Abstract
The interaction between inflammation and metabolism (immunometabolism) is a crucial factor in the pathophysiology of heart failure, whether the cardiac failure originates from ischaemic injury or systemic metabolic disorders, and whether it is associated with reduced or preserved ejection fraction. Ischaemia, metabolic stress and comorbidity-driven systemic inflammation attract innate and adaptive immune cells to the myocardium and induce their polarization towards pro-inflammatory or anti-inflammatory phenotypes through cell-intrinsic metabolic shifts involving oxidative phosphorylation and anaerobic glycolysis. These infiltrating immune cells modulate cardiac and systemic metabolism. The bidirectional metabolic crosstalk between immune cells and parenchymal and stromal cardiac cells contributes to adverse cardiac remodelling. In turn, ischaemic injury and deregulated metabolism stimulate bone marrow and extramedullary myelopoiesis, which increases immune cell recruitment and perpetuates a non-resolving chronic inflammatory state. Pharmacological interventions targeting metabolism have shown promise for improving outcomes in patients with heart failure, but immunomodulatory approaches face multiple challenges. Understanding the complex metabolic pathways and cell–cell interactions that regulate immunometabolism in heart failure is essential to identify new therapies that shift the balance from maladaptive to cardioprotective immune responses. In this Review, we provide a comprehensive overview of the intricate cellular and molecular mechanisms that govern immunometabolism in heart failure and discuss potential approaches to non-invasively monitor and treat patients with heart failure.
Key points
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The immunometabolic shift between oxidative phosphorylation and glycolysis is crucial for the immune response after acute myocardial infarction or prolonged exposure to metabolic disorders.
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The bone marrow and the spleen are sources of immune cells, which are released and recruited to the injured heart; the persistent recruitment of immune cells over prolonged periods contributes to the development and progression of heart failure.
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In heart failure, bidirectional metabolic crosstalk between immune cells and parenchymal and stromal cardiac cells contributes to adverse cardiac remodelling.
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Advances in molecular imaging techniques enable non-invasive tracking of immune cell trafficking to assess disease progression and response to treatments.
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Current and emerging therapeutic strategies that more precisely target inflammatory pathways and metabolic processes than guideline-recommended therapies present new opportunities to manage heart failure effectively.
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Acknowledgements
This article is based on work from COST Action EU-METAHEART (CA22169) supported by COST (European Cooperation in Science and Technology). Ι.Α. and P.-E.N. were supported by the 2nd Call for Hellenic Foundation for Research and Innovation (H.F.R.I.) Research Projects to Support Faculty Members and Researchers ‘ElucidatioN of LIGHt chain amyloidosis induced cardioToxicity: EstablishMENT of in vitro and in vivo models’ (ENLIGHTEnMENT). A.G. was supported by the Italian Ministry of Health (GR-2021-12371950) and Italian Ministry of Education, Universities and Research (PRIN 2022 20223YPL49 and PRIN PNRR 2022 P2022ZB72T). J.T.T. was supported by the German Research Foundation (Heisenberg Programme TH2161/3-1) and Fondation Leducq (Transatlantic Network ImmunoFib). G.H. was supported by the German Research Foundation (CRC 1116 B8 and RTG 2989) and Cost Action CARDIOPROTECTION (CA 16225 and ICG 16225). G.V. receives support from grants PID2021‐128891OB‐I00 and PLEC2021–007664‐NextGenerationEU funded by MCIN/AEI/10.13039/501100011033 and Fondo Europeo de Desarrollo Regional (FEDER) A way of making Europe; the Instituto de Salud Carlos III (CIBERCV CB16/11/00411); Fundació Investigació Marato TV3 #20154310; Generalitat of Catalunya-Secretaria d’Universitats i Recerca del Departament d’Economia i coneixement de la Generalitat (2017SGR1480); 2016PROD00043 (Agencia Gestión Ayudas Universitarias Investigación: AGAUR); and CERCA programme/Generalitat de Cataluña.
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The authors dedicate this article to the memory of Ioanna Andreadou (1965–2025)1, who died prematurely and unexpectedly during the preparation of this manuscript, and to whom we are all profoundly indebted, not only for shaping this manuscript but, most importantly, for her substantial influence on the field. Above all, we cherish her friendship and the inspiration she provided to us all.
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Andreadou, I., Ghigo, A., Nikolaou, PE. et al. Immunometabolism in heart failure. Nat Rev Cardiol 22, 751–772 (2025). https://doi.org/10.1038/s41569-025-01165-8
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DOI: https://doi.org/10.1038/s41569-025-01165-8
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