The ‘Goldilocks zone’ of fatty acid metabolism; to ensure that the relationship with cardiac function is just right

Fatty acids (FA) are the main fuel used by the healthy heart to power contraction, supplying 60–70% of the ATP required. FA generate more ATP per carbon molecule than glucose, but require more oxygen to produce the ATP, making them a more energy dense but less oxygen efficient fuel compared with glucose. The pathways involved in myocardial FA metabolism are regulated at various subcellular levels, and can be divided into sarcolemmal FA uptake, cytosolic activation and storage, mitochondrial uptake and β-oxidation. An understanding of the critical involvement of each of these steps has been amassed from genetic mouse models, where forcing the heart to metabolize too much or too little fat was accompanied by cardiac contractile dysfunction and hypertrophy. In cardiac pathologies, such as heart disease and diabetes, aberrations in FA metabolism occur concomitantly with changes in cardiac function. In heart failure, FA oxidation is decreased, correlating with systolic dysfunction and hypertrophy. In contrast, in type 2 diabetes, FA oxidation and triglyceride storage are increased, and correlate with diastolic dysfunction and insulin resistance. Therefore, too much FA metabolism is as detrimental as too little FA metabolism in these settings. Therapeutic compounds that rebalance FA metabolism may provide a mechanism to improve cardiac function in disease. Just like Goldilocks and her porridge, the heart needs to maintain FA metabolism in a zone that is ‘just right’ to support contractile function.