Serum Growth Differentiation Factor 15 (GDF15) Levels Reflect Ischemic Etiology in Heart Failure Patients with Iron Deficiency: A Cross-Sectional Study

Tajes, Marta; Ras-Jiménez, Maria del Mar; Girona, Josefa; Ramos-Polo, Raúl; Guardiola, Montse; García-Pinilla, José Manuel; Ribalta, Josep; Cobo-Marcos, Marta; Masana, Lluís; de Juan-Bagudá, Javier; Fonseca, Cândida; Enjuanes, Cristina; Vázquez-Carrera, Manuel; Comin-Colet, Josep; Rodríguez-Calvo, Ricardo

doi:10.3390/biom15091234

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Serum Growth Differentiation Factor 15 (GDF15) Levels Reflect Ischemic Etiology in Heart Failure Patients with Iron Deficiency: A Cross-Sectional Study

by

Marta Tajes

^1,2,†,

Maria del Mar Ras-Jiménez

^3,4,†

,

Josefa Girona

^5,6,7,8

,

Raúl Ramos-Polo

^1,2,3,4,9

,

Montse Guardiola

^5,6,7,8

,

José Manuel García-Pinilla

^2,10,11,12

,

Josep Ribalta

^5,6,7,8

,

Marta Cobo-Marcos

^2,13,

Lluís Masana

^5,6,7,8

,

Javier de Juan-Bagudá

^2,14,15

,

Cândida Fonseca

¹⁶

,

Cristina Enjuanes

^1,2,3,4,9,

Manuel Vázquez-Carrera

^8,17,18,19

,

Josep Comin-Colet

^1,2,3,4,9,*

and

Ricardo Rodríguez-Calvo

^5,6,7,8,*

¹

Bio-Heart Cardiovascular Diseases Research Group, Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, 08908 Barcelona, Spain

²

Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Instituto Salud Carlos III, 28029 Madrid, Spain

³

Community Heart Failure Program, Cardiology Department, Bellvitge University Hospital, L’Hospitalet de Llobregat, 08907 Barcelona, Spain

⁴

Department of Clinical Sciences, School of Medicine, Universitat de Barcelona, 08007 Barcelona, Spain

⁵

Research Unit on Lipids and Atherosclerosis, University Rovira i Virgili, 43201 Reus, Spain

⁶

Vascular Medicine and Metabolism Unit, “Sant Joan de Reus” University Hospital, 43204 Reus, Spain

⁷

Pere Virgili Health Research Institute (IISPV), 43007 Tarragona, Spain

⁸

Centro de Investigación Biomédica en Red en Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, 28029 Madrid, Spain

⁹

Cardiology Department, Heart Institute, Bellvitge University Hospital, L’Hospitalet de Llobregat, 08907 Barcelona, Spain

¹⁰

Cardiology Department, Virgen de la Victoria Hospital, 29010 Malaga, Spain

¹¹

IBIMA-Platafrma BIONAND, 29590 Malaga, Spain

¹²

Department of Medicine and Dermatology, Universidad of Málaga, 29071 Malaga, Spain

¹³

Cardiology Department, Puerta de Hierro University Hospital, 28222 Majadahonda, Spain

¹⁴

Cardiology Department, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), 12 de Octubre University Hospital, 28041 Madrid, Spain

¹⁵

Department of Medicine, Faculty of Biomedical and Health Sciences, Universidad Europea de Madrid, 28670 Madrid, Spain

¹⁶

Heart Failure Clínic, S. Francisco Xavier Hospital, Department of Medicine, ULS Lisboa Ocidental, NOVA Medical School, Universidade Nova de Lisboa, 1150-190 Lisboa, Portugal

¹⁷

Pharmacology Unit, Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, 08028 Barcelona, Spain

¹⁸

Institut de Biomedicina de la Universidad de Barcelona (IBUB), University of Barcelona, 08028 Barcelona, Spain

¹⁹

Institut de Recerca Sant Joan de Déu (IR-SJD), 08950 Barcelona, Spain

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^*

Authors to whom correspondence should be addressed.

^†

These authors contributed equally to this work.

