Optimization of cardiac metabolism in heart failure.

Abstract

The derangement of the cardiac energy substrate metabolism plays a key role in the pathogenesis of heart failure. The utilization of non-carbohydrate substrates, such as fatty acids, is the predominant metabolic pathway in the normal heart, because this provides the highest energy yield per molecule of substrate metabolized. In contrast, glucose becomes an important preferential substrate for metabolism and ATP generation under specific pathological conditions, because it can provide greater efficiency in producing high energy products per oxygen consumed compared to fatty acids. Manipulations that shift energy substrate utilization away from fatty acids toward glucose can improve the cardiac function and slow the progression of heart failure. However, insulin resistance, which is highly prevalent in the heart failure population, impedes this adaptive metabolic shift. Therefore, the acceleration of the glucose metabolism, along with the restoration of insulin sensitivity, would be the ideal metabolic therapy for heart failure. This review discusses the therapeutic potential of modifying substrate utilization to optimize cardiac metabolism in heart failure.

Full text

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3846 Current Pharmaceutical Design, 2011, 17, 3846-3853
1381-6128/11 $58.00+.00 © 2011 Bentham Science Publishers
Optimization of Cardiac Metabolism in Heart Failure
Tomohisa Nagoshi1,*, Michihiro Yoshimura1, Giuseppe M. C. Rosano2, Gary D. Lopaschuk3 and
Seibu Mochizuki1,4
1Division of Cardiology, Department of Internal Medicine, The Jikei University School of Medicine; 2Department of Medical Sciences,
IRCCS San Raffaele, Roma; 3Cardiovascular Research Centre, Mazankowski Alberta Heart Institute, The University of Alberta;
4Musashino University Medical Center
Abstract: The derangement of the cardiac energy substrate metabolism plays a key role in the pathogenesis of heart failure. The utiliza-
tion of non-carbohydrate substrates, such as fatty acids, is the predominant metabolic pathway in the normal heart, because this provides
the highest energy yield per molecule of substrate metabolized. In contrast, glucose becomes an important preferential substrate for me-
tabolism and ATP generation under specific pathological conditions, because it can provide greater efficiency in producing high energy
products per oxygen consumed compared to fatty acids. Manipulations that shift energy substrate utilization away from fatty acids toward
glucose can improve the cardiac function and slow the progression of heart failure. However, insulin resistance, which is highly prevalent
in the heart failure population, impedes this adaptive metabolic shift. Therefore, the acceleration of the glucose metabolism, along with
the restoration of insulin sensitivity, would be the ideal metabolic therapy for heart failure. This review discusses the therapeutic potential
of modifying substrate utilization to optimize cardiac metabolism in heart failure.
Keywords: myocardial glucose and fatty acid metabolism, insulin resistance, metabolic therapy, heart failure.
INTRODUCTION

across the globe. Although significant advances in the pharmacol-
ogical and mechanical (resynchronization therapy, left ventricular
assisted devices) treatments have improved the outcome of patients
with heart failure, the prognosis of such patients still remains poor.
At present, the optimal pharmacological treatment of heart failure
targets the suppression of neurohumral activation (such as the
renin-angiotensin-aldosterone system (RAAS) and/or ?-adrenergic
receptor signaling), as well as regulating the fluid volume overload
and hemodynamics, and optimizing heart rate. Novel therapeutic
strategies acting independently from the neurohumoral axis are
required to improve the patient outcomes. Emerging evidence sup-
ports the concept that disturbances in myocardial energy substrate
metabolism contribute to the progression of cardiac contractile
dysfunction and ventricular remodeling in patients with heart fail-
ure [1].
Heart failure is currently a leading cause of death and disability

ure have a reduced ability to generate ATP by myocardial oxidative
metabolism. Therefore, the optimization of cardiac energy metabo-
lism, without any direct negative hemodynamic effects, is a concep-
tually attractive therapeutic approach. In this review, we will first
outline the normal cardiac energy metabolism, and then focus on
the metabolic derangements that occur during heart failure. Finally,
we discuss the potential therapeutic applications of optimizing en-
ergy metabolism for treating heart failure.
There is ample evidence to suggest that patients with heart fail-
MYOCARDIAL SUBSTRATE METABOLISM IN THE
NORMAL HEART

heart failure can be fully appreciated, it is important to have a thor-
ough understanding of the regulation of physiological energy me-
tabolism in the normal heart (Fig. (1)).
Before the dysfunctional myocardial energy metabolism in
The first step: Metabolism

mitochondria accounts for the vast majority of ATP production in
The utilization of free fatty acids (FFAs) and glucose in the
*Address correspondence to this author at the Division of Cardiology, De-
partment of Internal Medicine, The Jikei University School of Medicine, 3-
25-8, Nishi-Shinbashi, Minato-ku, Tokyo, 105-8461, Japan; Tel: +81-3-
3433-1111 (ex. 3261); Fax: +81-3-3459-6043; E-mail: tnagoshi@jikei.ac.jp
the healthy adult heart [2]. Under normal circumstances at rest, 60-
90% of the acetyl-CoA which enters the tricarboxylic acid (TCA)
cycle comes from the ?-oxidation of FFAs, and 10-40% from the
oxidation of pyruvate that is derived in almost equal amounts from
glycolysis and lactate oxidation [1-4]. However, during conditions
of increased metabolic demands, such as increased heart rate or
blood pressure, a shift towards a greater utilization of glucose is
observed.
Glucose (Carbohydrate) Metabolism

concentration gradient and is regulated by the specific transmem-
brane glucose transporters (GLUTs) in the sarcolemma. Intracellu-
lar glucose is phosphorylated to glucose-6-phosphate (G-6-P) by
hexokinase, which is then utilized for the glycolytic pathway for
energy production and/or glycogen synthesis. Phosphofructokinase
(PFK)-1 catalyzes the phosphorylation of fructose-6-phosphate into
fructose-1,6-bisphosphate. AMP and fructose 2,6-bisphosphate are
positive effectors for this first irreversible step, whereas ATP, cit-
rate, and protons are negative allosteric effectors. Glyceraldehyde-
3-phosphate dehydrogenase (GAPDH) catalyzes the conversion of
glyceraldehyde 3-phosphate to 1,3-diphosphoglycerate [5], which is
ultimately broken down to pyruvate. Pyruvate dehydrogenase
(PDH), localized within the inner mitochondrial membrane, cata-
lyzes pyruvate decarboxylation and transformation into acetyl-CoA,
which is subsequently fed into the TCA cycle. PDH is inactivated
by a specific PDH kinase and is activated by a specific PDH phos-
phatase. The expression of PDH kinase is increased by starvation,
diabetes and peroxisome proliferator activated receptor (PPAR)-?
ligands, and the kinase is activated by acetyl-CoA and NADH (pro-
duced mainly by fatty acid oxidation (FAO)), which also directly
inhibit PDH. In contrast, PDH kinase is inhibited by pyruvate and
by decreases in the acetyl-CoA/free CoA and NADH/NAD+ ratios.
The PDH phosphatase is mainly activated by increased mitochon-
drial Ca2+ entry under such conditions as catecholamine stimula-
tion.
Glucose transport into cardiomyocytes occurs along a steep
Fatty Acid Metabolism

centration of nonesterified fatty acids (NEFAs) in the plasma. FFAs
enter the cardiomyocytes by either passive diffusion or by protein-
mediated transport across the sarcolemma, including transport by a
The rate of FFA uptake by the heart is determined by the con-

