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Modification of myocardial substrate use
as a therapy for heart failure
Khalid Abozguia*, Kieran Clarke, Leong Lee and Michael Frenneaux
S U M M A RY
INTRODUCTION
Despite advances in treatment, chronic heart failure is still associated with
significant morbidity and a poor prognosis. The scope for further advances
based on additional neurohumoral blockade is small. Effective adjunctive
therapies acting via a different cellular mechanism would, therefore, be
attractive. Energetic impairment seems to contribute to the pathogenesis
of heart failure. The findings from several studies have shown that the socalled metabolic agents could have potential as adjunctive therapies in heart
failure. These agents cause a shift in the substrate used by the heart away
from free fatty acids, the oxidation of which normally provides around 70%
of the energy needed, towards glucose. The oxygen cost of energy generation
is lessened when glucose is used as the substrate. In this review we aim to
draw attention to the metabolic alteration in heart failure and we present
evidence supporting the use of metabolic therapy in heart failure.
KEYWORDS cardiac energetic, heart failure, metabolic manipulation,
myocardial energy metabolism, myocardial substrate metabolism
REVIEW CRITERIA
All articles were identified by searching PubMed. The search used the following
key phrases in different combinations: “metabolic manipulation”, “myocardial
energy metabolism”, “myocardial substrate metabolism”, “heart failure”,
“perhexiline”, “trimetazidine”, “etomoxir”, “ranolazine” and “oxfenicine”. All
referenced articles were full-text, English-language papers, published from 1960
to 2005. We searched the articles’ bibliographies and our own database
for further relevant papers.
K Abozguia is a British Heart Foundation Research Fellow in and
M Frenneaux is the Head of the Department for Cardiovascular Medicine,
University of Birmingham, Birmingham, UK. K Clarke is a professor
of physiological biochemistry in the University Laboratory of Physiology,
University of Oxford, Oxford, UK, and L Lee is a Specialist Registrar in the
Department of Cardiology, Queens Medical Centre, Nottingham University
Hospital, Nottingham, UK.
Correspondence
*Department of Cardiovascular Medicine, University of Birmingham, Edgbaston,
Birmingham B15 2TT, UK
[email protected]
Received 5 December 2005 Accepted 12 April 2006
www.nature.com/clinicalpractice
doi:10.1038/ncpcardio0583
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©2006 Nature Publishing Group
An important role for an abnormal cardiac
energetic status has been indicated in the pathophysiology of heart failure, even in the absence
of coronary artery disease.1 Most studies on metabolism in the heart have been done on human
biopsy samples2 or in vivo by use of phosphorus31 nuclear magnetic resonance spectroscopy.3
Findings indicate that the concentration of ATP
is approximately 20–30% lower in failing human
hearts than in healthy hearts, although this finding
has not been reported in all studies. In the rapid
pacing canine model of heart failure, a progressive monotonic decay of both ATP and the total
adenine nucleotide pool begins well before the
onset of heart failure.4
Phosphocreatine is an important short-term
reserve energy source that maintains a high
phosphorylation potential under conditions
of increased energy demand (e.g. exercise).
