Targeting myocardial substrate metabolism in heart failure: potential for new therapies

Abstract

The incidence and prevalence of heart failure have increased significantly over the past few decades. Available data suggest that patients with heart failure independent of the aetiology have viable but dysfunctional myocardium that is potentially salvageable. Although a great deal of research effort has focused on characterizing the molecular basis of heart failure, cardiac metabolism in this disorder remains an understudied discipline. It is known that many aspects of cardiomyocyte energetics are altered in heart failure. These include a shift from fatty acid to glucose as a preferred substrate and a decline in the levels of ATP. Despite these demonstrated changes, there are currently no approved drugs that target metabolic enzymes or proteins in heart failure. This is partly due to our limited knowledge of the mechanisms and pathways that regulate cardiac metabolism. Better characterization of these pathways may potentially lead to new therapies for heart failure. Targeting myocardial energetics in the viable and potentially salvageable tissue may be particularly effective in the treatment of heart failure. Here, we will review metabolic changes that occur in fatty acid and glucose metabolism and AMP-activated kinase in heart failure. We propose that cardiac energetics should be considered as a potential target for therapy in heart failure and more research should be done in this area.

Figure 1

Cardiac metabolism and defects in heart failure. Under normal conditions, cardiomyocytes mostly utilize free fatty acids as their primary substrate. However, with pressure overload and heart failure, cardiomyocytes switch substrate preference to glucose. There is also decreased activity of fatty acid β-oxidation, tricarboxylic acid (TCA) cycle enzymes, and complexes involved in the electron transport chain (ETC) in heart failure. Red arrows show defects in cellular metabolism in heart failure. For more details, please refer to the text.

Figure 2

Insulin resistance in heart failure leads to decreased glucose uptake by cardiomyocytes via decreased translocation of GLUT4 to the sarcolemma. Fewer GLUT4 transporters result in decreased glucose flux into the myocyte. Strategies to augment glucose metabolism in heart failure include increasing glucose uptake and oxidation by the cardiomyocyte. Administration of exogenous insulin may increase GLUT4 transporter translocation. In addition, GLP-1 has been shown to increase GLUT1 translocation from intracellular vesicles to the plasma membrane. Glucose oxidation can be increased by blocking the inhibitory effects of PDK on PDH. Increased PDH activity allows for increased oxidation of pyruvate into acetyl-CoA which can enter the citric acid cycle to generate ATP. A-CoA, acetyl-CoA; DCA, dichloroacetate; ER, endoplasmic reticulum; GLP-1, glucagon-like peptide-1; GLUT4, glucose transporter type 4; IR, insulin receptor; MITO, mitochondria; PDH, pyruvate dehyrdogenase; PDK, pyruvate dehydrogenase kinase.

Figure 3

Role of AMP-activated protein kinase (AMPK) in cellular energy homeostasis. Not all processes have been demonstrated in myocardial cells.

Figure 4

Progressive metabolic derangements in heart failure. External insults or stimuli such as ischaemia/infarction or the development of cardiac hypertrophy are associated with early metabolic derangements that serve to increase glucose utilization and contribute to early insulin resistance. This cardiac dysfunction also leads to increased adrenergic tone, which has delayed effects on fatty acid metabolism and the cellular AMP:ATP ratio, ultimately compounding the early metabolic derangements and resulting in decreased myocardial energy efficiency and increased myocardial oxygen consumption. These metabolic derangements are partly blunted by the effects of the key metabolic regulator, AMP-activated protein kinase (AMPK). However the effects of AMPK cannot fully rectify these problems, and the alteration in substrate utilization and global myocardial metabolic dysregulation contribute to progressive myocardial dysfunction and overt heart failure.