Soluble Urokinase Plasminogen Activator Receptor as a Diagnostic and Prognostic Biomarker in Cardiac Disease

Dimitrios Velissaris, Nicholas Zareifopoulos, Ioanna Koniari, Vasilios Karamouzos, Dimitris Bousis, Andreas Gerakaris, Christina Platanaki, Nicholas Kounis, Dimitrios Velissaris, Nicholas Zareifopoulos, Ioanna Koniari, Vasilios Karamouzos, Dimitris Bousis, Andreas Gerakaris, Christina Platanaki, Nicholas Kounis

Abstract

This review summarizes the published literature referring to the use and validity of the biomarker soluble urokinase plasminogen activator receptor (suPAR) when used for the assessment of patients with cardiac diseases. It is measured by enzyme-linked immunosorbent assay (ELISA) in plasma samples. In cardiology a cut-off value range of 3.5 - 4.5 ng/mL has been commonly utilized. Different cut-off values may be applied based on the measuring kit used, the patient population and the clinical setting. A PubMed/Medline search was conducted aiming to identify all publications relevant to the use of suPAR in patients with cardiac diseases. A total of 39 studies were included in this review. suPAR as a marker of inflammation has been used more extensively in recent years, alone or in combination with other biomarkers of inflammation and cardiac pathology in the assessment of patients with acute and chronic cardiac diseases. suPAR is closely related to the pathophysiology of cardiac disease, and a number of publications encourages its use as a valuable biomarker in the assessment of patients presenting to the cardiology service. It may be most valuable in the risk assessment of patients with acute coronary syndromes and congestive heart failure, as suPAR elevation may be an independent predictor of mortality in these conditions. In conclusion, among several biomarkers used for clinical entities with underlying inflammatory pathophysiology including cardiac diseases, suPAR is a novel attractive index for the prognostic risk stratification of cardiac patients. More research is warranted to confirm its diagnostic and prognostic validity, alone or combined with other cardiac and inflammatory biomarkers.

Keywords: Acute coronary syndromes; Biomarker; Cardiac disease; Congestive heart failure; Coronary artery disease; Inflammation; Ischemic heart disease; Myocardial infarction.

Conflict of interest statement

The authors declare no conflict of interest.

Copyright 2021, Velissaris et al.

Figures

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Figure 1
Review flow chart.