The transfer of a phosphoryl group from phosphocreatine to ADP by the enzyme creatine
kinase generates ATP at a rate approximately
10 times faster than the maximum rate of ATP
generation via oxidative phosphorylation.5 In
patients with mild to moderate heart failure,
cardiac ATP flux mediated by creatine kinase
is reduced by approximately 50%.6 Studies of
human and animal models of heart failure have
demonstrated a progressive reduction in the
creatine pool of up to 60%. The magnitude of
this reduction is related to the severity of heart
failure,7–9 and is largely due to a decrease in
the number of creatine transporters at sites of
energy production and utilization.10 In healthy
hearts, approximately two-thirds of the total
creatine pool is phosphorylated via the creatine
kinase reaction to form phosphocreatine. In
heart failure, the available phosphocreatine is
depleted to a greater degree than ATP, as indicated by reduced phosphocreatine-to-ATP
ratios seen on phosphorus-31 nuclear magnetic
resonance spectroscopy.11 The risk of death
increases as this ratio decreases.12 As well as
the reduced creatine pool, the reduction in
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phosphocreatine in heart failure is partly due
to reduced expression of the creatine kinase
isoenzymes, particularly of mitochondrial
creatine kinase, leading to a reduced ratio of
phosphocreatine to total creatine.10 Nitric oxide
produced by inducible nitric oxide synthase
might also inhibit mitochondrial creatine kinase
activity.13 Short-term oral creatine supplementation in chronic heart failure has been
shown to increase skeletal muscle function,
but no effect was observed on left ventricular
ejection fraction.14
The reduced ATP production and depletion of phosphocreatine stores in heart failure
produce a short-term buffer to acute increases
in ATP demand. The ability to generate ATP is
normally modulated via effects on mitochondrial
density, substrate use, expression and activities of mitochondrial enzymes, and adenosine
5´-monophosphate-activated protein kinase
systems. Peroxisome proliferative activated
receptor γ coactivator 1-α (PGC-1α) appears
to be a key energy sensor in these homeostatic
systems.15 Mice that are deficient in PGC-1α
exhibit reduced expression of genes of oxidative metabolism in cardiac and skeletal muscle,
associated with reduced levels of ATP. Young mice
exhibit reduced cardiac work output in response
to chemical or electrical stimulation, and
resting cardiac dysfunction develops with age.15
Maneuvers that could increase ATP production
even slightly might substantially improve the
status of patients. In this review we aim to draw
attention to the metabolic alteration in heart
failure and we present evidence supporting the
use of metabolic therapy for this condition.
MYOCARDIAL SUBSTRATE USE
IN HEART FAILURE
The fetal heart uses glucose as its primary
substrate, but a shift to predominant use of free
fatty acids occurs soon after birth.16 In adulthood, approximately 70% of energy production
in healthy hearts is derived from β-oxidation of
fatty acids,17 with the balance being obtained
from a mix of lactate, pyruvate and ketones.
Concentrations of all these substances fluctuate
because of control by metabolic mechanisms, but
the heart has the ability to alter the proportions
of substrates used to meet metabolic demands
when oxygen availability is limited; for example,
during ischemia the use of glucose increases,
although that of free fatty acids typically remains
at more than 50%. This consistent use of free
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fatty acids as the main substrate is thought to
represent a particular advantage.17
Much of the data on substrate use in heart
failure have been obtained from animal models of
left ventricular hypertrophy or of left ventricular
hypertrophy progressing to heart failure. Heart
failure is a complex syndrome, and the pattern
of substrate use seems to depend on species,
etiology, duration, whether underlying coronary
artery disease is present, endothelial dysfunction,
gene expression and whether comorbid disorders,
such diabetes and hypertension, are present.18
An increase in glucose use has frequently been
reported19,20 and is partly a consequence of a
shift in cardiac gene expression from the postnatal
pattern to a fetal pattern.16 Some controversy
exists as to whether the shift towards glucose use
is adaptive or maladaptive. In the rapid pacing
canine model of heart failure, in contrast to
models of left ventricular hypertrophy, the main
substrate is free fatty acids rather than glucose.21
More importantly, most studies of heart failure
in humans have reported that free-fatty-acid
use is either unchanged or increased compared
with that in healthy controls.22,23 Taylor et al.23
noted increased uptake of free fatty acids and
reduced use of glucose in a PET study of heart
failure. Contributory factors to this change
might include reduced transport of glucose via
insulin-stimulated glucose transporter 4,21 and
increased concentrations of free fatty acids in
plasma. Randle24 proposed that these mechanisms lead to increased use of free fatty acids
and to suppression of glucose use (Figure 1).
Although PET scanning offers high sensitivity in
humans, it provides no chemical specificity and
cannot distinguish the various fates of a substrate
(such as storage, oxidation, back diffusion, etc.).
Development of technologies such as carbon-13
nuclear magnetic resonance spectroscopy and
hyperpolarization might improve the yield of
biochemical information, but have yet to be
tested in humans.25
SUBSTRATE USE AND MYOCARDIAL
OXYGEN USE
Simple stoichiometry suggests that the use of
fatty acids should cost approximately 12% more
oxygen per unit of ATP generated than glucose.