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Optimization of Cardiac Metabolism in Heart Failure Current Pharmaceutical Design, 2011, Vol. 17, No. 35 3847
fatty acid translocase (FAT) and a plasma membrane fatty acid
binding protein (FABP). Once transported across the sarcolemma,
NEFAs bind to FABP, and are then activated by esterification to
fatty acyl-CoA by fatty acyl-CoA synthetase (FACS). Long-chain
fatty acids on fatty acyl-CoA are then transferred to carnitine by
carnitine palmitoyltransferase (CPT)-I and the resultant long chain
acylcarnitine transported into the mitochondria. The long chain
fatty acids from acylcarnitine are then converted back to long chain
acyl-CoA by CPT-II. CPT-I plays a key regulatory role in control-
ling the rate of FFAs uptake by the mitochondria. Malonyl-CoA,
which is a potent inhibitor of CPT-I, is produced by acetyl-CoA
carboxylase (ACC) and is degraded by malonyl-CoA decarboxylase
(MCD). Once in the mitochondria, long chain acyl-CoA undergoes
?-oxidation, which releases acetyl-CoA for the TCA cycle, and also
regenerates acyl-CoA of two carbons shorter for another round of
?-oxidation. The principal products of fatty acid ß-oxidation (FAO)
are NADH, FADH2, and acetyl-CoA, which generates more NADH
and FADH2 in the TCA cycle.
Interaction of Fatty Acid and Glucose Metabolism

in the heart. High rates of FAO inhibit PDH by PDH kinase activa-
tion through an increase in the acetyl-CoA/free CoA and
NADH/NAD+ ratios (Fig. (1)). Conversely, inhibition of FAO in-
creases glycolysis and glucose oxidation both by decreasing citrate
levels (which releases inhibition of PFK), and by lowering the ace-
tyl-CoA and/or NADH levels in the mitochondrial matrix, thereby
relieving the inhibition of PDH. On the other hand, glucose may
FAO is the primary physiological regulator of glucose oxidation
also inhibit FAO. Conditions that increase the production of acetyl-
CoA from pyruvate stimulate the production of malonyl-CoA,
thereby inhibiting CPT activity.
The Second Step: Oxidation

FFAs, and some amino acids all converge on the formation of ace-
tyl-CoA, which serves as the metabolic substrate of the TCA cycle.
The TCA cycle has the dual purposes of completing the decarboxy-
lation of acetyl-CoA and of producing NADH and FADH2 used in
the electron transport chain to provide the energy for ATP synthe-
sis. The flux of the TCA cycle is tightly coupled to the capacity for
ATP generation, which depends on the availability of oxygen, the
cytosolic ATP/ADP+Pi ratio, and the NADH/ NAD+ ratio in the
mitochondria. An elevated ATP/ADP ratio under the conditions of
low myocardial demand for ATP or the non-availability of oxidized
cofactors (NAD+ or FAD) is a powerful inhibitor of this cycle.
The catabolic pathways for carbohydrates (glucose and lactate),

TCA cycle are shuttled through the electron transport chain for
oxidative phosphorylation. ATP is generated through the sequence
of electron transfer to oxygen.
The NADH and FADH2derived from glycolysis, FAO, and the
The third Step: ATP Transfer and Utilization

of the myocardial energetic metabolic loop. The reaction can be
expressed as follows:
The ATP transfer and utilization for contraction is the final step
Phosphocreatine (PCr) + ADP
(catalyzed by CK)
Creatine (Cr) + ATP
Fig. (1). Normal myocardial energy metabolism.
ANT, adenine nucleotide translocase; ACC, acetyl-CoA carboxylase; CPT, carnitine palmitoyltransferase; FABP, fatty acid binding protein; FACS, fatty acyl-
CoA synthase; FAT, fatty acid transporter; FFA, free fatty acid; GLUT, glucose transporter; G-6-P, glucose-6-phosphate; MCD, malonyl-CoA decarboxylase;
PFK, Phosphofructokinase; PDH, pyruvate dehydrogenase; TCA, tricarboxylic acid cycle.
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3848
Current Pharmaceutical Design, 2011, Vol. 17, No. 35 Nagoshi et al.

occurs via oxidative phosphorylation. PCr is a vital energy buffer
molecule that provides phosphoryl groups to ADP to rapidly gener-
ate ATP. The PCr/ATP ratio is a measure of myocardial energetics,
and its reduction may depend on an imbalance of the myocardial
oxygen supply and demand. Interestingly, this ratio is reduced in
human heart failure [6], thus indicating that this ratio is a significant
predictor of mortality [7].
This reaction can generate ATP ten times faster than that which

for muscle contraction, and for the maintenance of ATP-dependent
cellular processes, including ion transport and intracellular Ca2+
homeostasis. Approximately 60-70% of ATP hydrolysis fuels con-
tractile shortening, and the remaining 30-40% is primarily used for
sarcoplasmic reticulum Ca2+-ATPase (SERCA2A) and other ion
pumps (Fig. (2)) [1].
The heart has a high energy demand, due to the need for ATP
MYOCARDIAL SUBSTRATE METABOLISM IN HEART
FAILURE
Energy Production from Various Energy Substrates