References

    1. Thuno M, Macho B, Eugen-Olsen J. suPAR: the molecular crystal ball. Dis Markers. 2009;27(3):157–172. doi: 10.1155/2009/504294.
    1. Eugen-Olsen J, Giamarellos-Bourboulis EJ. suPAR: The unspecific marker for disease presence, severity and prognosis. Int J Antimicrob Agents. 2015;46(Suppl 1):S33–34. doi: 10.1016/j.ijantimicag.2015.10.011.
    1. Hodges GW, Bang CN, Wachtell K, Eugen-Olsen J, Jeppesen JL. suPAR: a new biomarker for cardiovascular disease? Can J Cardiol. 2015;31(10):1293–1302. doi: 10.1016/j.cjca.2015.03.023.
    1. Velissaris D, Pierrakos C, Karamouzos V, Pantzaris ND, Gogos C. The use of soluble urokinase plasminogen activator receptor (suPAR) as a marker of sepsis in the emergency department setting. A current review. Acta Clin Belg. 2021;76(1):79–84. doi: 10.1080/17843286.2019.1653519.
    1. Velissaris D, Dimopoulos G, Parissis J, Alexiou Z, Antonakos N, Babalis D, Gerakari S. et al. Prognostic role of soluble urokinase plasminogen activator receptor at the emergency department: a position paper by the Hellenic sepsis study group. Infect Dis Ther. 2020;9(3):407–416. doi: 10.1007/s40121-020-00301-w.
    1. Enocsson H, Wettero J, Skogh T, Sjowall C. Soluble urokinase plasminogen activator receptor levels reflect organ damage in systemic lupus erythematosus. Transl Res. 2013;162(5):287–296. doi: 10.1016/j.trsl.2013.07.003.
    1. Cyrille NB, Villablanca PA, Ramakrishna H. Soluble urokinase plasminogen activation receptor—An emerging new biomarker of cardiovascular disease and critical illness. Ann Card Anaesth. 2016;19(2):214–216. doi: 10.4103/0971-9784.179588.
    1. Hayek SS, Sever S, Ko YA, Trachtman H, Awad M, Wadhwani S, Altintas MM. et al. Soluble urokinase receptor and chronic kidney disease. N Engl J Med. 2015;373(20):1916–1925. doi: 10.1056/NEJMoa1506362.
    1. Backes Y, van der Sluijs KF, Mackie DP, Tacke F, Koch A, Tenhunen JJ, Schultz MJ. Usefulness of suPAR as a biological marker in patients with systemic inflammation or infection: a systematic review. Intensive Care Med. 2012;38(9):1418–1428. doi: 10.1007/s00134-012-2613-1.
    1. Lyngbaek S, Marott JL, Moller DV, Christiansen M, Iversen KK, Clemmensen PM, Eugen-Olsen J. et al. Usefulness of soluble urokinase plasminogen activator receptor to predict repeat myocardial infarction and mortality in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous intervention. Am J Cardiol. 2012;110(12):1756–1763. doi: 10.1016/j.amjcard.2012.08.008.
    1. Lyngbaek S, Andersson C, Marott JL, Moller DV, Christiansen M, Iversen KK, Clemmensen P. et al. Soluble urokinase plasminogen activator receptor for risk prediction in patients admitted with acute chest pain. Clin Chem. 2013;59(11):1621–1629. doi: 10.1373/clinchem.2013.203778.
    1. Wlazel RN, Migala M, Zielinska M, Pawlicki L, Rosniak-Bak K, Szadkowska I. Soluble urokinase plasminogen activator receptor in one-year prediction of major adverse cardiac events in patients after first myocardial infarction treated with primary percutaneous coronary intervention. Arch Med Sci. 2019;15(1):72–77. doi: 10.5114/aoms.2016.63596.
    1. Sorensen NA, Donmez G, Neumann JT, Nikorowitsch J, Rubsamen N, Blankenberg S, Westermann D. et al. Diagnostic value of soluble urokinase-type plasminogen activator receptor in addition to high-sensitivity troponin I in early diagnosis of acute myocardial infarction. Biomolecules. 2019;9(3):108. doi: 10.3390/biom9030108.
    1. Sorensen NA, Nikorowitsch J, Neumann JT, Rubsamen N, Gossling A, Hartikainen TS, Blankenberg S. et al. Predictive value of soluble urokinase-type plasminogen activator receptor for mortality in patients with suspected myocardial infarction. Clin Res Cardiol. 2019;108(12):1386–1393. doi: 10.1007/s00392-019-01475-1.
    1. Schernthaner C, Lichtenauer M, Wernly B, Paar V, Pistulli R, Rohm I, Jung C. et al. Multibiomarker analysis in patients with acute myocardial infarction. Eur J Clin Invest. 2017;47(9):638–648. doi: 10.1111/eci.12785.
    1. Eapen DJ, Manocha P, Ghasemzadeh N, Patel RS, Al Kassem H, Hammadah M, Veledar E. et al. Soluble urokinase plasminogen activator receptor level is an independent predictor of the presence and severity of coronary artery disease and of future adverse events. J Am Heart Assoc. 2014;3(5):e001118. doi: 10.1161/JAHA.114.001118.
    1. Rasmussen LJ, Knudsen A, Katzenstein TL, Gerstoft J, Obel N, Jorgensen NR, Kronborg G. et al. Soluble urokinase plasminogen activator receptor (suPAR) is a novel, independent predictive marker of myocardial infarction in HIV-1-infected patients: a nested case-control study. HIV Med. 2016;17(5):350–357. doi: 10.1111/hiv.12315.
