Our study established that a higher level of ST2 was a significant and independent predictor of cardiovascular events. In our study, we found that higher concentrations of ST2 (≥19ng/ml) were associated with an increased risk of MACEs and all-cause death in patients with CAD. Higher concentrations of ST2 remained an independent indicator of MACEs and all-cause mortality after adjusting for established traditional risk factors for cardiovascular disease. Furthermore, our study confirmed the incremental prognostic value of ST2 for MACEs and all-cause mortality beyond the clinical model. In the subgroup analysis depending on diabetes status, ST2 remained a significant predictor of MACEs and all-cause death in patients with and without T2DM after adjusting for age, sex and other confounders. In summary, our results suggest that the addition of plasma ST2 measurements to established cardiovascular risk factors may further improve risk stratification in patients with CAD and our results provide updated information on the long-term prognostic role of ST2 in established CAD patients with and without T2DM.
4.1 Prognostic value of biomarkers in CAD patients
Over the past two decades, biomarkers have become increasingly important tools that help to improve patient outcome prognosis [22-24]. Numerous biomarkers have been identified in the diagnosis, prognosis and risk prediction of cardiovascular disease, but few have made their way to clinical practice . The most extensively used cardiovascular biomarkers are natriuretic peptides in the diagnosis and prognosis of heart failure and cardiac troponins in the diagnosis of acute myocardial infarction. Deeper experimental studies of the pathophysiology of atherosclerosis have identified a large number of molecules as potential prognostic biomarkers in cardiovascular disease . To date, however, no marker has been shown to predict cardiovascular events with high accuracy. Therefore, the investigation of potential markers for predicting cardiovascular events is still of great value. There have been only 2 small studies reporting the prognostic value of ST2 in patients with CAD [16, 27]. A study showed that ST2 and IL-33 were associated with mortality in patients with ST elevation myocardial infarction (STEMI) but not patients with non-STEMI (NSTEMI) or stable angina (SAP) . Another study showed that increased concentrations of ST2 were an independent predictor of all-cause mortality in patients with stable CAD . Therefore, a large sample study including SAP and ACS is urgently needed to further demonstrate the predictive value of ST2 in CAD patients during long-term follow-up.
4.2 Prognostic value of ST2 in cardiovascular disease
Previous studies suggested that ST2 may be a potential biological marker for mechanical overload in the heart. ST2 was markedly upregulated in mechanically- stimulated cardiomyocytes. Furthermore, ST2 has been proven to be a predictor of outcome in patients with HF [12, 14, 17, 18]. Recent evidence suggests that ST2 may be predictive in patients with ACS [28, 29]. According to Eggers KM's research, ST2 levels are elevated early in NSTE-ACS and predict 1-year mortality . Wang YP's research showed that serum levels of ST2, IL-33 and BNP were positively correlated with MACEs in patients with AMI after PCI . However, no study has investigated the long-term value of ST2 in the prediction of MACEs or all-cause death in patients with CAD in a large population.
4.3 The underlying mechanisms
The inflammatory hypothesis of atherosclerosis suggests that inflammatory cell signaling drives the formation, development, and eventual instability of atherosclerotic plaques . IL-33 was originally reported as a modulator of inflammation, tipping the balance towards CD4+ T helper-cell type 2 mediated immune responses . The effect of IL-33 on the function of foam cells indicated the protective role of IL-33 in atherosclerosis . ST2 acts as a decoy receptor for IL-33, thus blocking its protective effects. It has been reported that ApoE (-/-) mice treated with soluble ST2 developed significantly larger atherosclerotic plaques in the aortic sinus compared with the control mice . Researchers have found that ST2 is particularly expressed in arterial endothelial cells and is involved in the progression of atherosclerosis . These results suggested that ST2 may be proposed as a marker of plaque burden and predictor of future cardiovascular events . In this respect, the IL-33-ST2 pathway deserves consideration. Although the above data suggest that ST2 has a role in the prognosis of patients presenting with ACS, whether ST2 contributes to cardiovascular risk prediction in a large scale CAD patients during a long-term follow-up remains uncertain.
To evaluate the prognostic value of a biomarker in CVD, researchers must demonstrate the elevated risk of cardiovascular events associated with higher levels of the new biomarker with adjustment for other established risk factors. The results should be presented as hazard ratio relative risk estimates from a Cox model and a probability value test of significance of the marker in the multivariable models . Our results indicated that after incorporating age, sex, and other clinically relevant covariates, the adjusted HRs for MACEs and all-cause death were 1.36 and 2.01, respectively, in the Cox proportional- hazards models. Moreover, in previous studies, the follow-up time for the predictive value of ST2 was relatively short. Brown et al assessed the prognostic value of ST2 during a short-term follow-up of 30 days for acute MI, ACS, and MACEs , Aldous et al revisited the prognostic value of ST2 in patients with chest pain with a longer follow-up of 18 months . Two reports were based on data from 3 clinical trials in STEMI that provided data on the prognostic value of plasma ST2 for 30 days after MI for adverse events, and a further article reported prognostic performance over an average follow-up time of 20 months [29, 40, 41]. Our results demonstrated that in a median follow-up of 6.4 years, a higher level of ST2 is significantly associated with all-cause death and MACEs and provides incremental prognostic value beyond traditional risk factors.
4.4 Prognostic value of ST2 in CAD patients with and without diabetes
Based on Lin’s research, ST2 levels were significantly elevated in patients with diabetes compared with normal subjects and each SD log ST2 was associated with a 1.57-fold increased risk of atherosclerosis . Another study proved that ST2 is regulated by the p75 neurotrophic receptor and predicts mortality in diabetic patients . Durga’s research suggested that elevated levels of ST2 were able to predict mortality and MACEs in ACS patients, along with an increased risk of MACEs and mortality in ACS patients with diabetes . Hasan’s research indicated that circulating ST2 may be used to establish a cutoff value for cardiometabolic risk/disease in individuals with glycemia in the normal/prediabetes range . However, on the other hand, subclinical cardiac dysfunction was associated with older age, male sex, and metabolic factors but not with the ST2 level . IL-33 serves as an important local link between tissue injury or metabolic disturbances and a physiological response of limiting or repairing tissue damage . It has been shown that circulating ST2 is associated with markers of liver function and lipid metabolism in severely obese patients and a reduction in ST2 occurs after successful bariatric surgery, most prominently in diabetic patients . IL-33 and ST2 are abundantly expressed in adipose tissues and IL-33 levels are correlated with high body mass index, suggesting an association of IL-33 with obesity and diabetes [47, 48]. Based on the above studies, we think ST2 may affect metabolism and further affect the prognosis of diabetic patients, but the underlying mechanism has not been confirmed. In our study, among patients with T2DM, the AUC increased from 0.896 to 0.923, so our results indicated that ST2 had a higher predictive value for the prognosis of CAD patients with diabetes and provided new evidence for the role of ST2.