Cardiovascular disease is the leading cause of death and disability for people living in western societies, with ischaemic
heart disease accounting for the majority of this health burden. The primary treatment for ischaemic
heart disease consists of either improving blood and
oxygen supply to the heart or reducing the heart's
oxygen demand. Unfortunately, despite recent advances with these approaches, ischaemic
heart disease still remains a major health problem. Therefore, the development of new treatment strategies is still required. One exciting new approach is to optimize cardiac energy metabolism, particularly by decreasing the use of
fatty acids as a fuel and by increasing the use of
glucose as a fuel. This approach is beneficial in the setting of ischaemic
heart disease, as it allows the heart to produce energy more efficiently and it reduces the degree of
acidosis associated with ischaemia/reperfusion.
Malonyl CoA is a potent endogenous inhibitor of cardiac
fatty acid oxidation, secondary to inhibiting
carnitine palmitoyl
transferase-I, the rate-limiting
enzyme in the mitochondrial uptake of
fatty acids.
Malonyl CoA is synthesized in the heart by
acetyl CoA carboxylase, which in turn is phosphorylated and inhibited by 5'AMP-activated
protein kinase. The degradation of myocardial
malonyl CoA occurs via
malonyl CoA decarboxylase (MCD). Previous studies have shown that inhibiting MCD will significantly increase cardiac
malonyl CoA levels. This is associated with an increase in
glucose oxidation, a decrease in
acidosis, and an improvement in cardiac function and efficiency during and following ischaemia. Hence, the
malonyl CoA axis represents an exciting new target for the treatment of ischaemic
heart disease.