suPAR as a biomarker for cardiovascular disease

• • Atherosclerosis¹
  • Ischemic heart disease^2,13,21
  • Poor prognosis^2,16,18,19
  • Venous thromboembolism²⁰

As well as the incidence of:

• • Cardiovascular diseases in the general population^7-11

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 strain^5,6. 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 individuals^7-11, 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.

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 plaques^21,10. 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.