Abstract
The number of patients with heart failure is expected to rise sharply owing to ageing populations, poor dietary habits, unhealthy lifestyles and improved survival rates from conditions such as hypertension and myocardial infarction. Heart failure is classified into two main types: heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF). These forms fundamentally differ, especially in how metabolism is regulated, but they also have shared features such as mitochondrial dysfunction. HFrEF is typically driven by neuroendocrine activation and mechanical strain, which demands a higher ATP production to sustain cardiac contraction. However, the primary energy source in a healthy heart (fatty acid β-oxidation) is often suppressed in HFrEF. Although glucose uptake increases in HFrEF, mitochondrial dysfunction disrupts glucose oxidation, and glycolysis and ketone oxidation only partially compensate for this imbalance. Conversely, HFpEF, particularly in individuals with metabolic diseases, such as obesity or type 2 diabetes mellitus, results from both mechanical and metabolic overload. Elevated glucose and lipid levels overwhelm normal metabolic pathways, leading to an accumulation of harmful metabolic byproducts that impair mitochondrial and cellular function. In this Review, we explore how disruptions in cardiac metabolism are not only markers of heart failure but also key drivers of disease progression. We also examine how metabolic intermediates influence signalling pathways that modify proteins and regulate gene expression in the heart. The growing recognition of the role of metabolic alterations in heart failure has led to groundbreaking treatments that target these metabolic disruptions, offering new hope for these patients.
Key points
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Both heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF) are associated with cardiac metabolic inflexibility and altered myocardial energetics, but with distinct underlying mechanisms.
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In HFrEF, mechanical overload increases the energy cost of contraction, leading to mitochondrial exhaustion and ultimately reduced oxidative capacity.
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HFpEF, particularly its cardiometabolic form, is driven by metabolic overload, which saturates myocardial oxidative capacity and results in the accumulation of toxic metabolic intermediates.
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These metabolic intermediates contribute to post-translational modifications of cardiac proteins across all subcellular compartments, affecting ionic fluxes, contraction, mitochondrial function and epigenetic regulation.
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Metabolic activity and flux assessments using tracers allow in vivo and ex vivo analysis of cardiac metabolism; future studies should integrate single-cell omics approaches to refine analyses and drive new discoveries.
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Current (SGLT2 inhibitors, GLP1R agonists) and emerging therapies (NAD precursors, ketone esters) targeting metabolic pathways at both systemic and myocardial levels offer promising treatment opportunities, particularly for HFpEF.
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Acknowledgements
This article is based on work from the COST Action EU-METAHEART (CA22169) Working Group 1 (Substrate and Intermediary Metabolism in Failing Cardiomyocytes; https://cost-metaheart.eu), supported by COST (European Cooperation in Science and Technology). M.M. is supported by Institut National pour la Santé et la Recherche Médicale (INSERM) and research grants from Agence Nationale pour la Recherche (ANR) and Fédération Française de Cardiologie (FFC). C.J.Z. is supported by a research grant from Boehringer Ingelheim and the European Foundation for the Study of Diabetes (EFSD). L.C.H. acknowledges support from the British Heart Foundation (FS/17/58/33072). A.K. is supported by the National Institutes of Health/National Heart, Lung and Blood Institute (R00-HL-141702, R01-HL-177461, R01-HL-173975) and National Institutes of Health/National Cancer Institute (R01-CA-283313). J.I. and M.R-M. are supported by the Instituto de Salud Carlos III of the Spanish Ministry of Health (FIS PI22/00513 and FIS PI23/00068). L.B. is supported by grants from the Fonds National de la Recherche Scientifique (FNRS, Belgium). G.K. acknowledges laboratory support provided by grants from the Icelandic Research Fund (217946-051), Icelandic Cancer Society Research Fund and University of Iceland Research Fund. C.M. is supported by Deutsche Forschungsgemeinschaft (German Research Foundation – SFB-1525/project No. 453989101 and Ma: 2528/8-1) and the German Centre for Cardiovascular Research (EX-22 and FKZ 81 × 2800227). G.G.S. is supported by the German Centre for Cardiovascular Research (81 × 3100210; 81 × 2100282), the Deutsche Forschungsgemeinschaft (German Research Foundation – SFB-1470–A02; SFB-1470–Z01) and the European Research Council (ERC StG 101078307).
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Mericskay, M., Zuurbier, C.J., Heather, L.C. et al. Cardiac intermediary metabolism in heart failure: substrate use, signalling roles and therapeutic targets. Nat Rev Cardiol 22, 704–727 (2025). https://doi.org/10.1038/s41569-025-01166-7
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DOI: https://doi.org/10.1038/s41569-025-01166-7
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