Optimization of cardiac metabolism in heart failure

Abstract

The derangement of the cardiac energy substrate metabolism plays a key role in the pathogenesis of heart failure. The utilization of non-carbohydrate substrates, such as fatty acids, is the predominant metabolic pathway in the normal heart, because this provides the highest energy yield per molecule of substrate metabolized. In contrast, glucose becomes an important preferential substrate for metabolism and ATP generation under specific pathological conditions, because it can provide greater efficiency in producing high energy products per oxygen consumed compared to fatty acids. Manipulations that shift energy substrate utilization away from fatty acids toward glucose can improve the cardiac function and slow the progression of heart failure. However, insulin resistance, which is highly prevalent in the heart failure population, impedes this adaptive metabolic shift. Therefore, the acceleration of the glucose metabolism, along with the restoration of insulin sensitivity, would be the ideal metabolic therapy for heart failure. This review discusses the therapeutic potential of modifying substrate utilization to optimize cardiac metabolism in heart failure.

Fig. (1).

Normal myocardial energy metabolism. ANT, adenine nucleotide translocase; ACC, acetyl-CoA carboxylase; CPT, carnitine palmitoyltransferase; FABP, fatty acid binding protein; FACS, fatty acyl-CoA synthase; FAT, fatty acid transporter; FFA, free fatty acid; GLUT, glucose transporter; G-6-P, glucose-6-phosphate; MCD, malonyl-CoA decarboxylase; PFK, Phosphofructokinase; PDH, pyruvate dehydrogenase; TCA, tricarboxylic acid cycle.

Fig. (2).

ATP regulates the electrolyte balance, including Ca²⁺ homeostasis. CICR, Ca-induced Ca release; NCX, Na⁺/Ca²⁺ exchanger; NHE, Na⁺/H⁺ exchanger; SERCA, sarcoplasmic reticulum Ca²⁺ ATPase pump.

Fig. (3).

A schematic representation of Akt-mediated feedback inhibition in heart failure. Insulin or IGF-1 signaling exerts cardioprotective effects through the acute activation of its down-stream effectors, such as IRS-1, PI3K and Akt. In contrast, the phosphorylation of IRS-1 induced by chronic Akt activation leads to their dissociation from PI3K, as well as proteasome-dependent degradation, thus leading to detrimental results. Similar negative feedback inhibition of IRS-1 is also observed in human heart failure where there is the persistent activation of Akt. Adapted from reference 45. DCM, dilated cardiomyopathy; GSK-3, glycogen synthase kinase-3; IGF-1, insulin like growth factor-1; IRS-1, insulin receptor substrate-1; PI3K, phosphoinositide 3-kinase