Pathophysiological pathways related to high plasma growth differentiation factor 15 concentrations in patients with heart failure

AIMS: Elevated concentrations of growth differentiation factor 15 (GDF‐15) in patients with heart failure (HF) have been consistently associated with worse clinical outcomes, but what disease mechanisms high GDF‐15 concentrations represent remains unclear. Here, we aim to identify activated pathophysiological pathways related to elevated GDF‐15 expression in patients with HF. METHODS AND RESULTS: In 2279 patients with HF, we measured circulating levels of 363 biomarkers. Then, we performed a pathway over‐representation analysis to identify key biological pathways between patients in the highest and lowest GDF‐15 concentration quartiles. Data were validated in an independent cohort of 1705 patients with HF. In both cohorts, the strongest up‐regulated biomarkers in those with high GDF‐15 were fibroblast growth factor 23 (FGF‐23), death receptor 5 (TRAIL‐R2), WNT1‐inducible signalling pathway protein 1 (WISP‐1), tumour necrosis factor receptor superfamily member 11a (TNFRSF11A), leucocyte immunoglobulin‐like receptor subfamily B member 4 (LILRB4), and trefoil factor 3 (TFF3). Pathway over‐representation analysis revealed that high GDF‐15 patients had increased activity of pathways related to inflammatory processes, notably positive regulation of chemokine production; response to interleukin‐6; tumour necrosis factor and death receptor activity; and positive regulation of T‐cell differentiation and inflammatory response. Furthermore, we found pathways involved in regulation of insulin‐like growth factor (IGF) receptor signalling and regulatory pathways of tissue, bones, and branching structures. GDF‐15 quartiles significantly predicted all‐cause mortality and HF hospitalization. CONCLUSION: Patients with HF and high plasma concentrations of GDF‐15 are characterized by increased activation of inflammatory pathways and pathways related to IGF‐1 regulation and bone/tissue remodelling.