calculated by the molar value or oxygen equivalents consumed per
high energy phosphate produced. FFAs, such as palmitate, provides
the highest energy (ATP) yield per molecule of substrate metabo-
lized, mainly through ?-oxidation [8]. However, while glucose pro-
vides less ATP yield per molecule, glucose metabolism has a
greater efficiency in producing high energy phosphates (there is an
up to a 40% increase in ATP production per oxygen molecule con-
sumed for glucose versus FFAs) [1, 4, 8, 9]. In other words, FAO
requires a greater oxygen consumption for an equivalent amount of
ATP synthesized compared to glucose oxidation (approximately
15% more oxygen is required to produce the same amount of ATP
from FAO [8, 10]). Moreover, increased FFAs levels, which are
frequently associated with heart failure [11, 12], promote the syn-
thesis of uncoupling proteins, which leads to proton leakage, and
subsequently, the dissipation of the electrochemical gradient across
the inner mitochondrial membrane, resulting in the reduction of
cardiac efficiency by limiting ATP production and increasing oxy-
Each of the myocardial substrates has a different ATP yield,
gen consumption [13-15]. Therefore, glucose may become a favor-
able substrate for energy production in the heart during a state of
increased energy metabolic demands, such as heart failure.
Significance of Glycolytic ATP Production

generated in the normally oxygenated heart [10]. During ischemia,
the mitochondrial metabolic dysfunction caused by reduced oxygen
delivery to the heart results in a decrease in ATP formation by oxi-
dative phosphorylation [4]. The reduction in aerobic ATP formation
accelerates glycolysis, glucose uptake and glycogen breakdown,
leading to an increase in the contribution of glycolysis as a source
of ATP production [2]. During moderate myocardial ischemia, the
sustenance of glycolysis may be beneficial. Glycolytically gener-
ated ATP is responsible for the maintenance of ion homeostasis,
particulary Na+/K+-ATPase and SERCA2A [16], and thus may be
essential for optimal diastolic relaxation [17] (Fig. (2)). However,
during anoxia or severe ischemia, when glucose oxidation cannot
be increased in parallel with the accelerated glycolysis, the in-
creased glycolysis flux results in an accumulation of protons (H+)
and lactate, which may be detrimental to the heart. Increased
Na+/H+ exchanger activity for the efflux of the accumulated H+
during ischemia-reperfusion increases the intracellular Na+ concen-
tration, which activates the reverse mode of the Na+/Ca2+ exchanger
and eventually leads to intracellular Ca2+ overload [18, 19].
Glycolysis contributes only approximately 5% of the total ATP
Metabolic Substrate Changes in Heart Failure

of myocardial energy substrate metabolism in the natural history of
heart failure, we continue to have a poor understanding of the pre-
cise regulatory mechanisms that affect the expression of metabolic
proteins. The normal adaptive response of the failing heart involves
a complex series of enzymatic shifts and changes in the regulation
of transcription factors, ultimately resulting in the switch in sub-
strate metabolism away from FAO toward greater glucose metabo-
lism to maximize efficiency [9, 20]. However, some studies have
shown that there is not a decrease in FAO in the early stages of
heart failure, and that a dramatic reduction of FAO enzymes, and
Although there is quite a large body of work describing the role
Fig. (2). ATP regulates the electrolyte balance, including Ca2+ homeostasis.
CICR, Ca-induced Ca release; NCX, Na+/Ca2+ exchanger; NHE, Na+/H+ exchanger; SERCA, sarcoplasmic reticulum Ca2+ ATPase pump.
T-tube
Ryanodine
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L-type
Ca-channel
SERCA
ATP
Na/K
ATPase
ATP
Na
+
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+
3Na
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2K
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+
2Na
+
2Na
+
H
+
mitochondria
Ca2+
Ca2+
Ca2+
Ca2+
Ca2+
NHENCX
ATP

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Optimization of Cardiac Metabolism in Heart Failure Current Pharmaceutical Design, 2011, Vol. 17, No. 35 3849
consequently, the increase in glucose metabolism, occurs only in
advanced or end-stage decompensated heart failure [21-23]. In fact,
one study using positron emission tomography (PET) demonstrated
increased myocardial FFA uptake and reduced glucose uptake in
human heart failure [24]. The discrepancies among these clinical
investigations may be attributed to the severity of heart failure in
the subjects being studied. However, there are also other potential
explanations for these results.

tance" which is highly prevalent in the heart failure population, and
plays the pivotal role in the pathogenesis of heart failure [9, 25].
Studies in the canine rapid pacing heart failure model demonstrated
a progressive increase in insulin resistance during disease progres-
sion [26]. Moreover, elevated plasma FFA levels, which are com-
monly present in heart failure, impair insulin signaling [27]. Fur-
thermore, the activation of the RAAS occurring in patients with
heart failure increases myocardial insulin resistance. In fact, angio-
tensin II stimulation of cardiac myocytes leads to the inhibition of
insulin receptor downstream signaling. Therefore, although glucose
is the preferential substrate for metabolism in patients with heart
failure (the metabolic shift from FAO to glucose metabolism), insu-
lin resistance inhibits this adaptive response, resulting in further
deterioration of heart failure and a state of energy deficiency.
Therefore, the ideal metabolic therapy for heart failure would be to
induce glucose metabolism, together with the improvement of insu-
lin sensitivity, while simultaneously blocking FFA uptake and
FAO.
One ptoential mechanism is the presence of "Insulin Resis-
Alternate Considerations for Metabolic Substrate Changes in
Heart Failure

in the carbohydrate utilization pathway, even though an increase in
glucose metabolism occurs during end-stage heart failure. Further-
more, there is actually either no change (GLUT1 and 4) or down-
regulation (GAPDH and PDH) of key enzymes involved in carbo-
hydrate metabolism in failing hearts, despite an increase in glucose
uptake and oxidation [22, 28]. Recently, a couple reports demon-
strated that myocardial lipid storage is reduced in heart failure [29,
30]. Moreover, it has been suggested that glucose oxidation at the
mitochondria increases via anaplerotic flux in heart failure, thereby
compensating for reduced PDH activity and maintaining the TCA
cycle flux [31, 32]. Together, these results suggest that any increase
in glucose metabolism in heart failure is due to alterations in path-
way regulation that are secondary to the suppression of FAO and/or
the upregulation of the anaplerotic pathway. However, these shifts
indicate a less efficient mode of carbon use for fueling energy syn-
thesis in the myocardium [31]. Therefore, restoration of endoge-
nous fatty acid stores, oxidation and mitochondrial function may be
potentially useful as an alternate therapeutic target for heart failure.
There is little evidence of the upregulation of proteins involved
Alterations in the Expression and Function of Metabolic Regu-
lators and Their Therapeutic Potential for Optimizing Energy
Metabolism in Heart Failure
AMPK