Biomolecules 2025, 15(9), 1234; https://doi.org/10.3390/biom15091234

Submission received: 28 July 2025 / Revised: 21 August 2025 / Accepted: 25 August 2025 / Published: 26 August 2025

(This article belongs to the Special Issue Chronic Heart Failure: From Molecular Mechanisms to Therapies Strategies)

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Abstract

Heart failure (HF), particularly of an ischemic etiology, is steadily increasing worldwide. Non-anemic iron deficiency (ID) is highly prevalent among HF patients, and it has been related to worse outcomes. Growth differentiation factor 15 (GDF15) has been related to atherosclerotic cardiovascular (CV) disease, HF and iron pathophysiology. Nevertheless, the specific potential role of GDF15 in HF patients with ID has not been fully explored. In this cross-sectional study we determined serum GDF15 levels in 60 HF patients with ID from the IRON-PATH II study. The discriminative capacity of GDF15 in logistic regression models for classifying these patients according to ischemic etiology was defined as the primary endpoint. Additionally, relationships between GDF15 levels and impaired right ventricle function, impaired functional capacity and HF were included as secondary endpoints. GDF15 was inversely related to tricuspid annular plane systolic excursion (TAPSE) and the six-minute walking test (6MWT), and positively related to hallmarks of HF [i.e., N-terminal prohormone of brain natriuretic peptide (NT-proBNP)] and other molecules influenced by HF progression [i.e., creatinine and ferritin]. Moreover, GDF15 was inversely related to hemoglobin, suggesting a potential link to iron homeostasis. Furthermore, GDF15 showed good classification capacity and improved the accuracy of a logistic regression model for ischemic HF classification in patients with ID. Overall, the findings of this study propose serum GDF15 levels as a potential tool for the classification of HF patients with ID according to the ischemic etiology.

Keywords: GDF15; heart failure; iron deficiency; ischemic etiology

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MDPI and ACS Style

Tajes, M.; Ras-Jiménez, M.d.M.; Girona, J.; Ramos-Polo, R.; Guardiola, M.; García-Pinilla, J.M.; Ribalta, J.; Cobo-Marcos, M.; Masana, L.; de Juan-Bagudá, J.; et al. Serum Growth Differentiation Factor 15 (GDF15) Levels Reflect Ischemic Etiology in Heart Failure Patients with Iron Deficiency: A Cross-Sectional Study. Biomolecules 2025, 15, 1234. https://doi.org/10.3390/biom15091234

AMA Style

Tajes M, Ras-Jiménez MdM, Girona J, Ramos-Polo R, Guardiola M, García-Pinilla JM, Ribalta J, Cobo-Marcos M, Masana L, de Juan-Bagudá J, et al. Serum Growth Differentiation Factor 15 (GDF15) Levels Reflect Ischemic Etiology in Heart Failure Patients with Iron Deficiency: A Cross-Sectional Study. Biomolecules. 2025; 15(9):1234. https://doi.org/10.3390/biom15091234

Chicago/Turabian Style

Tajes, Marta, Maria del Mar Ras-Jiménez, Josefa Girona, Raúl Ramos-Polo, Montse Guardiola, José Manuel García-Pinilla, Josep Ribalta, Marta Cobo-Marcos, Lluís Masana, Javier de Juan-Bagudá, and et al. 2025. "Serum Growth Differentiation Factor 15 (GDF15) Levels Reflect Ischemic Etiology in Heart Failure Patients with Iron Deficiency: A Cross-Sectional Study" Biomolecules 15, no. 9: 1234. https://doi.org/10.3390/biom15091234

APA Style

Tajes, M., Ras-Jiménez, M. d. M., Girona, J., Ramos-Polo, R., Guardiola, M., García-Pinilla, J. M., Ribalta, J., Cobo-Marcos, M., Masana, L., de Juan-Bagudá, J., Fonseca, C., Enjuanes, C., Vázquez-Carrera, M., Comin-Colet, J., & Rodríguez-Calvo, R. (2025). Serum Growth Differentiation Factor 15 (GDF15) Levels Reflect Ischemic Etiology in Heart Failure Patients with Iron Deficiency: A Cross-Sectional Study. Biomolecules, 15(9), 1234. https://doi.org/10.3390/biom15091234

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Serum Growth Differentiation Factor 15 (GDF15) Levels Reflect Ischemic Etiology in Heart Failure Patients with Iron Deficiency: A Cross-Sectional Study

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