Given that use of this substrate accounts for
approximately 70% of heart oxygen consumption in healthy individuals, and that interventions are unlikely to produce a complete
shift to either free-fatty-acid or glucose use,
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Insulin
FFA
Glucose
IR
Glut4
FATP1
Glucose
Hexokinase
→
FA-CoA
→
G6P
PFK
CPT1
Glycolysis
→
Citrate
ADP
ATP
Pyruvate
PDH
CPT2
→
Acetyl-CoA
Lactate
IMM
OMM
Figure 1 The glucose–fatty acid cycle in cardiomyocyte mitochondria. The relationship between glucose
and free fatty acid metabolism is thought to be reciprocal. Oxidation of free fatty acids can inhibit
catabolism of glucose in muscle, and the effects are mediated by inhibition of phosphofructokinase 1 and
of the pyruvate dehydrogenase complex. The mitochondrial concentration ratio of acetyl-coenzyme A to
coenzyme A inhibits the pyruvate dehydrogenase complex, the rise in citrate inhibits phosphofructokinase 1,
and the increase in glucose-6-phosphate inhibits hexokinase. Free fatty acid oxidation inhibits insulinstimulated accelerated glucose transport. While confirming the reciprocal relationship between metabolism
of free fatty acids and glucose, however, this mechanism has not been supported by the findings of several
human studies, and a cellular mechanism by which free fatty acids or their metabolites interfere with
glucose metabolism involving alteration of membrane properties and glucose transport is proposed.
Abbreviations: CoA, coenzyme A; CPT, carnitine palmitoyltransferase; FA-CoA, fatty acid coenzyme A;
FATP1, fatty acid transporter protein 1; FFA, free fatty acid; G6P, glucose-6-phosphate; Glut4, glucose
transporter 4; IMM, inner mitochondrial membrane; IR, insulin receptor; OMM, outer mitochondrial
membrane; PDH, pyruvate dehydrogenase; PFK, phosphofructokinase 1.
changes of less than 12% in oxygen consumption
would be anticipated. Several studies have
shown, however, that high concentrations of
free fatty acids were associated with a decrease in
cardiac mechanical efficiency of 30%.26,27 This
finding suggests an oxygen-wasting effect much
greater than that predicted by stoichiometry.
The difference in values might be explained by the
observation that activation of peroxisome
proliferative activated receptor α by free fatty
acids upregulates uncoupling-protein expression
in the mitochondria.28
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Normally, the electron transport chain results
in the generation of a net proton gradient across
the inner mitochondrial membrane. In tightly
coupled mitochondria little proton leakage
occurs across this membrane and all the energy
from the respiratory chain can be used to phosphorylate ADP to generate ATP. When mitochondria are uncoupled, protons leak into the
mitochondrion while long-chain fatty acids
from the mitochondrial matrix are transported
into the soluble cytoplasm; this process dissipates the electrochemical gradient.29 The export
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of long-chain fatty acids from the mitochondrion when fatty acid delivery exceeds oxidative
capacity seems, in fact, to be the primary role of
uncoupling proteins.29 Uncoupling could, therefore, be expected to occur when mitochondrial
concentrations of free fatty acids are raised.
The rate of this process will be increased when
uncoupling-protein expression rises, for example
when plasma concentrations of free fatty acids
become elevated because of sympathetic activation in heart failure. Consistent with this concept,
Murray and co-workers30 showed that mitochondrial uncoupling-protein expression in human
cardiac muscle correlated with a rise in plasma
concentrations of free fatty acids.30 An additional mechanism proposed for the extra oxygen
requirement in the use of free fatty acids as the
substrate is that high concentrations of free fatty
acids trigger intracellular futile metabolic cycles,
with wasteful cycling through intramyocardial
lipolysis and re-esterification.31
METABOLIC AGENTS AS THERAPY FOR
HEART FAILURE
In a study in the late 1990s, intracoronary
pyruvate was shown to acutely increase stroke
volume and reduce pulmonary capillary wedge
pressure.32 The implication of this finding is
that an acute beneficial shift away from fatty
acid metabolism can be achieved. Since that
study was reported, several others have demonstrated similar beneficial effects of modifying
substrate use in chronic heart failure. Several
pharmacologic agents have been shown to
inhibit the use of free fatty acids in the heart,
either by inhibiting uptake into the mitochondria or by inhibiting β-oxidation. Some of these
agents are used as antianginal agents because of
their oxygen-sparing actions.
