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EDITORIAL Cardiovascular Research (2011) 90, 191–193 doi:10.1093/cvr/cvr077 Spotlight on metabolic remodelling in heart failure Torsten Doenst 1* and E. Dale Abel 2 1 Department of Cardiothoracic Surgery, University of Jena, Erlanger Allee 101, Jena 07747, Germany; and 2Division of Endocrinology, Metabolism and Diabetes, and Program in Molecular Medicine, University of Utah School of Medicine, Salt Lake City, UT 84112, USA Online publish-ahead-of-print 23 March 2011 This editorial refers to a collection of nine review articles invited for this special issue on metabolic remodelling in heart failure, guest edited by Torsten Doenst and E. Dale Abel The term ‘remodelling’ has been abundantly used in the context of heart failure with many different meanings.1 – 3 It was originally described in a rat model as the structural and functional response of the remote heart muscle to a local infarct caused by the occlusion of the left anterior descending coronary artery.4 Thereafter, a plethora of experimental and clinical studies have addressed mechanisms of remodelling and the concept is widely linked to the development of heart failure.5 However, metabolic aspects of remodelling have until recently been less well investigated. The development of new molecular techniques, including diverse approaches to global analysis of gene expression6,7 and broad-based approaches such as proteomics and metabolomics8 – 10 has provided a wealth of new information on underlying mechanisms. However, the information derived from these techniques represent a ‘snapshot’ of a functional continuum because they require tissue samples which are usually derived from a specific time point. Although these approaches have proved to be extemely valuable, the functional relevance of many findings is not always obvious. For example, there has been a resurgence in the use of classic metabolic approaches such as assessing rates of substrate utilization, enzyme activities, and ATP synthesis rates. In the heart failure field, these developments are specifically important since changes in contractile function are associated with changes in energy demand (i.e. the processes involved in energy production and conversion). In this spotlight issue, a series of review articles are presented to address the current knowledge of changes in the energy-producing processes of the myocardium under conditions that directly or indirectly lead to heart failure—processes we define as ‘metabolic remodelling’. To understand these processes, some metabolism basics should be reviewed. Under normal conditions, the heart generates ATP by the consumption of energy substrates, mainly fatty acids (roughly 70%) with glucose and lactate contributing to the rest.11 The heart is also able to utilize other substrates such as pyruvate, amino acids, and ketone bodies. The main pathways include beta oxidation of fatty acids in the mitochondrion and cytosolic glycolysis of glucose followed by intramitochondrial oxidation of pyruvate. Important flux-determining steps are located at the level of the mitochondrion such as pyruvate dehydrogenase for glucose and carnitine palmitoyltransferase-1 for fatty acid oxidation, which both generate the common end-product acetyl-CoA. Acetyl-CoA enters the tricarboxylic acid (TCA, citric acid, or Krebs) cycle where it is oxidized to generate reducing equivalents in the form of NADH + H+ and FADH2, as well as GTP. The reducing equivalents then enter the electron transport chain, which is located in the inner mitochondrial membrane. Three of the four complexes pump protons out of the matrix into the intermembrane space, generating a proton gradient across the inner mitochondrial membrane. This gradient is used by the FoF1-ATPase (complex V) to generate ATP. Alternative mechanisms that dissipate the proton gradient (e.g. mitochondrial uncoupling proteins, UCPs) reduce the efficiency of ATP production. The TCA cycle plays a central role in the oxidation of all substrates and the function of the oxidative phosphorylation (ATP-producing) machinery. During normal turnover of this cycle, moieties are lost which need to be replenished to maintain normal cycle flux. Several pathways exist for the heart to replenish these losses and to maintain normal substrate concentrations. These mechanisms [e.g. pyruvate carboxylation by malic enzyme or the conversion of branched-chain amino acids (BCAA) to succinyl-CoA] are derived from 3-C carbon sources and exemplify the process known as anaplerosis.12 Thus, anaplerotic flux tightly correlates with the relative consumption of energy-producing substrates (i.e. the more glucose is utilized, the more anaplerosis is possible).11 Substrate selection can be influenced by differences in supply, hormones (e.g. insulin or catecholamines), and intracellular regulators such as the AMP-activated protein kinase (AMPK).13 Under conditions of pressure overload or ischaemia leading to heart failure, energy substrate uptake and selection as well as the associated metabolic regulatory mechanisms are altered. In general, an early shift from reliance on fatty acids as the main oxidative substrate to glucose occurs (substrate switch), followed by a general reduction in oxidative capacity.14 Under conditions of pressure overload, this is characterized by mitochondrial dysfunction including reduced complex I activities and impaired oxidative capacity.14 – 16 Cardiac insulin resistance occurs and anaplerotic pathways are activated.17 Many of these changes may contribute to limitations in ATP production and support the hypothesis that the onset of contractile dysfunction is based on relative insufficiency of ATP production to fuel myocardial contraction. The opinions expressed in this article are not necessarily those of the Editors of the Cardiovascular Research or of the European Society of Cardiology. * Corresponding author. Tel: +49-3641-932-2901; fax: +49-3641-932-2902, Email: [email protected] Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2011. For permissions please email: [email protected]. 