Download Spotlight on metabolic remodelling in heart failure

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].
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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
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