sensing/signaling system, which regulates FAO and glucose uptake
in response to altered energy supply and/or demand [33]. This
kinase is activated by an increased ratio of AMP to ATP and/or a
decreased ratio of PCr to creatine, which then counteracts the in-
creased rates of ATP utilization and maximizes ATP production to
meet the energy demands. AMPK stimulates glucose uptake by an
increase in GLUT1 expression and GLUT4 translocation to the
plasma membrane [34], and accelerates glycolysis by activating
PFK-2. The acute activation of AMPK also enhances FAO through
a phosphorylation and decrease in acetyl-CoA carboxylase (ACC)
activity [33]. In contrast, chronic AMPK activation is associated
AMP-activated protein kinase (AMPK) is an important energy-
with decreased expression of CPT-1 and medium chain acetyl-CoA
dehydrogenase (MCAD), resulting in decreased FAO [34]. There-
fore, AMPK plays an important energy metabolic role through the
insulin-independent activation of glucose uptake and glycolysis,
with biphasic actions on FAO. Further confirming this role, there is
a paper recently demonstrated that macrophage migration inhibitory
factor (MIF), which is released in the ischemic heart, stimulates
AMPK, and protects the heart against ischemic injury and apoptosis
[35].
Insulin/IGF-1 Signaling

ing, are key regulators of cardiomyocyte growth and survival [36,
37], and are also important modulators of metabolic substrate utili-
zation and cardiomyocyte function [38-40]. It is widely accepted
that acute activation or, to be more precise, the acute acceleration
(superinduction) of insulin/IGF-1-PI3K-Akt signaling has carido-
protective effects both in vitro and in vivo [38, 41-44]. In contrast,
we and others have previously demonstrated that chronic activation
of Akt leads to detrimental outcomes due to either negative feed-
back inhibition of its upstream molecules, such as insulin receptor
substrate (IRS)-1 [45], or a disruption of coordinated hypertrophy
and angiogenesis [46, 47]. From the viewpoint of the cardiac me-
tabolism, Akt activation generally promotes the intracellular trans-
port and metabolism of glucose, while it inhibits FFA metabolism
[48, 49]. The acute activation of Akt appears to increase glucose
uptake, predominantly through enhanced sarcolemmal GLUT4
localization [38], while its chronic activation leads to insulin resis-
tance, with a substantial decrease in GLUT4 both in the intracellu-
lar cytosol and on the sarcolemal membrane, in addition to negative
feedback inhibition of IRS-1-PI3K coupling [40, 45]. In human
advanced heart failure, Akt is paradoxically activated, with the
concomitant reduction of IRS-1 [45, 50], thus suggesting a mecha-
nism by which chronic Akt activation may become maladaptive, in
contrast to its acute activation (Fig. (3)). In contrast, other groups
have shown that Akt activity is not elevated in heart failure, or is
actually decreased in advanced heart failure due to the disturbed
signal transduction of the upstream effectors, including the insu-
lin/IGF-1 receptor, through the IRS-1-PI3K pathway [25, 51, 52].
This discrepancy could be related to the differences in the severity
and chronicity of ventricular dysfunction between the studies.
Taken together, superinduction of PI3K-Akt signaling appears to
play a central role in cardioprotection both via modification of en-
ergy metabolism and via mechanism(s) independent of metabolism,
such as the direct anti-apoptotic effects. Likewise, the activation of
the insulin/IGF-1 cascade preserves mitochondrial energy metabo-
lism, which in turn counteracts cardiotoxic oxidative stress and
promotes survival in heart failure [53].
PI3K-Akt, the down-stream effectors of insulin/IGF-1 signal-

PI3K-Akt signaling upregulates SERCA2A activity, which leads to
enhancement of sarcoplasmic reticulum Ca2+ uptake [54-56].
Therefore, the activation of this cascade could represent another
therapeutic strategy for the improvement of cardiac contractility in
heart failure, although this effect is mostly due to chronic activation
of Akt, and would need to be confirmed in additional experimental
models.
In addition to its metabolic effects, the activation of IGF-1-
Pyruvate

contractile effects of ?-adrenergic stimulation in both the normal
and failing myocardium [57, 58]. Pyruvate can increase the intracel-
lular Ca2+ transients as a result of increased sarcoplasmic reticulum
Ca2+ accumulation, as well as increased myofilament Ca2+ sensitiv-
ity as a result of the increased intracellular pH. Similarly, PDH
kinase inhibition activates PDH and increases pyruvate oxidation,
thus resulting in an increase in mechanical efficiency by switching
the heart towards a more efficient fuel.
Pyruvate increases the contractile function and potentiates the

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Current Pharmaceutical Design, 2011, Vol. 17, No. 35 Nagoshi et al.
GLP-1

glucose metabolism and inhibits FAO. Glucagon-like peptide
(GLP)-1 is one of the incretins which promotes post-prandial insu-
lin secretion and improves insulin sensitivity. GLP-1 infusion in-
creases glucose uptake and improves cardiac function in a pacing-
induced heart failure model [59], although in a human heart failure
study, short-term GLP-1 treatment failed to show any beneficial
effects [60]. Since GLP-1 is rapidly degraded by dipeptidyl pepti-
dase (DPP)-IV in vivo, synthetic GLP-1 analogues with an extended
plasma half-life (e.g. liraglutide) and GLP-1 receptor agonists (e.g.
exenatide) have been developed. A DPP-IV antagonist would pro-
vide an alternative promising agent in this context. Indeed, sita-
gliptin, one of the DPP-IV inhibitors, has been shown to improve
left ventricular performance in response to dobutamine stress in
patients with coronary artery disease in an insulin-independent
manner [61]. However, at present, there is insufficient evidence to
support and/or suggest the use of incretins in heart failure.
The elevation of the plasma insulin concentration enhances
FFA Metabolism Modulators

sumption, and is less efficient source of energy compared to glu-
cose metabolism (with regard to ATP production/oxygen con-
sumed), as discussed above. Moreover, if myocardial FFA uptake
overwhelms the oxidative capacity of the heart, FFAs can accumu-
late as intramyocardial lipids (triglycerides, diacylglycerol, long
chain acyl CoA’s and ceramides), which are associated with "lipo-
toxicity", leading to further impairment of the cardiac function, in
addition to insulin resistance [3, 27, 62, 63]. In fact, high circulating
lipid levels and intracellular accumulation of long-chain fatty acid
moieties, such as that which occurs during fasting or in patients
with diabetes, enhance PPAR-? mediated expression of PDH
kinase, thus resulting in the inhibition of the phosphorylation of
PDH. Therefore, pharmacological interventions aimed at lowering
Increasing FFA metabolism leads to an increase in oxygen con-
circulating FFA levels, inhibiting FFA cellular and/or mitochon-
drial uptake, and inhibiting fatty acid ?-oxidation could provide
another therapeutic strategy for optimizing cardiac metabolism.

