Review

Cardiovascular Research (2008) 79, 269278

doi:10.1093/cvr/cvn074

Role of diet and fuel overabundance in the development

and progression of heart failure
David J. Chess1,2 and William C. Stanley1,2*
1

Department of Physiology and Biophysics, School of Medicine, Case Western Reserve University, Cleveland, OH, USA;
and 2Division of Cardiology, Department of Medicine, University of Maryland, 20 Penn St, HSF-II, Room S022,
Baltimore, MD 21201, USA
Received 21 December 2007; revised 7 March 2008; accepted 11 March 2008; online publish-ahead-of-print 14 March 2008
Time for primary review: 24 days

Diabetes;
Diet;
Glucotoxicity;
Heart;
Lipotoxicity

Under physiological conditions, the human heart derives energy from glucose, fatty acids, and/or
lactate depending upon substrate availability, circulating hormone levels, and nutritional status. Circulating free fatty acid and glucose levels often exceed the normal range, as observed with type 2 diabetes, obesity, or physical inactivity. Chronic exposure of the heart to high plasma levels of free
fatty acids may cause accumulation of toxic lipid intermediates within cardiomyocytes. Furthermore,
suppression of glucose oxidation by increased fatty acid uptake shunts glucose into the oxidative
pentose phosphate and hexosamine biosynthetic pathways, both of which yield potentially harmful products. Noxious derivatives of aberrant glucose and fatty acid oxidation can activate signalling cascades
leading to myocyte dysfunction or death, processes termed glucotoxicity and lipotoxicity. This
review discusses the effects of dietary extremes (e.g. high fat and high carbohydrate consumption)
and substrate overabundance in the context of heart failure (HF) development and progression. Emerging data suggest that substrate excess leads to cardiac dysfunction and HF, which may be prevented or
slowed by maintaining low body fat and high insulin sensitivity and consuming a diet of low glycaemic
load that is high in mono- and polyunsaturated fatty acids.

1. Introduction
The constant demand for cardiac mechanical power is supported by a high rate of ATP production fueled by myocardial
fat and carbohydrate oxidation.1,2 The myocardium adjusts
quickly to changes in arterial substrate concentrations,3,4
giving it the metabolic exibility needed for feeding and
fasting and variations in food composition. The heart is
also built to meet the energy demands of intense exercise,
therefore at rest extracting and oxidizing fatty acids and
glucose at 5 to 30% of the maximal capacities for ux.
Under healthy conditions, there is little accumulation of
intracardiac triglyceride (TG) and glycogen despite high
rates of fatty acid and glucose uptake. This is attributed
to relatively low plasma free fatty acid (FFA) concentrations
(,0.8 mM) and tightly-regulated glucose homeostasis
(~45 mM). However, an elevation in plasma fatty acids,
such as with fasting or starvation, accelerates fatty acid
uptake and oxidation, inhibits glucose oxidation, and
increases myocardial TG and glycogen stores.57
Whole body insulin resistance, a hallmark of the metabolic
syndrome, obesity, a poor diet, or a sedentary lifestyle,

* Corresponding author. Tel: 1 410 706 3585; fax: 1 410 706 3583.
E-mail address: wstanley@medicine.umaryland.edu

triggers an elevation in plasma FFAs, TGs, glucose, and

insulin and presents the myocardium with an overabundance
of lipid and carbohydrate substrates. Chronic exposure to
excess circulating fuels can have a toxic effect on the
heart due to formation of noxious derivatives of glucose
and lipid metabolism, such as reactive oxygen species
(ROS) from glucose8,9 or ceramides from saturated fatty
acids.10,11 Recent studies where cardiac fatty acid uptake
and/or storage were increased in transgenic mice found
accumulation of TG and ceramides in cardiomyocytes associated with tissue pathology and deterioration in systolic
function.1215 In addition, chronic exposure of the heart to
hyperglycaemia or accelerated glucose uptake can increase
toxic non-glycolytic metabolism of glucose through the oxidative pentose phosphate8 or hexosamine biosynthetic
pathway.16 Taken together, this suggests that accumulation
of lipid and glucose metabolites in the myocardium could
contribute to the development and progression of heart
failure (HF), though there is little clinical evidence to
support this hypothesis.
Much has been made of the energy-starvation hypothesis,
the idea that the failing myocardium is chronically energy
deprived.1722 However, most of this literature suggests that
energy depletion originates from alterations in phosphate
metabolism (e.g. decreased creatine kinase-phosphocreatine

Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2008.
For permissions please email: journals.permissions@oxfordjournals.org.

Downloaded from http://cardiovascres.oxfordjournals.org/ by guest on April 8, 2012

KEYWORDS

270

2. Dietary lipid and carbohydrate: new

paradigm for prevention of cardiovascular
disease?
Diet is a primary determinant of substrate availability, the
hormonal milieu, and the development of obesity and
insulin resistance. Dietary guidelines for .50 years have
recommended consumption of a low saturated fat/high
complex carbohydrate diet to reduce the risk for CHD.26
Since the 1960s, low-fat and reduced-fat food has been
marketed, decreasing total fat intake and replacing it with
simple carbohydrates largely from highly-processed foods
and sugar-sweetened beverages. Concurrent with these
modications was increased prevalence of obesity and

