10.1161\/ATVBAHA.113.301655","article-title":"Chemokines in Atherosclerosis","volume":"34","author":"Zernecke","year":"2014","journal-title":"Arter. Thromb. Vasc. Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1016\/j.atherosclerosis.2005.11.013","article-title":"Plasma interleukin (IL)-18 concentrations is elevated in patients with previous myocardial infarction and related to severity of coronary atherosclerosis independently of C-reactive protein and IL-6","volume":"188","author":"Hulthe","year":"2006","journal-title":"Atherosclerosis"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/j.pharmthera.2011.02.005","article-title":"The IL-33\/ST2 pathway\u2014A new therapeutic target in cardiovascular disease","volume":"131","author":"Miller","year":"2011","journal-title":"Pharmacol. Ther."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Gregersen, I., Sandanger, \u00d8., Askevold, E.T., Sagen, E.L., Yang, K., Holm, S., Pedersen, T.M., Skjelland, M., Krohg-S\u00f8rensen, K., and Hansen, T.V. (2017). Interleukin 27 is increased in carotid atherosclerosis and promotes NLRP3 inflammasome activation. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0188387"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1260","DOI":"10.1136\/annrheumdis-2019-215119","article-title":"Blockade of CCL24 with a monoclonal antibody ameliorates experimental dermal and pulmonary fibrosis","volume":"78","author":"Mor","year":"2019","journal-title":"Ann. Rheum. Dis."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1016\/j.nefro.2018.08.004","article-title":"Rapid decline of kidney function in diabetic kidney disease is associated with high soluble Klotho levels","volume":"39","author":"Bob","year":"2019","journal-title":"Nefrolog\u00eda"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"11974","DOI":"10.1038\/s41598-019-47908-9","article-title":"Mechanism of Interleukin-4 Reducing Lipid Deposit by Regulating Hormone-Sensitive Lipase","volume":"9","author":"Shiau","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1016\/S0021-9150(03)00298-3","article-title":"Plasma osteopontin levels are associated with the presence and extent of coronary artery disease","volume":"170","author":"Ohmori","year":"2003","journal-title":"Atherosclerosis"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1087","DOI":"10.1161\/01.ATV.0000261548.49790.63","article-title":"Expression of Tumor Necrosis Factor Receptor-1 in Arterial Wall Cells Promotes Atherosclerosis","volume":"27","author":"Zhang","year":"2007","journal-title":"Arter. Thromb. Vasc. Biol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1186\/s12979-016-0080-1","article-title":"The inflammatory protein Pentraxin 3 in cardiovascular disease","volume":"13","author":"Fornai","year":"2016","journal-title":"Immun. Ageing"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Scarisbrick, I.A., Epstein, B., Cloud-Biebl, B., Yoon, H., Wu, J., Renner, D.N., Blaber, S.I., Blaber, M., Vandell, A.G., and Bryson, A.L. (2011). Functional Role of Kallikrein 6 in Regulating Immune Cell Survival. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0018376"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.vph.2006.06.012","article-title":"Statins and the endothelium","volume":"46","author":"Ii","year":"2007","journal-title":"Vasc. Pharmacol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1016\/S0021-9150(00)00729-2","article-title":"Cross-sectional association of soluble thrombomodulin with mild peripheral artery disease; The ARIC study","volume":"157","author":"Salomaa","year":"2001","journal-title":"Atherosclerosis"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1178","DOI":"10.3346\/jkms.2011.26.9.1178","article-title":"A Novel Biomarker of Coronary Atherosclerosis: Serum DKK1 Concentration Correlates with Coronary Artery Calcification and Atherosclerotic Plaques","volume":"26","author":"Kim","year":"2011","journal-title":"J. Korean Med. Sci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1079","DOI":"10.1016\/S0140-6736(96)05190-2","article-title":"Statins do more than just lower cholesterol","volume":"348","author":"Vaughan","year":"1996","journal-title":"Lancet"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1608","DOI":"10.1093\/eurheartj\/ehx107","article-title":"Statins and secondary prevention of venous thromboembolism: Pooled analysis of published observational cohort studies","volume":"38","author":"Kunutsor","year":"2017","journal-title":"Eur. Heart J."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1002\/clc.4960240511","article-title":"Thrombopoietin and mean platelet volume in coronary artery disease","volume":"24","author":"Ileri","year":"2001","journal-title":"Clin. Cardiol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1617","DOI":"10.1016\/j.stemcr.2017.04.025","article-title":"Inhibition of KLF4 by Statins Reverses Adriamycin-Induced Metastasis and Cancer Stemness in Osteosarcoma Cells","volume":"8","author":"Li","year":"2017","journal-title":"Stem Cell Rep."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12916-019-1469-4","article-title":"Multi-level transcriptome sequencing identifies COL1A1 as a candidate marker in human heart failure progression","volume":"18","author":"Hua","year":"2020","journal-title":"BMC Med."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1016\/j.cardiores.2004.03.028","article-title":"The role of perlecan in arterial injury and angiogenesis","volume":"63","author":"Segev","year":"2004","journal-title":"Cardiovasc. Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1042\/BST20140001","article-title":"Methylglyoxal and glyoxalase I in atherosclerosis","volume":"42","author":"Hanssen","year":"2014","journal-title":"Biochem. Soc. Trans."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"770","DOI":"10.1038\/ijo.2014.192","article-title":"IGFBP-2 inhibits adipogenesis and lipogenesis in human visceral, but not subcutaneous, adipocytes","volume":"39","author":"Yau","year":"2015","journal-title":"Int. J. Obes."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/12\/10\/1599\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:11:54Z","timestamp":1760166714000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/12\/10\/1599"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10,12]]},"references-count":45,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2021,10]]}},"alternative-id":["genes12101599"],"URL":"https:\/\/doi.org\/10.3390\/genes12101599","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,10,12]]}}}