treatment of myocardial ischemia. Its effect is achieved by shifting
the energy substrate preference from fatty acid oxidation to glucose
oxidation, secondary to inhibition of 3-ketoacylCoA thiolase (3-
KAT), the final enzyme in ?-oxidation [64]. In experimental stud-
ies, trimetazidine exerts a cardioprotective effect in in vitro models
of myocardial ischemia through a rapid restoration of oxidative
phosphorylation processes, protection of cardiac cells against the
accumulation of protons, and prevention of the intracellular accu-
mulation of sodium and calcium ions. These effects of trimetazidine
are believed to help maintain the integrity of cell membranes, as
well as maintain mitochondrial structure and function. Because of
the preferential promotion of glucose and pyruvate oxidation,
trimetazidine improves the activity of two membrane-bound pumps,
namely the Na+/K+-ATPase and SERCA2A, which are responsible
for left ventricular systolic and diastolic function, respectively. In
clinical studies, trimetazidine treatment leads to a substantial im-
provement in cardiac function and New York Heart Association
function (NYHA) class in the heart failure population [65, 66]. The
improvement of the left ventricular function is associated with a
reduction of the inflammatory response in patients treated with
trimetazidine [67]. Trimetazidine also improves the myocardial
PCr/ATP ratio, suggesting that this agent preserves the intracellular
levels of myocardial high energy phosphates [68].
Trimetazidine is a metabolic agent initially developed for the

reduce mitochondrial FFA uptake. As a consequence, myocardial
glucose substrate utilization increases [1, 10]. Studies with eto-
moxir demonstrated that chronic treatment with this agent results in
improved sarcoplasmic Ca2+ handling and increased SERCA2A
expression, leading to improved cardiac function [69, 70]. Unfortu-
nately, this drug can produce serious adverse effects, including liver
CPT-1 inhibitors (such as etomoxir, perhexiline and oxfenicine)
Fig. (3). A schematic representation of Akt-mediated feedback inhibition in heart failure.
Insulin or IGF-1 signaling exerts cardioprotective effects through the acute activation of its down-stream effectors, such as IRS-1, PI3K and Akt. In contrast,
the phosphorylation of IRS-1 induced by chronic Akt activation leads to their dissociation from PI3K, as well as proteasome-dependent degradation, thus
leading to detrimental results. Similar negative feedback inhibition of IRS-1 is also observed in human heart failure where there is the persistent activation of
Akt. Adapted from reference 45.
DCM, dilated cardiomyopathy; GSK-3, glycogen synthase kinase-3; IGF-1, insulin like growth factor-1; IRS-1, insulin receptor substrate-1; PI3K, phosphoi-
nositide 3-kinase
Akt
IRS-1
Insulin
IGF-I
PI3K
Cell Death
GSK3
P
degradation
IRS-1
Akt-kinase
assay
ControlFailing Heart(DCM)
IRS-1

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Optimization of Cardiac Metabolism in Heart Failure Current Pharmaceutical Design, 2011, Vol. 17, No. 35 3851
toxicity. Another recent study has revealed the salutary effects of
perhexiline in improving the myocardial oxygen consumption, left
ventricular ejection fraction, symptoms, and exercise capacity in
maximally treated heart failure patients [71].

PPAR?, all of which are expressed in the heart. While PPAR? and
PPAR? increase myocardial FAO rates, PPAR? agonists, such as,
thiazolidines, actually decrease FAO rates by decreasing circulating
FFA levels, and thus decreasing myocardial FFA uptake and oxida-
tion [72].
There are three isoforms of PPARs: PPAR?, PPAR?, and
Catecholamines

cose uptake, glycolysis and glucose oxidation. The activation of
protein kinase A (PKA) and Ca2+-calmodulin-dependent kinase
(CaMK) by epinephrine, an adrenergic receptor agonist, leads to
acute increases in PFK and Akt activity [73, 74]. Moreover, epi-
nephrine also increases mitochondrial Ca2+ uptake, which activates
PDH and other TCA cycle enzymes. In contrast, the long-term
upregulation of catecholamines, often present in patients with heart
failure, antagonizes the actions of insulin, promotes lipolysis, and
increases circulating FFA levels, all of which can lead to insulin
resistance [9]. This action is partly mediated through the negative
feedback inhibition of either the insulin receptor [74] or of IRS-1
[45]. Adrenergic blockade with carvedilol reduces FFA utilization
in favor of greater glucose utilization in heart failure patients [75].
This change in myocardial energetics could provide a potential
mechanism for the decreased myocardial oxygen consumption and
improved energy efficiency seen with ?-adrenergic receptor inhibi-
tors in the treatment of heart failure.
Short-term stimulation of ?-adrenergic receptors increases glu-
RAAS

ogy of heart failure. We and others have previously reported that
cardiac ACE activity and gene expression, as well as the local syn-
thesis of angiotensin II and aldosterone, are increased in the failing
hearts [76-78]. The persistent activation of these RAAS compo-
nents contributes to altered insulin/IGF-1 signaling pathways and
ROS formation, which induces endothelial dysfunction and insulin
resistance [79]. There have been several reports demonstrating that
persistent stimulation of aldosterone induces IRS-1 degradation,
thus leading to insulin resistance [80, 81]. Moreover, increased
aldosterone levels were shown to be associated with insulin resis-
tance in a heart failure population [82]. Therefore, angiotensin-
converting enzyme inhibitors, angiotensin receptor blockers, and
mineralocorticoid receptor inhibitors may all have favorable effects
on the glucose metabolism and thereby restore insulin sensitivity
[83, 84].
Alterations in RAAS is centraly involved in the pathophysiol-
CONCLUSION

a key role in the pathogenesis and progression of heart failure.
Shifting the energy metabolic pathways away from FFA utilization
and toward glucose utilization can be an attractive novel therapeutic
strategy for the prevention or early treatment of heart failure in
terms of providing a more energy-efficient substrate usage. Mean-
while, special attention should be paid to insulin resistance, which
is generally associated with advanced heart failure, and the devel-
opment of new therapies aimed at the improvement of insulin sensi-
tivity should be considered in order to take advantage of glucose as
the preferred metabolic substrate in heart failure.
The alterations in myocardial fuel selection and energetics play
CONFLICTS OF INTEREST
None.
ACKNOWLEDGEMENTS

