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Observational Study
. 2025 Feb;13(2):315-329.
doi: 10.1016/j.jchf.2024.10.023. Epub 2025 Jan 8.

Growth Differentiation Factor-15 Is Associated With Congestion-Related Anorexia and Weight Loss in Advanced Heart Failure

Luca Monzo  1 , Petr Jarolim  2 , Barry A Borlaug  3 , Jan Benes  4 , Ivana Jurcova  4 , Dominik Jenca  4 , Katerina Kroupova  4 , Peter Wohlfahrt  4 , Martin Kotrc  4 , Vojtech Melenovsky  5
Affiliations
Free article
Observational Study

Growth Differentiation Factor-15 Is Associated With Congestion-Related Anorexia and Weight Loss in Advanced Heart Failure

Luca Monzo et al. JACC Heart Fail. 2025 Feb.
Free article

Abstract

Background: Growth differentiation factor (GDF)-15 is a pleiotropic cytokine that is associated with appetite-suppressing effects and weight loss in patients with malignancy.

Objectives: This study aims to investigate the relationships between GDF-15 levels, anorexia, cachexia, and clinical outcomes in patients with advanced heart failure with reduced ejection fraction (HFrEF).

Methods: In this observational, retrospective analysis, a total of 344 patients with advanced HFrEF (age 58 ± 10 years, 85% male, 67% NYHA functional class III), underwent clinical and echocardiographic examination, body composition evaluation by skinfolds and dual-energy x-ray absorptiometry, circulating metabolite assessment, Minnesota Living with Heart Failure Questionnaire, and right heart catheterization.

Results: The median GDF-15 level was 1,503 ng/L (Q1-Q3: 955-2,332 ng/L) (reference range: <1,200 ng/L). Higher GDF-15 levels were associated with more prevalent anorexia and cachexia. Patients with higher GDF-15 had increased circulating free fatty acids and beta-hydroxybutyrate, lower albumin, cholesterol, and insulin/glucagon ratio, consistent with a catabolic state. Patients with higher GDF-15 had worse congestion and more severe right ventricular dysfunction. In multivariable Cox analysis, elevated GDF-15 was independently associated with risk of the combined endpoint of death, urgent transplantation, or left ventricular assist device implantation, even after adjusting for coexisting anorexia and cachexia (T3 vs T1 HR: 2.31 [95% CI: 1.47-3.66]; P < 0.001).

Conclusions: In patients with advanced HFrEF, elevated circulating GDF-15 levels are associated with a higher prevalence of anorexia and cachexia, right ventricular dysfunction, and congestion, as well as an independently increased risk of adverse events. Further studies are warranted to determine whether therapies altering GDF-15 signaling pathways can affect metabolic status and clinical outcomes in advanced HFrEF.

Keywords: anorexia; cachexia; growth differentiation factor-15; heart failure; right ventricular dysfunction.

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Conflict of interest statement

Funding Support and Author Disclosures This work was supported by the National Institute for Research of Metabolic and Cardiovascular Diseases (Program EXCELES, ID Project number LX22NPO5104), funded by the European Union, Next Generation EU, and by the Ministry of Health, Czech Republic, with conceptual development of research organization by the Institute for Clinical and Experimental Medicine (IKEM; IN 00023001) and by fund 103517 of the Biomarker Research and Clinical Trials Laboratory at Brigham and Women’s Hospital. Dr Borlaug is supported in part by research grants from the National Institutes of Health (NIH) (R01 HL128526 and U01 HL160226) and the United States Department of Defense (W81XWH2210245). Dr Jarolim has received grants through his institution from Abbott Laboratories, Amgen Inc, AstraZeneca, LP, Daiichi-Sankyo, Roche Diagnostic Corporation, and Siemens Healthineers. Dr Borlaug has received grants from AstraZeneca, Axon, GlaxoSmithKline, Medtronic, Mesoblast, Novo Nordisk, and Tenax Therapeutics; consulting fees from Actelion, Amgen, Aria, Axon Therapies, BD, Boehringer Ingelheim, Cytokinetics, Edwards LifeSciences, Eli Lilly, Imbria, Janssen, Merck, Novo Nordisk, NGM, NXT, and VADovations; and is named inventor (U.S. Patent number 10,307,179) for the tools and approach for a minimally invasive pericardial modification procedure to treat heart failure. Dr Melenovsky has received consulting fees from Bayer, Novo Nordisk, Merck Sharp & Dohme; and grants from Regeneron. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose

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