The heart consumes large amounts of energy in the form of ATP that is continuously replenished by oxidative phosphorylation in mitochondria and, to a lesser extent, by glycolysis. To adapt the ATP supply efficiently to the constantly varying demand of cardiac myocytes, a complex network of enzymatic and signalling pathways controls the metabolic flux of substrates towards their oxidation in mitochondria. In patients with heart failure, derangements of substrate utilization and intermediate metabolism, an energetic deficit, and oxidative stress are thought to underlie contractile dysfunction and the progression of the disease. In this Review, we give an overview of the physiological processes of cardiac energy metabolism and their pathological alterations in heart failure and diabetes mellitus. Although the energetic deficit in failing hearts — discovered >2 decades ago — might account for contractile dysfunction during maximal exertion, we suggest that the alterations of intermediate substrate metabolism and oxidative stress rather than an ATP deficit per se account for maladaptive cardiac remodelling and dysfunction under resting conditions. Treatments targeting substrate utilization and/or oxidative stress in mitochondria are currently being tested in patients with heart failure and might be promising tools to improve cardiac function beyond that achieved with neuroendocrine inhibition.
The healthy heart is metabolically flexible and can derive energy from various circulating substrates.
Heart failure (HF) and diabetes mellitus are characterized by an increased reliance on ketone bodies and fatty acid oxidation, respectively, for cardiac ATP production.
Metabolic inflexibility and accumulation of toxic intermediates, rather than unbalanced substrate utilization, might detrimentally affect cardiac function.
Metabolic intermediates can operate as signalling factors, inducing post-translational and epigenetic modifications or activating intracellular signalling cascades, which ultimately affect several cellular functions.
In the failing heart, derangements in metabolism and excitation–contraction coupling contribute to mitochondrial dysfunction and oxidative stress.
Targeting metabolic alterations and/or oxidative stress in mitochondria ameliorates HF development in animal models, and translation of these approaches to patients with HF is ongoing.
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C.M.’s research is currently supported by the Deutsche Forschungsgemeinschaft (DFG; SFB 894, TRR-219, and Ma 2528/7-1) and the Bundesministerium für Bildung und Forschung (BMBF; 01EO1504).
Nature Reviews Cardiology thanks C. Lygate, H. Taegtmeyer, and the other anonymous reviewer for their contribution to the peer review of this work.
C.M. serves as an adviser to Boehringer Ingelheim and Servier, and has received speaker honoraria from Berlin Chemie. E.B. declares no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Bertero, E., Maack, C. Metabolic remodelling in heart failure. Nat Rev Cardiol 15, 457–470 (2018). https://doi.org/10.1038/s41569-018-0044-6
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