istry of Education, Culture, Sports, Science and Technology (to T.
This study was supported in part by grants-in-aid from the Min-
Nagoshi and M. Yoshimura) and the Uehara Memorial Foundation
(to T. Nagoshi).
REFERENCES
[1] Stanley WC, Recchia FA, Lopaschuk GD. Myocardial substrate
metabolism in the normal and failing heart. Physiol Rev 2005; 85:
1093-129.
Depre C, Vanoverschelde JL, Taegtmeyer H. Glucose for the heart.
Circulation 1999; 99: 578-588.
Huss JM, Kelly DP. Mitochondrial energy metabolism in heart
failure: a question of balance. J Clin Invest 2005; 115: 547-55.
Rosano GM, Fini M, Caminiti G, Barbaro G. Cardiac metabolism
in myocardial ischemia. Curr Pharm Des 2008; 14: 2551-62.
Mochizuki S, Neely JR. Control of glyceraldehyde-3-phosphate
dehydrogenase in cardiac muscle. J Mol Cell Cardiol 1979; 11:
221-36.
Conway MA, Allis J, Ouwerkerk R, Niioka T, Rajagopalan B,
Radda GK. Detection of low phosphocreatine to ATP ratio in fail-
ing hypertrophied human myocardium by 31P magnetic resonance
spectroscopy. Lancet 1991; 338: 973-6.
Neubauer S, Horn M, Cramer M, et al. Myocardial phos-
phocreatine-to-ATP ratio is a predictor of mortality in patients with
dilated cardiomyopathy. Circulation 1997; 96: 2190-6.
Kantor PF, Lopaschuk GD, Opie LH. Myocardial Energy Metabo-
lism. Heart Physiology and Pathophysiology 2001; Fourth edition:
543-69.
Witteles RM, Fowler MB. Insulin-resistant cardiomyopathy clinical
evidence, mechanisms, and treatment options. J Am Coll Cardiol
2008; 51: 93-102.
Abozguia K, Shivu GN, Ahmed I, Phan TT, Frenneaux MP. The
heart metabolism: pathophysiological aspects in ischaemia and
heart failure. Curr Pharm Des 2009; 15: 827-35.
Paolisso G, Gambardella A, Galzerano D, et al. Total-body and
myocardial substrate oxidation in congestive heart failure. Metabo-
lism 1994; 43: 174-9.
Lommi J, Kupari M, Yki-Jarvinen H. Free fatty acid kinetics and
oxidation in congestive heart failure. Am J Cardiol 1998; 81: 45-
50.
Boudina S, Sena S, O'Neill BT, Tathireddy P, Young ME, Abel
ED. Reduced mitochondrial oxidative capacity and increased mito-
chondrial uncoupling impair myocardial energetics in obesity. Cir-
culation 2005; 112: 2686-95.
Murray AJ, Anderson RE, Watson GC, Radda GK, Clarke K. Un-
coupling proteins in human heart. Lancet 2004; 364: 1786-8.
Murray AJ, Panagia M, Hauton D, Gibbons GF, Clarke K. Plasma
free fatty acids and peroxisome proliferator-activated receptor al-
pha in the control of myocardial uncoupling protein levels. Diabe-
tes 2005; 54: 3496-02.
Xu KY, Zweier JL, Becker LC. Functional coupling between gly-
colysis and sarcoplasmic reticulum Ca2+ transport. Circ Res 1995;
77: 88-97.
Kusuoka H, Marban E. Mechanism of the diastolic dysfunction
induced by glycolytic inhibition. Does adenosine triphosphate de-
rived from glycolysis play a favored role in cellular Ca2+ homeo-
stasis in ferret myocardium? J Clin Invest 1994; 93: 1216-23.
Tani M. Mechanisms of Ca2+ overload in reperfused ischemic
myocardium. Annu Rev Physiol 1990; 52: 543-59.
Vaughan-Jones RD, Spitzer KW, Swietach P. Intracellular pH
regulation in heart. J Mol Cell Cardiol 2009; 46: 318-31.
Davila-Roman VG, Vedala G, Herrero P, et al. Altered myocardial
fatty acid and glucose metabolism in idiopathic dilated cardiomy-
opathy. J Am Coll Cardiol 2002; 40: 271-7.
Chandler MP, Kerner J, Huang H, et al. Moderate severity heart
failure does not involve a downregulation of myocardial fatty acid
oxidation. Am J Physiol Heart Circ Physiol 2004; 287: H1538-43.
Osorio JC, Stanley WC, Linke A, et al. Impaired myocardial fatty
acid oxidation and reduced protein expression of retinoid X recep-
tor-alpha in pacing-induced heart failure. Circulation 2002; 106:
606-12.
Sack MN, Rader TA, Park S, Bastin J, McCune SA, Kelly DP.
Fatty acid oxidation enzyme gene expression is downregulated in
the failing heart. Circulation 1996; 94: 2837-42.
Taylor M, Wallhaus TR, Degrado TR, et al. An evaluation of myo-
cardial fatty acid and glucose uptake using PET with [18F]fluoro-
[2]
[3]
[4]
[5]
[6]
[7]
[8]
[9]
[10]
[11]
[12]
[13]
[14]
[15]
[16]
[17]
[18]
[19]
[20]
[21]
[22]
[23]
[24]