192 However, it is currently not clear if the limitations in ATP-producing capacity are the cause or a consequence of heart failure. It may well be that reduced ATP-producing capacity could be an adaptive response to reduced energy demand by a dysfunctional heart that is generating less work. In contrast, reduced cardiac efficiency in heart failure15,18,19 increases the ATP cost of performing cardiac work, which would support the argument that the reduction in ATPgenerating capacity might be maladaptive. These and other burning questions that impact a metabolic perspective on heart failure are discussed in the articles in this spotlight issue. Two reviews address the role of glucose metabolism20 and fatty acid oxidation21 in the context of cardiac hypertrophy and heart failure, respectively. Kolwicz and Tian,20 addressing glucose metabolism in hypertrophy, describe the phenomenon of the relative increase in reliance on glucose as an oxidative substrate. They point out that, based on transgenic models and pharmacological studies, evidence is available that increasing glucose oxidation under conditions of hypertrophy is not harmful, but the therapeutic potential of metabolic strategies lies more in the arena of general improvement in oxidative capacity. This conclusion is consistent with those of Lionetti et al. 21 who focus on fatty acid oxidation in heart failure. They describe the generally accepted impairment in beta-oxidation and the occurrence of a substrate switch, but then pose the question whether this switch is adaptive or maladaptive. In their attempt to provide an answer to this question they review the currently available ways to influence fatty acid oxidation pharmacologically. They found that, although the evidence is not fully convincing, based on small clinical trials it is reasonable to expect that inhibition of fatty acid oxidation and stimulation of glucose oxidation under conditions of heart failure may be helpful. Des Rosier et al.22 describe anaplerotic mechanisms that could translate into metabolic treatment strategies. Anaplerotic pathways are potentially protective under conditions leading to heart failure. The authors review these pathways, explore potential ways to exploit them therapeutically, and illustrate lessons from specific human diseases involving defects in anaplerotic pathways as well as their metabolic treatment. Wang and colleagues23 complement the work of Des Rosiers et al. 22 by describing a field that has received much less attention in the metabolic arena over the past years, i.e. branched-chain amino acid (BCAA) metabolism. BCAA can be utilized as fuel for anaplerotic processes but also play a role in cardiac development. Recent genetic mouse models with defects in BCAA catabolism reveal that accumulation of BCAA and their degradation products can cause heart failure, thereby opening a new potential window for metabolic approaches for heart failure therapy. Beauloye et al.24 describe another potential metabolic target in heart failure—the AMPK. AMPK is considered the ‘fuel gauge’ of the cell, sensing states of low energy and activating practically all energy-producing processes. Thus, AMPK may be a good target for therapy in the failing heart that is potentially short of ATP. Contrary to expectations, these authors arrive at the conclusion that AMPK activation fails to restore normal energy conditions. They attribute this failure to defects in some downstream pathways that may be activated by AMPK such as beta oxidation. They also distinguish between metabolic and non-metabolic effects of AMPK and pinpoint current experimental shortcomings that require further investigation before a final verdict on the role of AMPK as a target for heart failure treatment can be made. Editorial As many of these pathways converge on mitochondria, it is no surprise that mitochondria have garnered increasing attention in metabolism research. The review by Abel and Doenst25 attempts to illustrate that metabolic characteristics of hypertrophic stimuli correlate strongly with the outcome of a hypertrophic stimulus as exemplified by hypertrophy that leads to heart failure (defined as pathologic hypertrophy) or hypertrophy that is associated with continuously normal function (defined as physiological hypertrophy). We review distinct mitochondrial adaptations that characterize and distinguish these two types of hypertrophy. We suggest that physiological hypertrophy is characterized by increased mitochondrial biogenesis, whereas stimuli causing pathological hypertrophy impair mitochondrial biogenesis and function. Baskin and Taegtmeyer26 draw important parallels between structural and metabolic changes in the heart and provide an interesting perspective on parallels between hypertrophic and atrophic remodelling. They review the metabolic and protein turnover responses to ventricular unloading that leads to cardiac atrophy and compare these changes to hypertrophic remodelling. They propose a unifying concept of hypertrophic and atrophic structural and metabolic remodelling that underscores similar patterns of regulatory pathways that govern protein synthesis and degradation. Tuunanen and Knuuti27 address the human relevance of metabolic remodelling and describe the current knowledge of heart failure-associated changes in human metabolism. They point out that cardiac insulin resistance, although still controversial regarding its actual presence, is an independent risk factor for the development of heart failure. Several metabolic approaches to treating heart failure are also described, although none have yet produced convincing evidence justifying metabolic interventions in heart failure, and the need for large randomized trials is highlighted. Finally, Terzic and colleagues28 focus on the ATP-sensitive K+ channel and review how the use of proteomics, gene ontology analyses, and gene expression profiling can be functionally integrated using systems biology approaches in mouse models to clearly identify the role of individual cellular components in metabolic function. These approaches can be used to predict disease susceptibility and suggest novel therapeutic strategies. In summary, this spotlight issue brings to the forefront the tight relationship between energy substrate metabolism and cardiac function and pinpoints clear targets for metabolic therapy that are immediately testable or that hold promising potential for future development. The use of powerful molecular technologies has enabled us to more clearly identify the role of individual cellular components that advances our global understanding of metabolism in the healthy or failing heart. Conflict of interest: none declared References 1. Gaudron P, Eilles C, Kugler I, Ertl G. Progressive left ventricular dysfunction and remodeling after myocardial infarction. Potential mechanisms and early predictors. Circulation 1993;87:755 – 763. 2. Tamura T, Said S, Harris J, Lu W, Gerdes AM. Reverse remodeling of cardiac myocyte hypertrophy in hypertension and failure by targeting of the renin-angiotensin system. Circulation 2000;102:253 – 259. 3. Cohn JN. Structural basis for heart failure. 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