Cardiac Energy Metabolism in Heart Failure

Abstract

Alterations in cardiac energy metabolism contribute to the severity of heart failure. However, the energy metabolic changes that occur in heart failure are complex and are dependent not only on the severity and type of heart failure present but also on the co-existence of common comorbidities such as obesity and type 2 diabetes. The failing heart faces an energy deficit, primarily because of a decrease in mitochondrial oxidative capacity. This is partly compensated for by an increase in ATP production from glycolysis. The relative contribution of the different fuels for mitochondrial ATP production also changes, including a decrease in glucose and amino acid oxidation, and an increase in ketone oxidation. The oxidation of fatty acids by the heart increases or decreases, depending on the type of heart failure. For instance, in heart failure associated with diabetes and obesity, myocardial fatty acid oxidation increases, while in heart failure associated with hypertension or ischemia, myocardial fatty acid oxidation decreases. Combined, these energy metabolic changes result in the failing heart becoming less efficient (ie, a decrease in cardiac work/O 2 consumed). The alterations in both glycolysis and mitochondrial oxidative metabolism in the failing heart are due to both transcriptional changes in key enzymes involved in these metabolic pathways, as well as alterations in NAD redox state (NAD + and nicotinamide adenine dinucleotide levels) and metabolite signaling that contribute to posttranslational epigenetic changes in the control of expression of genes encoding energy metabolic enzymes. Alterations in the fate of glucose, beyond flux through glycolysis or glucose oxidation, also contribute to the pathology of heart failure. Of importance, pharmacological targeting of the energy metabolic pathways has emerged as a novel therapeutic approach to improving cardiac efficiency, decreasing the energy deficit and improving cardiac function in the failing heart.

Lipotoxicity: a driver of heart failure with preserved ejection fraction?

“…Data suggest that both types of dysfunction are characterised by reduced mitochondrial oxidative metabolism, resulting in reduced ATP production, which is compensated for to some extent by increasing glycolysis [76]. During systolic dysfunction and HFrEF, myocardial fatty acid oxidation (FAO) is reduced, concordant with a generalised reduction in mitochondrial respiration [77]. However, the story is a little more complex in HFpEF.…”

“…This may be through effects on the mitochondrial membrane: both ROS and peroxynitrite can target mitochondrial membrane phospholipids such as cardiolipin to generate lipid peroxidation products, which have been observed to accumulate in heart failure and are known to induce mitochondrial uncoupling and calcium overload [136]. This is problematic, as mitochondrial calcium homeostasis is critical for mitochondrial function; any deviations from optimal levels can result in reduced metabolic enzyme activity or activation of cell death pathways [77]. The mitochondrial membrane may additionally be altered directly by excess lipids themselves.…”

“…Pressure overload-induced heart failure is associated with significantly impaired cardiac oxidative capacity, mainly due to mitochondrial defects [145]. Furthermore, the enhanced mitophagy and reduced mitochondrial biogenesis observed in heart failure could reduce mitochondrial numbers, thereby potentially reducing the oxidative capacity of the cell further [77]. Correspondingly, the ratio of phosphocreatine to ATP -an indicator of myocardial energy reserve -is significantly reduced in HFpEF [146].…”

Senescence and Type 2 Diabetic Cardiomyopathy: How Young Can You Die of Old Age?

“…Under physiological conditions fatty acid oxidation (FAO) accounts for approximately 70%, whilst the remaining contribution is from oxidation of carbohydrates via pyruvate and lactate. Substrate usage by the heart is flexible, as the substrate utilisation ratio is rapidly adjusted in order to maintain a continuous ATP supply (reviewed in (Lopaschuk et al, 2021)). Severe metabolic alterations characterise the diabetic heart, with changes in substrate utilization, alterations in mitochondrial organisation and function, together with enhanced ROS production all being observed and which collectively lead to energetic deficit (reviewed in (Marelli-Berg and Aksentijevic, 2019)).…”

GCN5L1 promotes diastolic dysfunction by inhibiting cardiac pyruvate oxidation

“…Deleterious changes in energy metabolism underpin the development of heart failure with preserved ejection fraction (HFpEF) [1] . Studies on two recently developed murine models of HFpEF have reported altered cardiac fuel substrate utilization, culminating in changes to the relative oxidation rates of fatty acids, ketone bodies, and glucose in failing hearts [2,3] .…”