Alterations in cardiac and systemic metabolism in heart failure

Altered cardiac and systemic metabolism is a hallmark of heart failure (HF). In the failing heart, cardiomyocytes develop alterations in substrate preference, mitochondrial oxidative metabolism, and the shuttling of high-energy phosphates from mitochondria to the cytosol that compromise energetic efficiency and contribute to disease progression. At the systemic level, neurohormonal activation plays a dominant role in HF with reduced ejection fraction, whereas HF with preserved ejection fraction is shaped by the clustering of multiple comorbidities, such as diabetes, obesity and hypertension, which disrupt the physiological crosstalk between the heart and metabolically active organs. This review provides a perspective on cardiac metabolism in HF. We delineate the specific alterations in substrate metabolism that characterize HF with reduced ejection fraction versus HF with preserved ejection fraction, examine the impact of interorgan communication on myocardial function, and highlight how the benefits of emerging HF therapies, including sodium-glucose cotransporter 2 inhibitors and GLP-1 receptor agonists, may be mediated, at least in part, through the restoration of metabolic homeostasis.