Metabolic Drivers and Rescuers of Heart Failure

• Published in: Missouri medicine 2023-09, Vol.120 (5), p.354-358
• Main Authors: Weiss, Rachel C, Menezes, Thiago N, McCommis, Kyle S
• Format: Article
• Language: English
• Subjects: Adenosine triphosphate; Diet; Enzymes; Fatty acids; Glucose; Heart failure; Hypertension; Ketosis; Kinases; Metabolism; Oxidation; Phosphates; Protein synthesis; Proteins; Scientific
• ISSN: 0026-6620

Phosphocreatine (PCr) also plays an important role in buffering the high-energy phosphates in the heart, with (PCr) concentrations - 1.5-fold higher than ATP concentrations.3 Due to extremely high ATP hydrolysis rates and relatively low PCr and ATP pool sizes, constant ATP generation is required so that high-energy phosphate pools are not depleted within a matter of seconds.4 The principal cardiac metabolic pathways and how they are altered in hypertrophy and heart failure are summarized in Figure 1. Altered Metabolism in Hypertrophy and Heart Failure Decreased Fat Oxidation and Overall Oxidative Capacity In both human heart failure patients and animal models of hypertrophy/failure, one of the most consistent metabolic findings is a reduction in cardiac fatty acid uptake and oxidation.5"7 This decrease in fat oxidation is due, at least in part, to a transcriptional downregulation of fat oxidation enzymes and transporters, and other mitochondrial enzymes.6,8"10 As the heart normally relies on fat oxidation for the majority of ATP synthesis, unsurprisingly, failing human hearts contain significantly decreased ATP and PCr levels.3 Patients with fatty acid oxidation disorders as well as mouse models of cardiac fat oxidation enzyme/transporter deficiency can develop cardiomyopathy11"14 suggesting that loss of fat oxidation directly contributes to heart failure pathology. With increased glucose uptake and decreased glucose oxidation, one would expect glycogen stores to increase, as we have found in failing mitochondrial pyruvate carrier-deficient hearts.1617 Indeed, G6P is an allosteric activator of glycogen synthase, the rate-limiting step of glycogen formation.22 Interestingly, in hypertrophied hearts, it has been suggested that glycolysis is increased from exogenous glucose, but glycogenolysis remains normal.23 Typically, glycogen stores are very low in cardiomyocytes, and it is well-established that glycogen storage diseases are associated with cardiac hypertrophy and cardiomyopathy24 One potential mechanism for cardiac glycogen accumulation affecting hypertrophic growth would be that glycogen can sequester and inhibit the activation of the energy sensor adenosine monophosphate-activated protein kinase (AMPK),25 leading to mTOR activation and anabolic growth. In support of this, it should be noted that mice with cardiac deletion of carnitine palmitoyltransferase 2 and defective fat oxidation develop heart failure that is not rescued by a ketogenic diet.13 Du