    1. Mehta A, Desai SR, Ko YA, Liu C, Dhindsa DS, Nayak A, Hooda A. et al. Sex differences in circulating soluble urokinase-type plasminogen activator receptor (suPAR) levels and adverse outcomes in coronary artery disease. J Am Heart Assoc. 2020;9(5):e015457. doi: 10.1161/JAHA.119.015457.
    1. Kruger R, Schutte R, Huisman HW, Hindersson P, Olsen MH, Eugen-Olsen J, Schutte AE. NT-proBNP, C-reactive protein and soluble uPAR in a bi-ethnic male population: the SAfrEIC study. PLoS One. 2013;8(3):e58506. doi: 10.1371/journal.pone.0058506.
    1. Huang Y, Zhou H, Wu Y, Yang Y, Li W, Lu J, Hu Y. Soluble urokinase plasminogen activator receptor and the risk of coronary artery disease in young Chinese patients. Dis Markers. 2017;2017:4719403. doi: 10.1155/2017/4719403.
    1. Mirna M, Lichtenauer M, Wernly B, Paar V, Jung C, Kretzschmar D, Uhlemann M. et al. Novel cardiovascular biomarkers in patients with cardiovascular diseases undergoing intensive physical exercise. Panminerva Med. 2020;62(3):135–142. doi: 10.23736/S0031-0808.20.03838-0.
    1. Ghasemzedah N, Hayek SS, Ko YA, Eapen DJ, Patel RS, Manocha P, Al Kassem H. et al. Pathway-specific aggregate biomarker risk score is associated with burden of coronary artery disease and predicts near-term risk of myocardial infarction and death. Circ Cardiovasc Qual Outcomes. 2017;10(3):e001493. doi: 10.1161/CIRCOUTCOMES.115.001493.
    1. Lyngbaek S, Marott JL, Sehestedt T, Hansen TW, Olsen MH, Andersen O, Linneberg A. et al. Cardiovascular risk prediction in the general population with use of suPAR, CRP, and Framingham Risk Score. Int J Cardiol. 2013;167(6):2904–2911. doi: 10.1016/j.ijcard.2012.07.018.
    1. Frary CE, Blicher MK, Olesen TB, Stidsen JV, Greve SV, Vishram-Nielsen JK, Rasmussen SL. et al. Circulating biomarkers for long-term cardiovascular risk stratification in apparently healthy individuals from the MONICA 10 cohort. Eur J Prev Cardiol. 2020;27(6):570–578. doi: 10.1177/2047487319885457.
    1. Isola G, Polizzi A, Alibrandi A, Williams RC, Leonardi R. Independent impact of periodontitis and cardiovascular disease on elevated soluble urokinase-type plasminogen activator receptor (suPAR) levels. J Periodontol. 2020 doi: 10.1002/JPER.20-0242.
    1. Wu W, Cui Y, Hu J, Liao R, Li S, Mo L, Xu L. et al. Soluble urokinase plasminogen activator receptor is associated with coronary artery calcification and cardiovascular disease in patients undergoing hemodialysis. Kidney Blood Press Res. 2018;43(3):664–672. doi: 10.1159/000489623.
    1. Sorensen MH, Gerke O, Eugen-Olsen J, Munkholm H, Lambrechtsen J, Sand NP, Mickley H. et al. Soluble urokinase plasminogen activator receptor is in contrast to high-sensitive C-reactive-protein associated with coronary artery calcifications in healthy middle-aged subjects. Atherosclerosis. 2014;237(1):60–66. doi: 10.1016/j.atherosclerosis.2014.08.035.
    1. Mekonnen G, Corban MT, Hung OY, Eshtehardi P, Eapen DJ, Al-Kassem H, Rasoul-Arzrumly E. et al. Plasma soluble urokinase-type plasminogen activator receptor level is independently associated with coronary microvascular function in patients with non-obstructive coronary artery disease. Atherosclerosis. 2015;239(1):55–60. doi: 10.1016/j.atherosclerosis.2014.12.025.
    1. Jirak P, Mirna M, Wernly B, Paar V, Thieme M, Betge S, Franz M. et al. Analysis of novel cardiovascular biomarkers in patients with peripheral artery disease. Minerva Med. 2018;109(6):443–450. doi: 10.23736/S0026-4806.18.05628-8.
    1. Samman Tahhan A, Hayek SS, Sandesara P, Hajjari J, Hammadah M, O'Neal WT, Kelli HM. et al. Circulating soluble urokinase plasminogen activator receptor levels and peripheral arterial disease outcomes. Atherosclerosis. 2017;264:108–114. doi: 10.1016/j.atherosclerosis.2017.06.019.
    1. van den Berg VJ, Bouwens E, Umans V, de Maat M, Manintveld OC, Caliskan K, Constantinescu AA. et al. Longitudinally measured fibrinolysis factors are strong predictors of clinical outcome in patients with chronic heart failure: the Bio-SHiFT study. Thromb Haemost. 2019;119(12):1947–1955. doi: 10.1055/s-0039-1696973.
    1. Koller L, Stojkovic S, Richter B, Sulzgruber P, Potolidis C, Liebhart F, Mortl D. et al. Soluble urokinase-type plasminogen activator receptor improves risk prediction in patients with chronic heart failure. JACC Heart Fail. 2017;5(4):268–277. doi: 10.1016/j.jchf.2016.12.008.