Trimetazidine
Trimetazidine (1-[2,3,4-trimethoxybenzyl]
piperazine dihydrochloride) can lessen oxidation
of free fatty acids via inhibition of the enzyme
long-chain 3-ketoacyl coenzyme A thiolase,
which is crucial in the β-oxidation pathway.33
This mechanism might not, however, be the only,
or even the principal, route of action for this
drug.34 Trimetazidine, an effective antianginal
therapy, has a favorable side-effect profile and
exhibits no notable vasodilator properties at rest
or during dynamic exercise.35 Left ventricular
systolic and diastolic function and quality of
life improved after trimetazidine therapy in a
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double-blind, placebo-controlled trial involving
47 patients with coronary artery disease and a
reduced left ventricular function who were
limited by angina but not by heart failure.36
In an open-label study of 18 months’ duration, Di Napoli et al.37 demonstrated a significant improvement in left ventricular function
in patients who had ischemic cardiomyopathy
with left ventricular ejection fractions lower than
40%. Patients were excluded if they had experienced acute myocardial infarction less than
3 months previously, or had acute heart failure
or cardiac decompensation, and many patients
were taking suboptimum conventional therapy.
Rosano and colleagues38 demonstrated improvements in left ventricular ejection fraction among
patients with diabetes and coronary heart disease
and left ventricular systolic dysfunction, but
without frank heart failure, following 6 months
of trimetazidine therapy. By contrast, another
study, which assessed the effects of trimetazidine
in patients with heart failure who were diabetic,
demonstrated no significant effect on exercise
capacity and only minor effects on left ventricular systolic function in both resting and exercise states.39 Most of the patients studied so far,
however, do not have overt heart failure and
findings need clarification for this indication.
Ranolazine
Ranolazine has been shown to partly inhibit fatty
acid β oxidation,40,41 but these findings have not
been reliably replicated in large experimental
or human studies. The principal mechanism of
action for this drug as an antianginal remains
controversial, although data demonstrating
blockade of the late sodium current have been
published.42 Ranolazine reduces sodium entry
into ischemic myocardial cells and, therefore, is
thought indirectly to reduce calcium uptake via
the sodium–calcium exchanger, to preserve ionic
homeostasis, and to reverse ischemia-induced
contractile dysfunction.42 In a study of a canine
microembolization model of heart failure, intravenous ranolazine increased myocardial work
without increasing myocardial oxygen use, which
implies an increase in cardiac efficiency.43 Acute
intravenous administration of ranolazine has
also improved left ventricular systolic function
in dogs with heart failure.44 The effects of ranolazine in humans with chronic heart failure have
not yet been reported. In experimental studies, the
drug slightly prolongs the QT interval on electrocardiograms. This effect has been associated with
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FFA
Glucose
Perhexiline
Etomoxir
Oxfenicine
? β-blockers
FATP1
Glut4
Glucose
FA-CoA
Trimetazidine
? ranolazine
Hexokinase
Malonyl-CoA
G6P
CPT1
Glycolysis
CPT2
Acyl-CoA
β-oxidation
Acetyl-CoA
carboxylase
Acetyl-CoA
PDH
ADP
ATP
Pyruvate
Lactate
IMM
OMM
Figure 2 Effects of metabolic agents on myocardial metabolism in cardiomyocyte mitochondria. Perhexiline,
oxfenicine, and etomoxir prevent uptake of free fatty acids via inhibition of carnitine palmitoyltransferase I,
which is a key enzyme in this process in mitochondria. Trimetazidine and possibly ranolazine inhibit
β-oxidation of free fatty acids. Evidence suggests that ranolazine acts via inhibiting late sodium entry into the
cardiomyocyte. These actions shift myocardial substrate use from free fatty acids to glucose, which is more
efficient in terms of energy production, leading to an oxygen-sparing effect. Abbreviations: CoA, coenzyme A;
CPT, carnitine palmitoyltransferase; FA-CoA, fatty acid coenzyme A; FATP1, fatty acid transporter protein 1;
FFA, free fatty acid; G6P, glucose-6-phosphate; Glut4, glucose transporter 4; IMM, inner mitochondrial
membrane; OMM, outer mitochondrial membrane; PDH, pyruvate dehydrogenase.
