Despite recent advances in therapy, heart failure remains a major cause of mortality and morbidity and is
a growing healthcare burden worldwide. Alterations in myocardial energy substrate metabolism are a hallmark of
heart failure, and are associated with an energy deficit in the failing heart. Previous studies have shown that a
metabolic shift from mitochondrial oxidative metabolism to glycolysis, as well as an uncoupling between glycolysis
and glucose oxidation, plays a crucial role in the development of cardiac inefficiency and functional impairment
in heart failure. Therefore, optimizing energy substrate utilization, particularly by increasing mitochondrial glucose
oxidation, can be a potentially promising approach to decrease the severity of heart failure by improving mechanical
cardiac efficiency. One approach to stimulating myocardial glucose oxidation is to inhibit fatty acid oxidation.
This review will overview the physiological regulation of both myocardial fatty acid and glucose oxidation in the
heart, and will discuss what alterations in myocardial energy substrate metabolism occur in the failing heart. Furthermore,
lysine acetylation has been recently identified as a novel post-translational pathway by which mitochondrial
enzymes involved in all aspects of cardiac energy metabolism can be regulated. Thus, we will also discuss the effect of acetylation
of metabolic enzymes on myocardial energy substrate preference in the settings of heart failure. Finally, we will focus on pharmacological
interventions that target enzymes involved in fatty acid uptake, fatty acid oxidation, transcriptional regulation of fatty acid oxidation,
and glucose oxidation to treat heart failure.