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   Introduction
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Table of Contents
EXPERT BRIEF COMMUNICATION  
Year : 2016  |  Volume : 19  |  Issue : 2  |  Page : 214-216
Soluble urokinase plasminogen activation receptor - An emerging new biomarker of cardiovascular disease and critical illness


1 Division of Cardiovascular Diseases, Montefiore Medical Center/Albert Einstein College of Medicine, New York, NY, USA
2 Division of Cardiovascular and Thoracic Anesthesiology, Mayo Clinic, Phoenix, AZ, USA

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Date of Submission20-Mar-2016
Date of Acceptance26-Mar-2016
Date of Web Publication1-Apr-2016
 

   Abstract 

Soluble urokinase plasminogen activation receptor (suPAR) is an emerging new biomarker, which has been shown to not only correlate with traditional biomarkers but also outperform CRP at prognosticating CVD. More clinical trials on suPAR is in the future research agenda.

Keywords: Biomarkers; Cardiovascular disease; Critical illness; Heart failure

How to cite this article:
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;19:214-6

How to cite this URL:
Cyrille NB, Villablanca PA, Ramakrishna H. Soluble urokinase plasminogen activation receptor - An emerging new biomarker of cardiovascular disease and critical illness. Ann Card Anaesth [serial online] 2016 [cited 2020 Aug 11];19:214-6. Available from: http://www.annals.in/text.asp?2016/19/2/214/179588



   Introduction Top


The pathogenesis of cardiovascular disease (CVD) is multifactorial. Conventional risk factors such as cigarette smoking, diabetes, hyperlipidemia, and hypertension are absent in 15-20% of patients with CVD. [1] Given the established role of chronic inflammation in patients with CVD, the identification of serum biomarkers, which may aid in early intervention and risk prediction has been of increasing importance. Biomarkers including N-terminal probrain natriuretic peptide, urine albumin/creatinine ratio, and high sensitivity C-reactive protein (CRP) have been recognized as strong predictors of adverse cardiovascular outcomes. [2],[3]

Soluble urokinase plasminogen activation receptor (suPAR) is an emerging new biomarker, which has been shown to not only correlate with traditional biomarkers but also outperform CRP at prognosticating CVD. [4],[5] Urokinase-type plasminogen activator receptor (uPAR) is a membrane-linked protein, found in several cell types including immunologic and vascular endothelial cells. It comprised three domains (D1, D2, and D3) and is anchored to the cell membrane by a glycosylphosphatidylinositol molecule attached to D3. Biologically, uPAR is involved in the regulation of atherogenesis and plays a role in cell migration, adhesion, angiogenesis, fibrinolysis, and cell proliferation. The uPAR molecule may undergo cleavage into three soluble forms (suPAR), the full-length D1 D2 D3 molecule and the fragments D1 and D2 D3. The physiologic function of suPAR is not as well understood; however, suPAR levels correlate with proinflammatory markers such as tumor necrosis factor, and it has been associated with endothelial dysfunction, neo-intimal formation of atherosclerosis, and plaque destabilization. It is also associated with conventional CVD risk factors including smoking and physical inactivity; however, unlike CRP, it has not been linked to obesity. Compared to other inflammatory markers, suPAR is not an acute phase reactant, with levels remaining stable even during acute cardiac events such as acute myocardial infarction. It exhibits limited circadian variation and generally tends to be higher in women despite lower CVD risk compared to men. [4],[6]

The Danish MONICA 10 cohort is one of the largest to be investigated for the predictive value of suPAR in CVD. In this population, an elevated suPAR level was associated with an increased risk of cancer, CVD, Type 2 diabetes mellitus, and mortality. [7] After adjustment for Framingham Risk Score (FRS) variables, women with suPAR levels in the highest tertile had a 1.74-fold (95% confidence interval [CI]: 1.08-2.81) and men had a 2.09-fold (95% CI: 1.37-3.18) increase in CVD risk compared to the lowest tertile. Inclusion of both suPAR and CRP in the model resulted in stronger risk prediction with a 3.30-fold (95% CI: 1.36-7.99) increase for women and a 3.53-fold (1.78-7.02) increase for men when both biomarkers were in the highest compared to the lowest tertile. In men, the C statistics improved significantly from 0.722 (95% CI: 0.686-0.757) when tertile levels of suPAR (0.733, 95% CI: 0.699-0.769), CRP (0.734, 95% CI: 0.699-0.769) and their combination (0.737, 95% CI: 0.703-0.772) were added to FRS. Reclassification of individuals (risk of composite outcome in 10 years of <10%, 10-20%, and >20%) measured by the net reclassification index (NRI) and integrated discrimination improvement (IDI) was profoundly improved with the addition of suPAR into the risk model for men (NRI: 51%, 95% CI: 0.240, 0.772; IDI: 1.6%, 95% CI: 0.005-0.026) and for women (NRI: 57%, 95% CI: 0.253-0.889; IDI: 1.2%, 95% CI: 0.003-0.021). Favorable, but less robust results were observed for CRP only among men (NRI: 31%, 95% CI: 0.081-0.534; IDI: 1.8%, 95% CI: 0.008-0.028). [5]

