Mitochondrial fatty acid oxidation alterations in heart failure, ischaemic heart disease and diabetic cardiomyopathy

Abstract

Heart disease is a leading cause of death worldwide. In many forms of heart disease, including heart failure, ischaemic heart disease and diabetic cardiomyopathies, changes in cardiac mitochondrial energy metabolism contribute to contractile dysfunction and to a decrease in cardiac efficiency. Specific metabolic changes include a relative increase in cardiac fatty acid oxidation rates and an uncoupling of glycolysis from glucose oxidation. In heart failure, overall mitochondrial oxidative metabolism can be impaired while, in ischaemic heart disease, energy production is impaired due to a limitation of oxygen supply. In both of these conditions, residual mitochondrial fatty acid oxidation dominates over mitochondrial glucose oxidation. In diabetes, the ratio of cardiac fatty acid oxidation to glucose oxidation also increases, although primarily due to an increase in fatty acid oxidation and an inhibition of glucose oxidation. Recent evidence suggests that therapeutically regulating cardiac energy metabolism by reducing fatty acid oxidation and/or increasing glucose oxidation can improve cardiac function of the ischaemic heart, the failing heart and in diabetic cardiomyopathies. In this article, we review the cardiac mitochondrial energy metabolic changes that occur in these forms of heart disease, what role alterations in mitochondrial fatty acid oxidation have in contributing to cardiac dysfunction and the potential for targeting fatty acid oxidation to treat these forms of heart disease.

Keywords: PPARα; glucose oxidation; malonyl CoA; pyruvate dehydrogenase.

Figure 1

Overview of fatty acid and glucose oxidation in the heart. ACC, acetyl CoA carboxylase; AMPK, AMP-activated protein kinase; CPT, carnitine palmitoyl transferase; CAT, carnitine translocase; FACS, fatty acyl CoA synthetase; FAT, fatty acid transporter; GLUT, glucose transporter; LDH, lactate dehydrogenase; MCD, malonyl CoA decarboxylase; MPC, mitochondrial pyruvate carrier; PDH, pyruvate dehydrogenase; PDK, pyruvate dehydrogenase kinase; PDP, pyruvate dehydrogenase phosphatase; TCA, tricarboxylic acid; TG, triacylglycerol.

Figure 2

Diagram of how the alterations in fatty acid oxidation that occur in (A) heart failure, (B) ischaemic/reperfusion and (C) diabetic cardiomyopathy can lead to impaired cardiac function.

Figure 3

Diagrams of how drugs that inhibit fatty acid oxidation [trimetazidine, etomoxir, perhexiline, PPAR agonists and malonyl CoA decarboxylase (MCD) inhibitors] and increase glucose oxidation (dichloroacetate/DCA) improve cardiac function in (A) heart failure, (B) ischaemia/reperfusion and (C) diabetic cardiomyopathy.