Cardiac contractile function is strictly dependent on proper metabolic energy provision. Long-chain fatty acids and glucose are the primary energy substrates and are also indispensable for serving additional cellular roles including synthesis of biosynthetic precursors and post-translational modification of proteins. The balance between fatty acid and glucose utilization in the heart, and myocardial contractile function appear inextricably linked. A chronic shift towards a greater dependence on a single substrate, either fatty acids or glucose, results in a metabolic imbalance, and is associated with impaired cardiac function. As a result, re-balancing fatty acid and glucose utilization is an effective approach to restore cardiac contractile performance. In this article we discuss the significance of the fatty-acid-to-glucose fuel balance for maintaining homeostatic control, and show recent evidence that the membrane substrate transporters CD36 (for fatty acid uptake) and GLUT4 (for glucose uptake) are key targets to recover the myocardial substrate balance. In conclusion, the fatty acid-to-glucose substrate balance is both an effective target to treat heart failure and a useful parameter to monitor myocardial function in health and disease.
Jan et al. (2026) studied this question. Rebalancing fatty acid and glucose utilization via CD36 and GLUT4 membrane transporters restores myocardial substrate balance and improves cardiac function.