risk of ventricular tachycardia, particularly torsade
de pointes polymorphic ventricular tachycardia,
and with sudden cardiac death.45 The long-term
safety of ranolazine remains to be established.
Oxfenicine
Oxfenicine is an inhibitor of carnitine palmitoyltransferase I (CPT1), a key enzyme involved in
the uptake of long-chain fatty acids into the mitochondria (Figure 2). In a randomized, placebocontrolled study using the canine rapid pacing
model of heart failure, oxfenicine delayed the
development of terminal heart failure, attenuated adverse hemodynamic changes, prevented
wall thinning, prevented the activation of
matrix metalloproteinases, and resulted in the
transcriptional downregulation of CPT1 and
of key enzymes involved in cardiac energy metabolism.46 In animal models, oxfenicine therapy
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was associated with dose-related increases in
cardiac weight due to uniform myocardial
fiber hypertrophy involving all cardiac chambers,47 as well as an increase in liver and kidney
weights.48 The mechanisms responsible for these
observations are not yet clearly understood.
Etomoxir
Etomoxir is an oxirane carboxylic acid derivative
that inhibits CPT1.49 This drug was introduced
as a potential therapy for diabetes because of its
hypoglycemic effects.50 Its effects on ischemia,
left ventricular hypertrophy, and left ventricular
impairment have been studied in animals.51,52
Therapy with this drug favorably modified
ventricular mass, geometry and function in
pressure-overloaded rats,51 and reduced the
occurrence of ventricular failure in diabetic rat
hearts.52 In a human, open-label, uncontrolled
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Perhexiline
Perhexiline seems to cause a shift in cardiac
substrate use from fatty acids to carbohydrates.58
In isolated Langendorff-perfused rat hearts,
perhexiline inhibited both CPT1 and carnitine palmitoyltransferase II (Figure 2).59,60
Perhexiline was frequently used as antianginal
agent in the 1970s and is an effective monotherapy for relieving symptoms of angina,61
improving exercise tolerance, and increasing
the workload needed to induce ischemia.62 Use
declined dramatically in the late 1970s and early
1980s following reports of hepatotoxic effects63
and peripheral neuropathy.64 These effects were
later demonstrated to occur in patients in whom
hydroxylation is slow and who have a genetic
variant of a cytochrome P450 enzyme, which
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22–
20–
VO2max (ml kg–1 min–1)
β-blockers
β-adrenoreceptor blockade improves left ventricular function and prognosis in patients with
ischemic or nonischemic cardiomyopathy.54,55
The mechanisms of this beneficial effect are
multifactorial and could include a shift from free
fatty acid to glucose use. Wallhaus et al.56 demonstrated a 57% reduction in myocardial free fatty
acid uptake following treatment with carvedilol in
patients with heart failure. In this relatively small
study, however, neither mean myocardial uptake
of labeled glucose tracers nor the rate of glucose
use increased significantly. This finding might
reflect a type II error, since a marked fall in the
ratio of myocardial free fatty acid to glucose use
does suggest a so-called metabolic shift induced
by carvedilol. The authors of the study speculated that this effect was related to CPT1 inhibition, although little supporting evidence for this
effect is available. Furthermore, Al-Hesayen and
colleagues57 showed that 4 months of carvedilol
therapy increased myocardial lactate consumption and reduced myocardial uptake of free fatty
acids in patients with chronic heart failure. This
finding implies that carvedilol therapy causes a
significant shift in myocardial substrate use from
free fatty acids to glucose.
