suPAR as a biomarker for cardiovascular disease
The suPAR level is elevated in patients with cardiovascular diseases compared to healthy individuals, and elevated suPAR level is associated with:
- Ischemic heart disease2,13,21
- Poor prognosis2,16,18,19
- Venous thromboembolism20
As well as incidence of:
- Cardiovascular diseases in the general population7-11
suPAR is a promising biomarker of cardiovascular diseases, as it reflects “low-grade inflammation” and is associated with lifestyle factors like smoking, alcohol, and an inactive lifestyle. Previous studies have shown, that the uPA/uPAR-system plays a key role in the pathogenesis of atherosclerosis1. Physiologically the system is involved in fibrinolysis, angiogenesis, and immune function, including leucocyte migration, proliferation, and degradation of matrix during tissue remodeling in the atherosclerotic plaque2. uPAR is expressed in various cells involved in the development of atherosclerosis, including macrophages, endothelial cells, and smooth muscle cells, and an accumulation of uPAR in the atheroma has been found3. uPAR plays a role in the coagulation cascade during plasminogen activation and fibrinolysis4. So far, no causal relationship between the uPAR system and atherosclerosis or cardiovascular diseases has been shown2. However, new data have demonstrated an association between suPAR and focal segmental glomerulosclerosis. The kidneys play a key role in blood pressure and fluid balance regulation, and therefore suPAR may be associated with heart failure and myocardial strain5,6. A similar suPAR-mediated effect on endothelial cells and platelets may potentially play a role in vascular inflammation and thrombosis5.
In five large studies, including a total of 4866 individuals7-11, suPAR is a predictor of cardiovascular morbidity and mortality in the general population even after adjustment for the well-validated Framingham risk score11 and taking into account well-known risk factors, CRP, and other biomarkers associated with cardiovascular diseases. In general, the prognostic value of baseline suPAR level appears to be strongest in the younger age groups and in males11.
In patients with ST-segment elevation myocardial infarction (STEMI) treated with primary PCI, the suPAR level is elevated the first 24 hours after admission. Following adjustment for traditional risk factors, age, sex, CRP, creatinine, troponin T, total cholesterol, diabetes, and hypertension, suPAR remains associated with mortality and a new myocardial infarction2. In non-survivors, baseline suPAR values are significantly higher than in survivors (4.9 ng/mL vs. 3.9 ng/mL), and all-cause mortality increases significantly with higher suPAR values2.
“suPAR is an early predictive marker for complications in type 1 diabetes … and is a potent risk factor in prediction of cardiovascular and renal diseases.”
Viktor Rotbain Curovic,
Dr. MD, Steno Diabetes Center Copenhagen, Denmark
suPAR News Vol. 2, Sept. 2019
Following adjustment for sex and age, suPAR was associated with an increased risk of developing atrial fibrillation. However, this association disappeared following adjustment for well-known risk factors6.
In uremic patients receiving peritoneal dialysis or hemodialysis, the suPAR level and the carotid intima-media thickness (IMT) in the two dialysis groups are significantly higher than in healthy age- and sex-matched controls, and in a smaller study, suPAR is associated with IMT12.
suPAR is also a prognostic marker of cardiovascular diseases in patients with mild to moderate chronic renal diseases, including cardiac mortality, non-fatal MI, myocardial ischemia, coronary intervention, ischemic stroke, and newly diagnosed peripheral vascular diseases13. suPAR and eGFR are comparable in estimating mortality risk, however, in this population suPAR was a stronger cardiovascular risk predictor than eGFR13.
In patients admitted with suspected acute coronary syndrome (ACS), suPAR is a strong predictor of mortality and of readmission due to heart failure and a new myocardial infarction. Thus, in non-survivors, the baseline suPAR level was significantly higher than in survivors, and, similarly, the suPAR level was higher in readmitted patients than in non-readmitted patients. The study concluded that in patients with suspected ACS, suPAR improves risk stratification beyond traditional risk factors16.
In a South African study, the baseline suPAR level was not able to predict development of hypertension, but on the other hand, a change in suPAR level was to some extent associated with increasing blood pressure during the observation period17.
In patients resuscitated from a cardiac arrest and treated with hypothermia, suPAR was studied as a potential prognostic tool. One study found that the suPAR level 6 hours after the cardiac arrest was strongly associated with mortality and neurological outcome18. Similarly, in another study, suPAR was strongly associated with mortality but not with neurological outcome19. In patients with non-shockable rhythms, the baseline suPAR level was significantly higher than in patients with shockable rhythms19.
In males and females with carotid plaques, the suPAR level is significantly higher than in individuals with no carotid plaques21,10. Similarly, suPAR is a predictor of ischemic heart disease (IHD), and in patients with both elevated suPAR level and carotid plaques, the risk of developing IHD is significantly increased21.
Following adjustment for traditional risk factors and subclinical organ damage, suPAR remains associated with cardiovascular mortality10.
Furthermore, in a study of 1126 Danes it was shown that suPAR is able to predict coronary artery calcifications in healthy individuals, as assessed by cardiac CT scan, and that suPAR is associated with calcium score8.
Surgical stress related to coronary bypass does not induce significant changes in suPAR level 6 or 24 hours postoperatively compared to the preoperative value23.
Finally, suPAR levels were determined in 1314 patients presenting to the emergency department with suspected AMI. Patients were followed up for 12 months to assess all-cause mortality. suPAR levels reliably predicted all-cause mortality after 1 year. Hazard ratio for 1- year mortality was 12.6 (p < 0.001) in the highest suPAR quartile compared to the lowest suPAR quartile24. The prognostic value for 6- months mortality was comparable to an established risk prediction model, the Global Registry of Acute Coronary Events (GRACE) score, with an AUC of 0.79 (95% CI 0.72-0.86) for the GRACE score and 0.77 (95% CI 0.69-0.84) for suPAR. Addition of suPAR improved the GRACE score, as shown by integrated discrimination improvement statistics of 0.036 (p = 0.03), suggesting a further discrimination of events from non-events by the addition of suPAR24.
2. Lyngbaek S, Marott JL, Moller DV, et al. Am J Cardiol. 2012;110(12):1756-1763.
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16. Lyngbaek S, Andersson C, Marott JL, et al. Clin Chem. 2013;59(11):1621-1629.
17. Botha S, Fourie CM, Schutte R, Eugen-Olsen J, Schutte AE. Hypertens Res. 2015;38(6):439-444.
18. Rundgren M, Lyngbaek S, Fisker H, Friberg H. Ther Hypothermia Temp Manag. 2015;5(2):89-94.
19. Jalkanen V, Vaahersalo J, Pettila V, et al. Resuscitation. 2014;85(11):1562-1567.
20. Engstrom G, Zoller B, Svensson PJ, Melander O, Persson M. Thromb Haemost. 2015;115(3).
21. Persson M, Ostling G, Smith G, et al. Stroke. 2014;45(1):18-23.
22. Mekonnen G, Corban MT, Hung OY, et al. Atherosclerosis. 2015;239(1):55-60.
23. Gozdzik W, Adamik B, Gozdzik A, Rachwalik M, Kustrzycki W, Kubler A. PLoS One. 2014;9(6):e98923.
24. Sörensen NA et al. Clin Res Cardiol.2019 doi: 10.1007/s00392-019-01475-1.