Targeting Myocardial Substrate Metabolism in the Failing Heart: Ready for Prime Time?

Abstract

Purpose of review: We review the clinical benefits of altering myocardial substrate metabolism in heart failure.

Recent findings: Modulation of cardiac substrates (fatty acid, glucose, or ketone metabolism) offers a wide range of therapeutic possibilities which may be applicable to heart failure. Augmenting ketone oxidation seems to offer great promise as a new therapeutic modality in heart failure. The heart has long been recognized as metabolic omnivore, meaning it can utilize a variety of energy substrates to maintain adequate ATP production. The adult heart uses fatty acid as a major fuel source, but it can also derive energy from other substrates including glucose and ketone, and to some extent pyruvate, lactate, and amino acids. However, cardiomyocytes of the failing heart endure remarkable metabolic remodeling including a shift in substrate utilization and reduced ATP production, which account for cardiac remodeling and dysfunction. Research to understand the implication of myocardial metabolic perturbation in heart failure has grown in recent years, and this has raised interest in targeting myocardial substrate metabolism for heart failure therapy. Due to the interdependency between different pathways, the main therapeutic metabolic approaches include inhibiting fatty acid uptake/fatty acid oxidation, reducing circulating fatty acid levels, increasing glucose oxidation, and augmenting ketone oxidation.

Keywords: Cardiac metabolism; Fatty acid; Glucose; Heart failure; Ketone bodies.

Fig. 1

Metabolic modulation in heart failure. Reduction of fatty acid oxidation (FAO) can be achieved by decreasing circulating fatty acid levels (with the use peroxisome proliferator–activated receptor (PPAR) agonists and β-adrenoceptor antagonists), decreasing mitochondrial uptake of fatty acid (with the use of carnitine palmitoyl transferase 1 (CPT1) inhibitors etomoxir and perhexiline), or inhibiting FAO directly (with the use of trimetazidine). Stimulating glucose uptake and/or oxidation can be done by increasing glucose uptake (with the use of glucagon-like peptide-1 receptor agonists (GLP-1RAs) or increasing glucose oxidation (with the use of dichloroacetate that increases pyruvate dehydrogenase (PDH) complex activity by inhibiting PDK4). Ketone oxidation can be augmented by increasing ketone availability with the use of sodium-glucose co-transporter 2 (SGLT2 inhibitors) and ketone supplementation (e.g., ketone salts, ketone ester). CD36, fatty acid translocase (FAT); GLUT4, glucose transporters 4; MCT1, monocarboxylate transporter 1; BDH, beta-hydroxybutyrate dehydrogenase; SCOT, succinyl-CoA:3-ketoacid-CoA transferase; ATP, adenosine triphosphate; TCA, tricarboxylic acid; ETC, electron transport chain. Part of the illustrations elements courtesy of Servier Medical Art. Servier Medical Art by Servier is licensed under a Creative Commons Attribution 3.0