A
18–
16–
14–
12–
10–
B
Before placebo
After placebo
Before perhexiline After perhexiline
Before placebo
After placebo
Before perhexiline After perhexiline
40–
30–
LVEF (%)
trial conducted in 10 patients with NYHA class
II–III heart failure, a 3-month period of etomoxir
treatment in addition to standard therapy was
associated with a significant improvement in left
ventricular ejection fraction, cardiac output at
peak exercise, and clinical status.53 Etomoxir has
yet, however, to be investigated in a long-term,
randomized, controlled trial in heart failure.
20–
10–
0–
Figure 3 The effect of perhexiline treatment in patients with ischemic or
nonischemic heart failure. (A) Effect on peak exercise oxygen consumption.
(B) Effect on left ventricular ejection fraction. Reproduced, with permission, from
reference 68 © (2005) Lippincott, Williams & Wilkins. Abbreviations: LVEF, left
ventricular ejection fraction; VO2max, maximum volume of oxygen consumption.
metabolizes the drug, resulting in drug accumulation and, subsequently, accumulation of
phospholipids in the liver and nerves.65 The risk
of toxic effects is virtually eliminated by maintaining plasma concentrations at between 150
and 600 ng/ml, at which level the drug remains
efficacious.66 A rise in use of perhexiline as an
adjunctive therapy for refractory angina has,
therefore, been seen in some countries, particularly Australia, with good results.62 At plasma
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levels within the therapeutic range, perhexiline
is not negatively inotropic and does not alter
systemic vascular resistance.67
We have demonstrated beneficial short-term
effects of perhexiline in patients with ischemic
or nonischemic heart failure in a double-blind,
randomized, placebo-controlled trial.68 Patients
taking optimum conventional medical therapy
were randomized to perhexiline or placebo for
8 weeks, with dummy dose adjustment in the
placebo group. We noted a large increase in
the combined primary endpoint of peak oxygen
uptake (approximate increase 3 ml kg–1 min–1)
and left ventricular ejection fraction (approximate increase 10%; Figure 3), and a substantial improvement in the predefined secondary
endpoint of symptomatic status as assessed
by the Minnesota Living with Heart Failure
Questionnaire. The study design involved
separate randomization of the ischemic and
nonischemic groups, permitting separate
analysis of the primary endpoint in each group.
Importantly, maximum oxygen uptake was similarly and significantly increased in the ischemic
and nonischemic groups; therefore, the mechanism of benefit is not primarily anti-ischemic.68
This study, however, was short. Further work is
required to show that the clinical benefit is maintained in the longer term, to investigate whether
use of the agent leads to reverse remodeling (left
ventricular end-systolic volume did not fall in this
8-week study), and, most importantly, to assess
the effects on mortality and hospitalization.
CONCLUSION
Irrespective of cause, heart failure is associated
with an energy deficit. Agents that cause a shift
in the myocardial substrate used from free fatty
acids towards glucose have an oxygen-sparing
effect. Unsurprisingly, some of these agents
are effective as antiangina therapies. A series of
studies have demonstrated that the use of agents
that alter substrate use might be useful in heart
failure. Interestingly, perhexiline yields beneficial
effects in both ischemic and nonischemic heart
failure. Some of these agents are currently used
in highly symptomatic patients with heart failure
who are already receiving optimum medical
therapy. Most of the available evidence on the
use of these metabolic agents in humans is
derived from small studies. Further larger-scale
and longer-term human studies must be done
before use of these drugs can be considered on a
widespread basis.
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KEY POINTS
■
Emerging evidence shows that, irrespective
of the etiology, an energetic impairment
contributes to the pathogenesis of heart failure
■
Patterns of substrate use in heart failure are
complex and depend on species, cause,
duration, underlying coronary artery disease,
endothelial dysfunction, and the presence of
genetic and other comorbidities
■
Myocardial use of fatty acids costs more
oxygen per unit of ATP generated than glucose
■
Animal models and small-scale human studies
suggest benefits with the use of agents that
shift myocardial substrate use from free fatty
acids towards glucose, but larger human
studies are needed
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Competing interests
Michael Frenneaux has
applied for a patent for the
use of perhexiline therapy
in chronic heart failure
patients. The other authors
declared they have no
competing interests.
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