Modulating fatty acid oxidation in heart failure

Abstract

In the advanced stages of heart failure, many key enzymes involved in myocardial energy substrate metabolism display various degrees of down-regulation. The net effect of the altered metabolic phenotype consists of reduced cardiac fatty oxidation, increased glycolysis and glucose oxidation, and rigidity of the metabolic response to changes in workload. Is this metabolic shift an adaptive mechanism that protects the heart or a maladaptive process that accelerates structural and functional derangement? The question remains open; however, the metabolic remodelling of the failing heart has induced a number of investigators to test the hypothesis that pharmacological modulation of myocardial substrate utilization might prove therapeutically advantageous. The present review addresses the effects of indirect and direct modulators of fatty acid (FA) oxidation, which are the best pharmacological agents available to date for 'metabolic therapy' of failing hearts. Evidence for the efficacy of therapeutic strategies based on modulators of FA metabolism is mixed, pointing to the possibility that the molecular/biochemical alterations induced by these pharmacological agents are more complex than originally thought. Much remains to be understood; however, the beneficial effects of molecules such as perhexiline and trimetazidine in small clinical trials indicate that this promising therapeutic strategy is worthy of further pursuit.

Figure 1

Cardiomyocyte substrates utilization. (A) Healthy cardiomyocyte. Cardiomyocyte mainly uses FAs that enter into the cell and are converted in the mitochondria through the carnitine palmitoyltransferase type 1 and type 2 (CPT-1 and CPT-2), and the carnitine acylcarnitine translocase (CT) before being used by β-oxidation (β-Ox) to produce FADH₂, H₂O, NADH, and acetyl-CoA. Glucose and lactate enter into the cells and are transformed into pyruvate by glycolysis and lactate dehydrogenase, respectively. (B) Early HF cardiomyocyte. In early HF, FA utilization is blunted, mitochondrial FA β-Ox decreases, while uptake and metabolism of the competing substrate glucose increase. (C) End-stage HF cardiomyocyte. In overt HF, FA uptake and metabolism are significantly depressed; although, the glucose uptake and metabolism is significantly enhanced. RV, right ventricle; LV, left ventricle; FA-CoA, fatty acyl-coenzyme A; FADH₂, reduced form of flavine adenine dinucleotide; NADH, reduced form of nicotinamide adenine dinucleotide.

Figure 2

Targets for modulation of myocardial FA metabolism. Indirect modulators of FAO: β-blockers, glucose–insulin–potassium solution (GIK), nicotinic acid or related analogues (acipimox). Direct modulators of FAO: PPARα agonists, carnitine palmitoyltransferase type 1 (CPT-1) inhibitors, β-oxidation (β-Ox) inhibitors. FA-CoA, fatty acyl-coenzyme A; CPT-2, carnitine palmitoyltransferase type 2; CT, carnitine acylcarnitine translocase.