Our study established a higher level of ST2 was a significant and independent predictor of cardiovascular event. In this study, we found that higher concentrations of ST2(≥ 19 ng/ml) was associated with an increased risk of all-cause death in patients with coronary heart disease. Higher concentrations of ST2 remained an independent indicator of MACEs and all-cause mortality after adjustment for established risk factors for CV disease and other prognostic biomarkers. Furthermore, our study confirmed that the incremental prognostic value of ST2 for MACEs and all-cause mortality beyond the clinical model by ROC curve analysis .Our results provide updated information on the long-term prognostic role of ST2 in established CAD patients. Our results suggest that the addition of plasma ST2 measurements to established CV risk factors may further improve risk stratification.
Biomarkers have become increasingly important tools helping to improve patient care over the past two decades. 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 the 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.Previous studies suggested that ST2 maybe a potential biological marker for mechanical overload in the heart.ST2 was markedly upregulated in mechanically-stimulated cardiomyocytes. Furthermore, ST2 has been proved to be a predictor of outcome in patients with HF    .Recent evidences suggest that ST2 may be predictive in patients with ACS  . It has been shown to be a powerful independent prognosticator for patients with acute myocardial infarction (AMI)  .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 correlate with MACEs in patients with acute myocardial infarction (AMI) after percutaneous coronary intervention (PCI) .However, there was no to investigate the long-term value of ST2 in the prediction of MACEs or all cause death in patients with CAD in a large population.
The inflammatory hypothesis of atherosclerosis suggests that inflammatory cell signaling drives the formation, development, and eventual instability of atherosclerotic plaques . Under this respect, the IL-33-ST2 pathway deserves consideration. In fact, ST2 are particularly expressed in arterial endothelial cells, involving in the progression of atherosclerosis  .IL-33 was originally reported as a modulator of inflammation, tipping the balance towards CD4 + T helper-cell type 2 mediated immune responses . IL-33 may play a protective role in the development of atherosclerosis. The effect of IL-33 on the function of foam cells indicated the protect 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 mice treated with soluble ST2 developed significantly larger atherosclerotic plaques in the aortic sinus of the ApoE(-/-) mice compared with the control mice .These results suggested that ST2 may be proposed as a marker of plaque burden and predictors of future cardiovascular event .Although the above data suggest that ST2 has a role in the prognosis of patients presenting with an acute coronary syndrome, 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 an cardiovascular events associated with higher levels of the new biomarker with adjustment for other established risk factors. The results should be presented as hazards ratios relative risk estimates from a Cox model and a probability value test of significance of the marker in the multivariable models . Our result indicated that after incorporating age, sex, and other clinically relevant covariates, the adjusted HR for MACEs and all cause death was 1.31 and 1.78 respectively in COX proportional-hazards models. Moreover, in the previous studies, the follow-up time for the predictive value of ST2 was relatively short. Brown et al assess 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 ST elevation MI (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   .Our result demonstrated that in a median follow up of 6.4 years, higher level of ST2 is significantly associated with all-cause death, MACEs and provides incremental prognostic value beyond traditional risks factors.
While the study provides a large, well characterized study sample with adjudicated outcomes, the research is limited to a single center, these data represent the results of an observational analysis in a clinical trial population. As in any observational study, we cannot exclude residual confounding. However, this is probably minimal because we used a comprehensive adjustment strategy to control for known variables that are commonly used to stratify the risk of CAD patients.