Cardiac metabolism in heart failure: implications beyond ATP production

Abstract

The heart has a high rate of ATP production and turnover that is required to maintain its continuous mechanical work. Perturbations in ATP-generating processes may therefore affect contractile function directly. Characterizing cardiac metabolism in heart failure (HF) revealed several metabolic alterations called metabolic remodeling, ranging from changes in substrate use to mitochondrial dysfunction, ultimately resulting in ATP deficiency and impaired contractility. However, ATP depletion is not the only relevant consequence of metabolic remodeling during HF. By providing cellular building blocks and signaling molecules, metabolic pathways control essential processes such as cell growth and regeneration. Thus, alterations in cardiac metabolism may also affect the progression to HF by mechanisms beyond ATP supply. Our aim is therefore to highlight that metabolic remodeling in HF not only results in impaired cardiac energetics but also induces other processes implicated in the development of HF such as structural remodeling and oxidative stress. Accordingly, modulating cardiac metabolism in HF may have significant therapeutic relevance that goes beyond the energetic aspect.

Keywords: heart failure; hypertrophy/remodeling; metabolism; mitochondria.

Figures

Figure 1. Schematic representation of classic pathways of cardiac metabolism

Substrates are transported across the extracellular membrane into the cytosol and are metabolized in various ways. For oxidation, the respective metabolic intermediates (e.g., pyruvate or acyl-CoA) are transported across the inner mitochondrial membrane by specific transport systems. Once inside the mitochondrion, substrates are oxidized or carboxylated (anaplerosis) and fed into the Krebs cycle for the generation of reducing equivalents (NADH2 and FADH) and GTP. The reducing equivalents are used by the electron transport chain to generate a proton gradient, which in turn is used for the production of ATP. This principal functionality can be affected in various ways during HF thereby limiting ATP production or affecting cellular function in other ways (see text and further Figures for details). IMS: mitochondrial intermembrane space; GLUT: glucose transporter; FAT: fatty acid transporter. MPC: mitochondrial pyruvate transporter. (Illustration Credit: Ben Smith)

Figure 2. Alterations in substrate metabolism and mitochondria during the development of HF

Bold lines indicate pathways reported to be activated. Thin lines represent pathways reported decreased. The question marks imply unknown changes or inconsistent observations. IMS: mitochondrial intermembrane space; GLUT: glucose transporter; FAT: fatty acid transporter. (A) Fatty acid oxidation is impaired in cardiac hypertrophy and failure leading to reduced ATP production. (B) HBP: hexosamine biosynthetic pathway; PPP: pentose phosphate pathway; TG: triglyceride. Most evidence suggests that glucose oxidation is unchanged in compensated hypertrophy and decreased in HF, but discrepancies exist. In contrast, several non-ATP-generating pathways of glucose metabolism (HBP, PPP, anaplerosis) are induced. (C) Increased generation of mitochondrial ROS (perhaps due to changes in the electron transport chain) causes direct mitochondrial damage, which may further increase mitochondrial ROS production to create a vicious cycle. Mitochondrial damage results in ATP deficiency. Mitochondrial ROS may also cause oxidative damage to other cellular components and may contribute to adverse structural remodeling. (Illustration Credit: Ben Smith)

Figure 3. Overview of metabolic remodeling and proposed mechanisms linking it to other processes in the progression to HF

H: Hexosamine biosynthetic pathway (HBP); P: Pentose phosphate pathway (PPP); G: Glycolysis; A: Anaplerosis; O: Oxidation; ETC: Electron transport chain; ROS: reactive oxygen species; UPS: ubiquitin-proteasome system. Metabolic pathways are blue. Bold lines indicate pathways/ processes that are increased or dominant. Thin lines represent pathways/ processes that are decreased. The question marks imply unknown causes/ effects. In general, metabolic remodeling in cardiac hypertrophy and failure is characterized by a shift away from energy production to activation of biosynthetic pathways required for structural remodeling processes such as ventricular hypertrophy and fibrosis. Particularly, fatty acid oxidation is decreased and may not be sufficiently compensated given the lack of increase in glucose oxidation. These alterations and further mitochondrial defects result in ATP depletion. Instead of being oxidized, pyruvate may be preferentially used for anaplerosis to maintain Krebs cycle moieties, which might be increasingly channeled into protein synthesis. Hypertrophic mediators such as MAPKs and NFAT are activated as a result of increased mitochondrial ROS and flux through the HBP, respectively. Overproduction of mitochondrial ROS causes oxidative damage. Although the flux through the PPP is increased, anti-oxidative defense might be inadequate due to the consumption of NADPH by the anaplerotic malic enzyme. Mitochondrial damage and ATP depletion may stimulate autophagy. Increased activity of autophagy and the UPS may contribute to hypertrophy by providing amino acids and other metabolites. Increase in mitophagy may trigger myocardial inflammation by releasing mitochondrial DNA.

Figure 4. Simplified illustration of the relationship between cardiac metabolism and contractile function, reflecting the role of ATP production and non-ATP producing processes

In the normal heart under steady state conditions (A), the main metabolic task is to produce ATP for contractile function. Alternative pathways such as the pentose phosphate pathway (PPP), the hexosamine biosynthetic pathway (HBP), the activation of autophagy or the production of reactive oxygen species (ROS) and others play a minor role. In the progression to HF (B), ATP producing capacity is reduced. In addition, the alternative pathways may be activated to various degrees. Such activation may provide additional metabolic mechanisms influencing contractile function that could represent potential new metabolic targets for therapy.