    1. Fujisaka T, Fujita SI, Maeda D, Shibata K, Takahashi H, Morita H, Takeda Y. et al. Association between suPAR and cardiac diastolic dysfunction among patients with preserved ejection fraction. Heart Vessels. 2017;32(11):1327–1336. doi: 10.1007/s00380-017-1002-7.
    1. Theilade S, Rossing P, Eugen-Olsen J, Jensen JS, Jensen MT. suPAR level is associated with myocardial impairment assessed with advanced echocardiography in patients with type 1 diabetes with normal ejection fraction and without known heart disease or end-stage renal disease. Eur J Endocrinol. 2016;174(6):745–753. doi: 10.1530/EJE-15-0986.
    1. Borne Y, Persson M, Melander O, Smith JG, Engstrom G. Increased plasma level of soluble urokinase plasminogen activator receptor is associated with incidence of heart failure but not atrial fibrillation. Eur J Heart Fail. 2014;16(4):377–383. doi: 10.1002/ejhf.49.
    1. Lichtenauer M, Jirak P, Wernly B, Paar V, Rohm I, Jung C, Schernthaner C. et al. A comparative analysis of novel cardiovascular biomarkers in patients with chronic heart failure. Eur J Intern Med. 2017;44:31–38. doi: 10.1016/j.ejim.2017.05.027.
    1. Ichihara N, Miyamura M, Maeda D, Fujisaka T, Fujita SI, Morita H, Takeda Y. et al. Association between serum soluble urokinase-type plasminogen activator receptor and atrial fibrillation. J Arrhythm. 2017;33(5):469–474. doi: 10.1016/j.joa.2017.05.003.
    1. Fujita SI, Tanaka S, Maeda D, Morita H, Fujisaka T, Takeda Y, Ito T. et al. Serum soluble urokinase-type plasminogen activator receptor is associated with low left ventricular ejection fraction and elevated plasma brain-type natriuretic peptide level. PLoS One. 2017;12(1):e0170546. doi: 10.1371/journal.pone.0170546.
    1. Westin O, Rasmussen LJH, Andersen O, Buch E, Olsen JE, Friberg J. Soluble urokinase plasminogen activator receptor (suPAR) as a predictor of incident atrial fibrillation. J Atr Fibrillation. 2018;10(6):1801. doi: 10.4022/jafib.1801.
    1. Rundgren M, Lyngbaek S, Fisker H, Friberg H. The inflammatory marker suPAR after cardiac arrest. Ther Hypothermia Temp Manag. 2015;5(2):89–94. doi: 10.1089/ther.2014.0027.
    1. Jalkanen V, Vaahersalo J, Pettila V, Kurola J, Varpula T, Tiainen M, Huhtala H. et al. The predictive value of soluble urokinase plasminogen activator receptor (SuPAR) regarding 90-day mortality and 12-month neurological outcome in critically ill patients after out-of-hospital cardiac arrest. Data from the prospective FINNRESUSCI study. Resuscitation. 2014;85(11):1562–1567. doi: 10.1016/j.resuscitation.2014.08.017.
    1. Hodges GW, Bang CN, Eugen-Olsen J, Olsen MH, Boman K, Ray S, Gohlke-Barwolf C. et al. SuPAR predicts cardiovascular events and mortality in patients with asymptomatic aortic stenosis. Can J Cardiol. 2016;32(12):1462–1469. doi: 10.1016/j.cjca.2016.04.012.
    1. Hodges GW, Bang CN, Eugen-Olsen J, Olsen MH, Boman K, Ray S, Kesaniemi AY. et al. SuPAR predicts postoperative complications and mortality in patients with asymptomatic aortic stenosis. Open Heart. 2018;5(1):e000743. doi: 10.1136/openhrt-2017-000743.
    1. Kruger R, Rasmussen LM, Argraves WS, Eugen-Olsen J, Nielsen OW, Blyme A, Willenheimer R. et al. Extracellular matrix biomarker, fibulin-1, is closely related to NT-proBNP and soluble urokinase plasminogen activator receptor in patients with aortic valve stenosis (the SEAS study) PLoS One. 2014;9(7):e101522. doi: 10.1371/journal.pone.0101522.
    1. Mirna M, Wernly B, Paar V, Jung C, Jirak P, Figulla HR, Kretzschmar D. et al. Multi-biomarker analysis in patients after transcatheter aortic valve implantation (TAVI) Biomarkers. 2018;23(8):773–780. doi: 10.1080/1354750X.2018.1499127.
    1. Intzilakis T, Hartmann G, Mouridsen MR, Eugen-Olsen J, Kumarathurai P, Madsbad S, Almdal TP. et al. Soluble urokinase plasminogen activator receptor, C-reactive protein and triglyceride are associated with heart rate variability in non-diabetic Danes. Eur J Clin Invest. 2013;43(5):457–468. doi: 10.1111/eci.12070.
    1. Persson M, Ostling G, Smith G, Hamrefors V, Melander O, Hedblad B, Engstrom G. Soluble urokinase plasminogen activator receptor: a risk factor for carotid plaque, stroke, and coronary artery disease. Stroke. 2014;45(1):18–23. doi: 10.1161/STROKEAHA.113.003305.
    1. Sehestedt T, Lyngbaek S, Eugen-Olsen J, Jeppesen J, Andersen O, Hansen TW, Linneberg A. et al. Soluble urokinase plasminogen activator receptor is associated with subclinical organ damage and cardiovascular events. Atherosclerosis. 2011;216(1):237–243. doi: 10.1016/j.atherosclerosis.2011.01.049.

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