GDF-15 and TRAIL-R2 are powerful predictors of long-term mortality in patients with acute myocardial infarction

This study is the first to evaluate the prognostic significance of a large set of CVD/inflammatory biomarkers in order to predict long-term all-cause mortality after acute myocardial infarction (AMI). Advances in treatment of AMI have significantly reduced short-term mortality, but longer-term complications remain a serious problem. Given the complex process of injury repair and remodeling that follows an AMI, biomarkers with prognostic power would aid risk stratification and could guide treatment strategies.

847 patients from the Västmanland Myocardial Infarction Study were followed for a median period of almost 7 years, with baseline data established using demographics and medical history, plasma protein analysis using Olink CVD I and using all-cause mortality as the primary end-point. 81 proteins in the panel showed detectability of >80% and were included in the analysis. A penalize regression analysis of the data revealed a best predictor set of 32 proteins that predicted long-term mortality with an accuracy (ROC AUC) of 0.85. Further statistical analysis showed that the predictor set could be reduced to just 2 principal markers without any loss in accuracy: growth differentiation factor 15 (GDF-15) and tumour necrosis factor-related apoptosis-inducing ligand receptor 2 (TRAIL-R2). When these two markers were combined with age & sex adjustment and conventional risk factors, the overall accuracy of the prediction equation gave a ROC AUC of 0.88.

The GDF-15 data provides confirmation to earlier reports that this protein may be a powerful predictor of mortality in CVD patients. GDF-15 is part of the TGF-beta superfamily, and is generally expressed at low levels unless upregulated following tissue injury. Functionally, it is believed to be involved in regulation of apoptosis, cell growth and cell repair, which are likely to be important processes in the long-term response to AMI. The identification of TRAIL-R2 as a powerful predictor of post-AMI mortality was a novel and more unexpected finding. This protein is widely expressed in most tissues and is believed to trigger a broad range of different cellular responses, suggesting that it may be a more general marker of disease burden, rather than being specific for CVD. One possible link to AMI mortality could be that increased TRAIL-R2 binds and reduces the availability of the TRAIL ligand, which has been inversely linked to poor CVD prognosis in other studies.