suPAR as a biomarker for cardiovascular disease

The suPAR level is elevated in patients with cardiovascular diseases as compared to healthy individuals. An elevated suPAR level is associated with:

    • Atherosclerosis1
    • Ischemic heart disease2,13,21
    • Poor prognosis2,16,18,19
    • Venous thromboembolism20

As well as the 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 the 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. An accumulation of uPAR in the atheroma has also been found3. uPAR plays a role in the coagulation cascade during plasminogen activation and fibrinolysis4. 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

Use of suPAR in monitoring ambulant cardiologic patients

Cardiovascular diseases have an impact on patients, populations, and health systems and generate substantial healthcare costs, driven by hospitalization and the post-event monitoring of patients that went through a cardiovascular event.

Those ambulatory check-ups play a crucial role in assessing the current state of the patient’s health and monitoring the potential risk for future cardiovascular events, which differs from patient to patient. Some have a higher risk and require to be monitored more frequently. Others have a lower risk and won’t need as many check-ups.

With the current procedures, disregarding variations in individual risk profiles, the financial and human resources are allocated uniformly amongst those groups which is a result of uncertainty regarding future patient outcomes. That imposes unnecessary costs. That is where incorporation of suPAR can be extremely beneficial to recognize patients’ risk and facilitate better-informed, more tailored resource allocation to different risk groups. That will significantly reduce the expenses of hospitals and increase the quality of patient care by committing more to patients that need medical attention.

A simple measure of the suPAR level in a cardiologic patient’s blood during ambulatory check-ups can indicate the risk of negative health outcomes. As it is widely known, soluble urokinase plasminogen activator receptor (suPAR) is an immune-derived mediator of kidney disease, and its levels are strongly associated with cardiovascular outcomes.

According to the finding of the study conducted by Hindy et al. increased suPAR levels were causally linked to atherosclerotic phenotypes in the UK Biobank, notably coronary artery disease, myocardial infarction, and peripheral arterial disease in addition to kidney disease. It was found that cardiovascular patients with elevated suPAR are more likely to have adverse outcomes such as new cardiovascular diseases, chronic kidney diseases, and cardiovascular death in the coming years.

By integrating suPAR measurements into ambulatory check-ups, healthcare providers can identify patients at higher risk of adverse outcomes. This allows for a more efficient allocation of resources, ensuring that individuals requiring increased medical attention receive the necessary care while patients with lower risks undergo fewer unnecessary check-ups. Implementing suPAR as a risk stratification tool will potentially reduce hospital expenses while enhancing the quality of patient care.

“There is a potential for suPAR to be among the biomarkers that we measure to create a strategy for personalizing care for individual patients. We could use it to differentiate between admitted patients who are at low and high risk of worsening heart failure. Then we could better allocate post-discharge resources to those at higher risk, which would lessen the cost burden of managing disease. There are many potential opportunities to use suPAR to improve care.”

Arshed Ali Quyyumi, M.D., FACC
Director of the Emory Clinical Cardiovascular Institute and
Professor of medicine in the Division of Cardiology at Emory University School of Medicine

Article from Health Lab from Michigan Medicine website, 2022

NEW ONE-PAGER: The use of suPAR in monitoring of ambulant cardiologic patients

Cardiovascular patients with elevated suPAR are more likely to adverse outcomes in coming years.

The use of suPAR in monitoring of ambulant cardiology patients

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 the 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 six hours after 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.

High suPAR levels are associated with the incidence of venous thromboembolism20. No significant association between pulmonary embolism and suPAR was found20.

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 levels 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 six 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. The addition of suPAR improved the GRACE score, as shown by integrated discrimination improvement statistics of 0.036 (p = 0.03), suggesting further discrimination of events from non-events by the addition of suPAR24.

1. Fuhrman B. Atherosclerosis. 2012;222(1):8-14.
2. Lyngbaek S, Marott JL, Moller DV, et al. Am J Cardiol. 2012;110(12):1756-1763.
3. Edsfeldt A, Nitulescu M, Grufman H, et al. Stroke. 2012;43(12):3305-3312.
4. Blasi F, Sidenius N. FEBS Lett. 2010;584(9):1923-1930.
5. Hayek SS, Sever S, Ko YA, et al. N Engl J Med. 2015;373(20):1916-1925.
6. Borne Y, Persson M, Melander O, Smith JG, Engstrom G. Eur J Heart Fail. 2014;16(4):377-383.
7. Botha S, Fourie CM, Schutte R, Eugen-Olsen J, Pretorius R, Schutte AE. Int J Cardiol. 2015;184:631-636.
8. Sorensen MH, Gerke O, Eugen-Olsen J, et al. Atherosclerosis. 2014;237(1):60- 66.
9. Eugen-Olsen J, Andersen O, Linneberg A, et al. J Intern Med. 2010;268(3):296-308.
10. Sehestedt T, Lyngbaek S, Eugen-Olsen J, et al. Atherosclerosis. 2011;216(1):237-243.
11. Lyngbaek S, Marott JL, Sehestedt T, et al. Int J Cardiol. 2013;167(6):2904-2911.
12. Pawlak K, Mysliwiec M, Pawlak D. Thromb Res. 2008;122(3):328-335.
13. Meijers B, Poesen R, Claes K, et al. Kidney Int. 2015;87(1):210-216.
14. Pawlak K, Pawlak D, Mysliwiec M. Thromb Res. 2007;120(6):871-876.
15. Intzilakis T, Hartmann G, Mouridsen MR, et al. Eur J Clin Invest. 2013;43(5):457-468.
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.

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