Abstract
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.
| Original language | English |
|---|---|
| Pages (from-to) | 308-320 |
| Number of pages | 13 |
| Journal | European Journal of Heart Failure |
| Volume | 24 |
| Issue number | 2 |
| DOIs | |
| Publication status | Published - Feb 2022 |
| Externally published | Yes |
Bibliographical note
Funding Information:The UMCG, which employs several of the authors, has received research grants and/or fees from AstraZeneca, Abbott, Boehringer Ingelheim, Cardior Pharmaceuticals Gmbh, Ionis Pharmaceuticals, Inc., Novo Nordisk, and Roche. J.T. has received speaker and or consultancy fees from Roche diagnostics, Us2.ai and holds a patent (U.S. Patent No. 10,702,247) unrelated to the present work. R.A.d.B. received speaker fees from Abbott, AstraZeneca, Bayer, Novartis, and Roche. C.C.L. declares receiving consultancy fees and/or research grants from Amgen, Applied Therapeutics, AstraZeneca, Boehringer Ingelheim, MSD, Novartis, and Novo Nordisk. S.D.A. reports receiving fees from Abbott, Bayer, Boehringer Ingelheim, Cardiac Dimension, Cordio, Impulse Dynamics, Novartis, Occlutech, Servier, and Vifor Pharma, and grant support from Abbott and Vifor Pharma. M.M. has received personal fees from Actelion, Amgen, AstraZeneca, Abbott Vascular, Servier, Edwards Therapeutics, Livanova, Vifor pharma, WindTree Therapeutics, as member of Trials' Committees or for speeches at sponsored meetings in the last three years. All other authors have nothing to disclose. Conflict of interest:
Funding Information:
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).
Funding Information:
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). Conflict of interest: The UMCG, which employs several of the authors, has received research grants and/or fees from AstraZeneca, Abbott, Boehringer Ingelheim, Cardior Pharmaceuticals Gmbh, Ionis Pharmaceuticals, Inc., Novo Nordisk, and Roche. J.T. has received speaker and or consultancy fees from Roche diagnostics, Us2.ai and holds a patent (U.S. Patent No. 10,702,247) unrelated to the present work. R.A.d.B. received speaker fees from Abbott, AstraZeneca, Bayer, Novartis, and Roche. C.C.L. declares receiving consultancy fees and/or research grants from Amgen, Applied Therapeutics, AstraZeneca, Boehringer Ingelheim, MSD, Novartis, and Novo Nordisk. S.D.A. reports receiving fees from Abbott, Bayer, Boehringer Ingelheim, Cardiac Dimension, Cordio, Impulse Dynamics, Novartis, Occlutech, Servier, and Vifor Pharma, and grant support from Abbott and Vifor Pharma. M.M. has received personal fees from Actelion, Amgen, AstraZeneca, Abbott Vascular, Servier, Edwards Therapeutics, Livanova, Vifor pharma, WindTree Therapeutics, as member of Trials' Committees or for speeches at sponsored meetings in the last three years. All other authors have nothing to disclose.
Publisher Copyright:
© 2022 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.