Page 7

3852 Current Pharmaceutical Design, 2011, Vol. 17, No. 35 Nagoshi et al.
6-thia-heptadecanoic acid and [18F]FDG in Patients with Conges-
tive Heart Failure. J Nucl Med 2001; 42: 55-62.
Cook SA, Varela-Carver A, Mongillo M, et al. Abnormal myocar-
dial insulin signalling in type 2 diabetes and left-ventricular dys-
function. Eur Heart J 2009.
Nikolaidis LA, Sturzu A, Stolarski C, Elahi D, Shen YT, Shannon
RP. The development of myocardial insulin resistance in conscious
dogs with advanced dilated cardiomyopathy. Cardiovasc Res 2004;
61: 297-306.
An D, Rodrigues B. Role of changes in cardiac metabolism in
development of diabetic cardiomyopathy. Am J Physiol Heart Circ
Physiol 2006; 291: H1489-506.
Lei B, Lionetti V, Young ME, et al. Paradoxical downregulation of
the glucose oxidation pathway despite enhanced flux in severe
heart failure. J Mol Cell Cardiol 2004; 36: 567-76.
O'Donnell JM, Fields AD, Sorokina N, Lewandowski ED. The
absence of endogenous lipid oxidation in early stage heart failure
exposes limits in lipid storage and turnover. J Mol Cell Cardiol
2008; 44: 315-22.
Melenovsky V, Benes J, Skaroupkova P, et al. Metabolic charac-
terization of volume overload heart failure due to aorto-caval fis-
tula in rats. Mol Cell Biochem 2011.
Sorokina N, O'Donnell JM, McKinney RD, et al. Recruitment of
compensatory pathways to sustain oxidative flux with reduced car-
nitine palmitoyltransferase I activity characterizes inefficiency in
energy metabolism in hypertrophied hearts. Circulation 2007; 115:
2033-41.
Pound KM, Sorokina N, Ballal K, et al. Substrate-enzyme competi-
tion attenuates upregulated anaplerotic flux through malic enzyme
in hypertrophied rat heart and restores triacylglyceride content: at-
tenuating upregulated anaplerosis in hypertrophy. Circ Res 2009;
104: 805-12.
Winder WW. Energy-sensing and signaling by AMP-activated
protein kinase in skeletal muscle. J Appl Physiol 2001; 91: 1017-
28.
Tian R, Musi N, D'Agostino J, Hirshman MF, Goodyear LJ. In-
creased adenosine monophosphate-activated protein kinase activity
in rat hearts with pressure-overload hypertrophy. Circulation 2001;
104: 1664-9.
Miller EJ, Li J, Leng L, et al. Macrophage migration inhibitory
factor stimulates AMP-activated protein kinase in the ischaemic
heart. Nature 2008; 451: 578-82.
Matsui T, Nagoshi T, Rosenzweig A. Akt and PI 3-Kinase Signal-
ing in Cardiomyocyte Hypertrophy and Survival. Cell Cycle 2003;
2: 220-3.
Matsui T, Rosenzweig A. Convergent signal transduction pathways
controlling cardiomyocyte survival and function: the role of PI 3-
kinase and Akt. J Mol Cell Cardiol 2005; 38: 63-71.
Matsui T, Tao J, del Monte F, et al. Akt activation preserves car-
diac function and prevents injury after transient cardiac ischemia in
vivo. Circulation 2001; 104: 330-5.
Matsui T, Li L, Wu JC, et al. Phenotypic spectrum caused by
transgenic overexpression of activated Akt in the heart. J Biol
Chem 2002; 277: 22896-901.
Matsui T, Nagoshi T, Hong EG, et al. Effects of chronic Akt acti-
vation on glucose uptake in the heart. Am J Physiol Endocrinol
Metab 2006; 290: E789-97.
Matsui T, Li L, del Monte F, et al. Adenoviral gene transfer of
activated phosphatidylinositol 3'-kinase and Akt inhibits apoptosis
of hypoxic cardiomyocytes in vitro. Circulation 1999; 100: 2373-9.
Fujio Y, Nguyen T, Wencker D, Kitsis RN, Walsh K. Akt promotes
survival of cardiomyocytes in vitro and protects against ischemia-
reperfusion injury in mouse heart. Circulation 2000; 101: 660-7.
Aikawa R, Nawano M, Gu Y, et al. Insulin prevents cardiomyo-
cytes from oxidative stress-induced apoptosis through activation of
PI3 kinase/Akt. Circulation 2000; 102: 2873-9.
Yamashita K, Kajstura J, Discher DJ, et al. Reperfusion-activated
Akt kinase prevents apoptosis in transgenic mouse hearts overex-
pressing insulin-like growth factor-1. Circ Res 2001; 88: 609-14.
Nagoshi T, Matsui T, Aoyama T, et al. PI3K rescues the detrimen-
tal effects of chronic Akt activation in the heart during ische-
mia/reperfusion injury. J Clin Invest 2005; 115: 2128-38.
Shiojima I, Sato K, Izumiya Y, et al. Disruption of coordinated
cardiac hypertrophy and angiogenesis contributes to the transition
to heart failure. J Clin Invest 2005; 115: 2108-18.
[25]
[26]
[27]
[28]
[29]
[30]
[31]
[32]
[33]
[34]
[35]
[36]
[37]
[38]
[39]
[40]
[41]
[42]
[43]
[44]
[45]
[46]
[47] Shimizu I, Minamino T, Toko H, et al. Excessive cardiac insulin
signaling exacerbates systolic dysfunction induced by pressure
overload in rodents. J Clin Invest 2010; 120: 1506-14.
Lawlor MA, Alessi DR. PKB/Akt: a key mediator of cell prolifera-
tion, survival and insulin responses? J Cell Sci 2001; 114: 2903-10.
Brazil DP, Hemmings BA. Ten years of protein kinase B signal-
ling: a hard Akt to follow. Trends Biochem Sci 2001; 26: 657-64.
Haq S, Choukroun G, Lim H, et al. Differential activation of signal
transduction pathways in human hearts with hypertrophy versus
advanced heart failure. Circulation 2001; 103: 670-7.
Ananthakrishnan R, Moe GW, Goldenthal MJ, Marin-Garcia J. Akt
signaling pathway in pacing-induced heart failure. Mol Cell Bio-
chem 2005; 268: 103-10.
Yu Q, Gao F, Ma XL. Insulin says NO to cardiovascular disease.
Cardiovasc Res 2011; 89: 516-524.
Schulz TJ, Westermann D, Isken F, et al. Activation of mitochon-
drial energy metabolism protects against cardiac failure. Aging
(Albany NY) 2010; 2: 843-53.
Kim YK, Kim SJ, Yatani A, et al. Mechanism of enhanced cardiac
function in mice with hypertrophy induced by overexpressed Akt. J
Biol Chem 2003; 278: 47622-8.
Kim SJ, Abdellatif M, Koul S, Crystal GJ. Chronic treatment with
insulin-like growth factor I enhances myocyte contraction by
upregulation of Akt-SERCA2a signaling pathway. Am J Physiol
Heart Circ Physiol 2008; 295: H130-5.
Catalucci D, Latronico MV, Ceci M, et al. Akt increases sarco-
plasmic reticulum Ca2+ cycling by direct phosphorylation of phos-
pholamban at Thr17. J Biol Chem 2009; 284: 28180-7.
Hermann HP, Arp J, Pieske B, et al. Improved systolic and dia-
stolic myocardial function with intracoronary pyruvate in patients
with congestive heart failure. Eur J Heart Fail 2004; 6: 213-8.
Hasenfuss G, Maier LS, Hermann HP, et al. Influence of pyruvate
on contractile performance and Ca(2+) cycling in isolated failing
human myocardium. Circulation 2002; 105: 194-9.
Nikolaidis LA, Elahi D, Hentosz T, et al. Recombinant glucagon-
like peptide-1 increases myocardial glucose uptake and improves
left ventricular performance in conscious dogs with pacing-induced
dilated cardiomyopathy. Circulation 2004; 110: 955-61.
Halbirk M, Norrelund H, Moller N, et al. Cardiovascular and meta-
bolic effects of 48-h glucagon-like peptide-1 infusion in compen-
sated chronic patients with heart failure. Am J Physiol Heart Circ
Physiol 2010; 298: H1096-102.
Read PA, Khan FZ, Heck PM, Hoole SP, Dutka DP. DPP-4 inhibi-
tion by sitagliptin improves the myocardial response to dobutamine
stress and mitigates stunning in a pilot study of patients with coro-
nary artery disease. Circ Cardiovasc Imaging 2010; 3: 195-201.
Finck BN, Lehman JJ, Leone TC, et al. The cardiac phenotype
induced by PPARalpha overexpression mimics that caused by dia-
betes mellitus. J Clin Invest 2002; 109: 121-30.
Yagyu H, Chen G, Yokoyama M, et al. Lipoprotein lipase (LpL)
on the surface of cardiomyocytes increases lipid uptake and pro-
duces a cardiomyopathy. J Clin Invest 2003; 111: 419-26.
Kantor PF, Lucien A, Kozak R, Lopaschuk GD. The antianginal
drug trimetazidine shifts cardiac energy metabolism from fatty acid
oxidation to glucose oxidation by inhibiting mitochondrial long-
chain 3-ketoacyl coenzyme A thiolase. Circ Res 2000; 86: 580-8.
Vitale C, Wajngaten M, Sposato B, et al. Trimetazidine improves
left ventricular function and quality of life in elderly patients with
coronary artery disease. Eur Heart J 2004; 25: 1814-21.
Fragasso G, Palloshi A, Puccetti P, et al. A randomized clinical
trial of trimetazidine, a partial free fatty acid oxidation inhibitor, in
patients with heart failure. J Am Coll Cardiol 2006; 48: 992-8.
Di Napoli P, Taccardi AA, Barsotti A. Long term cardioprotective
action of trimetazidine and potential effect on the inflammatory
process in patients with ischaemic dilated cardiomyopathy. Heart
2005; 91: 161-5.
Fragasso G, Perseghin G, De Cobelli F, et al. Effects of metabolic
modulation by trimetazidine on left ventricular function and phos-
phocreatine/adenosine triphosphate ratio in patients with heart fail-
ure. Eur Heart J 2006; 27: 942-8.
Zarain-Herzberg A, Rupp H, Elimban V, Dhalla NS. Modification
of sarcoplasmic reticulum gene expression in pressure overload
cardiac hypertrophy by etomoxir. FASEB J 1996; 10: 1303-9.
Rupp H, Vetter R. Sarcoplasmic reticulum function and carnitine
palmitoyltransferase-1 inhibition during progression of heart fail-
ure. Br J Pharmacol 2000; 131: 1748-56.
[48]
[49]
[50]
[51]
[52]
[53]
[54]
[55]
[56]
[57]
[58]
[59]
[60]
[61]
[62]
[63]
[64]
[65]
[66]
[67]
[68]
[69]
[70]