With regard to patients with established CVD, data supporting the utility of suPAR in coronary artery disease (CAD) have shown that elevated levels of plasma suPAR are associated with the presence and severity of CAD (P < 0.0001) and are independent predictors of death (hazard ratio [HR]: 2.62; P < 0.0001) and myocardial infarction (HR: 3.2; P < 0.0001). [8] This has also been proven in cerebrovascular diseases, where suPAR was associated with increased occurrence of carotid plaque HR: 1.51 (95% CI: 1.05-2.17) and increased incidence of ischemic stroke (HR: 2.21 (95% CI: 1.52-3.22). [9]

The importance of suPAR in critical illness, especially sepsis, has also garnered a lot of interest. Among critically ill patients, it appears to be of less diagnostic utility compared to other biomarkers. For instance, Koch et al. found that in a cohort of 273 critically ill patients (197 with sepsis, 73 without sepsis), suPAR levels were higher than in healthy controls. However, the area under the receiver operating characteristic curve for predicting sepsis was only 0.62 for suPAR compared to 0.86 and 0.78 for CRP and procalcitonin. On the other hand, the prognostic value of suPAR among critically ill patients is inconclusive. In the aforementioned study by Koch et al., suPAR levels correlated with disease severity scores and low levels of suPAR at hospital days 3 and 7 predicted improved Intensive Care Unit and overall survival. [10] Data from Jalkanen et al. [11] found that the highest concentration quintiles were associated with poor outcome in patients with out-patient cardiac arrest admitted to critical care units; however, suPAR alone had inadequate predictive value for poor outcome and did not associate with 12-month neurological outcome.

Based on the current literature, suPAR is a promising biomarker of chronic inflammation and subclinical organ dysfunction with proven prognostic value in CVD and critical illness. However, further research is necessary before acceptance into clinical practice, especially with regard to CVD. First, whether suPAR has a causal role in CVD or whether it is merely a marker of underlying disease is still uncertain. A better understanding of the regulation of suPAR and its interaction with other biomarkers may help explain some of the current discrepancies such as the lack of an association with obesity and the higher levels observed in women compared to men. At this time, there are also no well-validated cut-off values and no established therapies that target suPAR levels. Furthermore, the studies evaluating suPAR have been conducted in predominantly Caucasian individuals, which pose significant selection bias and limit the generalizability of findings. We will likely see more outcome data with suPAR in the future, adding to the evergrowing body of knowledge of biomarkers in cardiovascular disease and critical illness.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
   References Top

1.
Khot UN, Khot MB, Bajzer CT, Sapp SK, Ohman EM, Brener SJ, et al. Prevalence of conventional risk factors in patients with coronary heart disease. JAMA 2003;290:898-904.  Back to cited text no. 1
    
2.
McKie PM, Cataliotti A, Sangaralingham SJ, Ichiki T, Cannone V, Bailey KR, et al. Predictive utility of atrial, N-terminal pro-atrial, and N-terminal pro-B-type natriuretic peptides for mortality and cardiovascular events in the general community: A 9-year follow-up study. Mayo Clin Proc 2011;86:1154-60.  Back to cited text no. 2
    
3.
Chronic Kidney Disease Prognosis Consortium, Matsushita K, van der Velde M, Astor BC, Woodward M, Levey AS, et al. Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts: A collaborative meta-analysis. Lancet 2010;375:2073-81.  Back to cited text no. 3
[PUBMED]    
4.
Hodges GW, Bang CN, Wachtell K, Eugen-Olsen J, Jeppesen JL. suPAR: A new biomarker for cardiovascular disease? Can J Cardiol 2015;31:1293-302.  Back to cited text no. 4
    
5.
Lyngbæk S, Marott JL, Sehestedt T, Hansen TW, Olsen MH, Andersen O, et al. Cardiovascular risk prediction in the general population with use of suPAR, CRP, and Framingham Risk Score. Int J Cardiol 2013;167:2904-11.  Back to cited text no. 5
    
6.
Lyngbæk S, Sehestedt T, Marott JL, Hansen TW, Olsen MH, Andersen O, et al. CRP and suPAR are differently related to anthropometry and subclinical organ damage. Int J Cardiol 2013;167:781-5.  Back to cited text no. 6
    
7.
Eugen-Olsen J, Andersen O, Linneberg A, Ladelund S, Hansen TW, Langkilde A, et al. Circulating soluble urokinase plasminogen activator receptor predicts cancer, cardiovascular disease, diabetes and mortality in the general population. J Intern Med 2010;268:296-308.  Back to cited text no. 7
    
8.
Eapen DJ, Manocha P, Ghasemzadeh N, Patel RS, Al Kassem H, Hammadah M, 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:e001118.  Back to cited text no. 8
    
9.
Persson M, Östling G, Smith G, Hamrefors V, Melander O, Hedblad B, et al. Soluble urokinase plasminogen activator receptor: A risk factor for carotid plaque, stroke, and coronary artery disease. Stroke 2014;45:18-23.  Back to cited text no. 9
    
10.
Koch A, Voigt S, Kruschinski C, Sanson E, Dückers H, Horn A, et al. Circulating soluble urokinase plasminogen activator receptor is stably elevated during the first week of treatment in the intensive care unit and predicts mortality in critically ill patients. Crit Care 2011;15:R63.  Back to cited text no. 10
    
11.
Jalkanen V, Vaahersalo J, Pettilä V, Kurola J, Varpula T, Tiainen M, 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;85:1562-7.  Back to cited text no. 11
    

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Correspondence Address:
Harish Ramakrishna
Division of Cardiovascular and Thoracic Anesthesiology, Mayo Clinic, Phoenix, AZ
USA
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0971-9784.179588

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