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

TY - JOUR

T1 - Pathophysiological pathways related to high plasma growth differentiation factor 15 concentrations in patients with heart failure

AU - Ceelen, Daan

AU - Voors, Adriaan A.

AU - Tromp, Jasper

AU - van Veldhuisen, Dirk Jan

AU - Dickstein, Kenneth

AU - de Boer, Rudolf A.

AU - Lang, Chim C.

AU - Anker, Stefan D.

AU - Ng, Leong Loke

AU - Metra, Marco

AU - Ponikowski, Piotr

AU - Figarska, Sylwia

N1 - Funding: This work was supported by an educational grant from Roche Diagnostics. The BIOSTAT-CHF project was funded by a grant from the European Commission (FP7-242209-BIOSTAT-CHF; EudraCT 2010–020808–29). Dr. De Boer is supported by a grant from the European Research Council (ERC CoG 818715, SECRETE-HF).

PY - 2022/2

Y1 - 2022/2

N2 - 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.

AB - 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.

KW - Biomarkers

KW - Growth differentiation factor 15

KW - Heart failure

KW - Pathway analysis

UR - https://www.scopus.com/pages/publications/85123505182

U2 - 10.1002/ejhf.2424

DO - 10.1002/ejhf.2424

M3 - Article

C2 - 34989084

SN - 1388-9842

VL - 24

SP - 308

EP - 320

JO - European Journal of Heart Failure

JF - European Journal of Heart Failure

IS - 2

ER -