Page 8

Optimization of Cardiac Metabolism in Heart Failure Current Pharmaceutical Design, 2011, Vol. 17, No. 35 3853
[71] Lee L, Campbell R, Scheuermann-Freestone M, et al. Metabolic
modulation with perhexiline in chronic heart failure: a randomized,
controlled trial of short-term use of a novel treatment. Circulation
2005; 112: 3280-8.
Gilde AJ, van der Lee KA, Willemsen PH, et al. Peroxisome pro-
liferator-activated receptor (PPAR) alpha and PPARbeta/delta, but
not PPARgamma, modulate the expression of genes involved in
cardiac lipid metabolism. Circ Res 2003; 92: 518-24.
Kitamura K, Kangawa K, Matsuo H, Uyeda K. Phosphorylation of
myocardial fructose-6-phosphate,2-kinase:
bisphosphatase by cAMP-dependent protein kinase and protein
kinase C. Activation by phosphorylation and amino acid sequences
of the phosphorylation sites. J Biol Chem 1988; 263: 16796-801.
Morisco C, Condorelli G, Trimarco V, et al. Akt mediates the
cross-talk between beta-adrenergic and insulin receptors in neona-
tal cardiomyocytes. Circ Res 2005; 96: 180-8.
Wallhaus TR, Taylor M, DeGrado TR, et al. Myocardial free fatty
acid and glucose use after carvedilol treatment in patients with
congestive heart failure. Circulation 2001; 103: 2441-6.
Mizuno Y, Yoshimura M, Yasue H, et al. Aldosterone production
is activated in failing ventricle in humans. Circulation 2001; 103:
72-7.
Yoshimura M, Nakamura S, Ito T, et al. Expression of aldosterone
synthase gene in failing human heart: quantitative analysis using
modified real-time polymerase chain reaction. J Clin Endocrinol
Metab 2002; 87: 3936-40.
[72]
[73]
fructose-2,6-
[74]
[75]
[76]
[77]
[78] Nakamura S, Yoshimura M, Nakayama M, et al. Possible associa-
tion of heart failure status with synthetic balance between aldoster-
one and dehydroepiandrosterone in human heart. Circulation 2004;
110: 1787-93.
Cooper SA, Whaley-Connell A, Habibi J, et al. Renin-angiotensin-
aldosterone system and oxidative stress in cardiovascular insulin
resistance. Am J Physiol Heart Circ Physiol 2007; 293: H2009-3.
Hitomi H, Kiyomoto H, Nishiyama A, et al. Aldosterone sup-
presses insulin signaling via the downregulation of insulin receptor
substrate-1 in vascular smooth muscle cells. Hypertension 2007;
50: 750-5.
Wada T, Ohshima S, Fujisawa E, Koya D, Tsuneki H, Sasaoka T.
Aldosterone inhibits insulin-induced glucose uptake by degradation
of insulin receptor substrate (IRS) 1 and IRS2 via a reactive oxygen
species-mediated pathway in 3T3-L1 adipocytes. Endocrinology
2009; 150: 1662-9.
Freel EM, Tsorlalis IK, Lewsey JD, et al. Aldosterone status asso-
ciated with insulin resistance in patients with heart failure--data
from the ALOFT study. Heart 2009; 95: 1920-4.
Pfeffer MA, Swedberg K, Granger CB, et al. Effects of candesartan
on mortality and morbidity in patients with chronic heart failure:
the CHARM-Overall programme. Lancet 2003; 362: 759-66.
Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Ef-
fects of an angiotensin-converting-enzyme inhibitor, ramipril, on
cardiovascular events in high-risk patients. The Heart Outcomes
Prevention Evaluation Study Investigators. N Engl J Med 2000;
342: 145-53.
[79]
[80]
[81]
[82]
[83]
[84]
Received: August 22, 2011 Accepted: September 5, 2011