type 2 diabetes, both of which are at pandemic proportions

and increase the risk for cardiovascular disease.27,28
Recent epidemiological studies show a positive association
between dietary carbohydrate consumption and CHD,29,30
with reduced risk with high vegetable fat intake
(Figure 1). Importantly, eating a diet high in sugar and
rapidly-absorbed starch increased the risk for CHD.2931
Regarding fat intake, numerous epidemiological studies
have shown that diets low in saturated fat, trans fat, and
cholesterol signicantly lower risk for CHD.32,33 However,
in the Womens Health Initiative, reducing total fat from
37.8% of energy intake at baseline to 28.8% after 6 years
of follow-up did not affect the rate of CHD events or
stroke compared to no intervention.34 Furthermore, high
carbohydrate diets raise postprandial glycaemia and
promote insulin resistance, thereby increasing risk of cardiovascular disease, dyslipidaemia, obesity, and diabetes.
Increased fat intake, when coupled with restricted intake
of rened carbohydrate, has benecial effects on weight
loss, glycaemic control, lipid prole, and inammatory
markers. Low carbohydrate/high fat diets have also been
shown to improve biomarkers of cardiovascular disease in
normal weight, normolipidemic subjects independent of
weight loss.35 Based on these and other ndings, nutritional
guidelines have shifted away from the old diet-CHD paradigm that paid little attention to carbohydrate intake.
Current recommendations emphasize increasing consumption of polyunsaturated fatty acids and reducing glycaemic
load and total energy intake.26,30,36 Nevertheless, there is
limited experimental and clinical evidence examining the
role of diet in the pathogenesis of HF. Thus, at present, it
is unclear if this new nutritional paradigm will be effective
in the treatment of HF. In the following sections, we shall
review the effects of diet and substrate overabundance on
the myocardium and postulate how they may affect the
natural history of HF.

3. Excess lipids and the heart

Plasma fatty acids are the primary carbon fuel for the
myocardium but, when elevated, can adversely impact
the heart. Early work found a strong association between
elevated plasma FFA and ventricular arrhythmias during an

Figure 1 Risk for coronary heart disease (CHD) after multivariate adjustment in women according to consumption of macronutrients. Plot displays mean (lled
circles) and range of hazard ratio per decile of macronutrient intake. Increased glycaemic load correlated with increased risk for CHD. Greater consumption of
vegetable fat signicantly reduced risk for CHD, while the level of total fat intake had no effect. Figure drawn from data published in Halton et al.30

Downloaded from http://cardiovascres.oxfordjournals.org/ by guest on April 8, 2012

shuttle activity), ATP transport (e.g. impaired adenine

nucleotide translocase function), and/or respiratory chain
dysfunction secondary to mitochondrial DNA damage,
protein modication/downregulation, and/or cardiolipin
depletion.2,2224 While the capacity for glucose and fatty
acid oxidation are both downregulated in severe HF,2,25 it is
difcult to assess changes in cardiac metabolism due to the
increase in circulating fatty acids, glucose, and insulin
derived from peripheral metabolic abnormalities in end-stage
disease. Thus, maintenance of energy balance and a normal
metabolic milieu is required to nourish the myocardium and
perhaps slow the progression of HF.
There is a worldwide epidemic in metabolic disorders and
heart disease due to obesity, physical inactivity, and overconsumption of diets rich in highly-rened foods. Thus,
there is growing interest in understanding the effects of
chronic excess of circulating substrates. This review will
discuss recent ndings on the role of carbohydrate and
lipid overabundance, emphasizing the toxic effects of fuel
substrates in cardiomyocytes and on the development of
cardiac hypertrophy and HF. The contribution of diet to
atherosclerosis and coronary disease, which potentially
leads to myocardial damage via infarction, has been
reviewed elsewhere and will be discussed only as a means
of presenting epidemiological evidence relating diet to
cardiovascular risk. Our focus here is to illuminate the
direct effects of substrate availability and diet on the
myocardium independent of coronary heart disease (CHD).

D.J. Chess and W.C. Stanley

271

Diet and fuel overabundance in heart failure

mass index. Furthermore, cardiac biopsies from HF patients

with obesity or type 2 diabetes have elevated myocardial
TGs compared with healthy controls.60 To date, no evidence
provides a causal link between myocardial lipid accumulation and cardiac dysfunction or HF in a clinical population.
On the other hand, some non-clinical studies have found
evidence for lipid-induced cardiac pathology and HF and
suggest several potential mechanisms.11,15,67

3.1 Cellular mechanisms

In the setting of divergent uptake and oxidation, increased
exposure of the heart to circulating fatty acids raises the
intracellular pool of long-chain fatty acyl-CoA. Accumulation of fatty acyl-CoA provides a substrate for nonoxidative processes, such as triacylglycerol, diacylglycerol,
and ceramide synthesis with subsequent cardiomyocyte dysfunction and apoptosis68 (Figure 2B). Increased cellular
content of diacylglycerol may lead to chronic activation of
protein kinase Cs, which has been associated with cardiomyopathy.69 FFAs may have direct effects on mitochondria,
possibly increasing membrane permeability and cytochrome
c release.7072 Excess FFAs also can reduce phosphatidylinositol 3-kinase/Akt signalling and activate NF-kB.73,74
Fatty acids modulate cardiac metabolism and mitochondrial function through the PPAR family.12,75,76 PPARa is activated by long-chain fatty acids, eicosanoids, and brate
drugs and controls expression of genes involved in fatty
acid uptake, esterication, transport into mitochondria,
and b-oxidation. Though having a more diffuse expression
pattern, PPARb/d has been shown to increase palmitate oxidation in neonatal and adult cardiomyocytes77,78 and to partially rescue expression of b-oxidation enzymes imposed by
PPARa deciency.79 PPARg is highly expressed in adipose
tissue, promoting glucose uptake and triglyceride storage,
and is the target of the insulin-sensitizing thiazolidinediones
used in the treatment of type 2 diabetes.80,81 PPARg
indirectly modulates cardiac metabolism through direct
effects on circulating fatty acids, adipokines, and insulin
sensitivity.
Cardiac-specic overexpression of PPARa results in
increased fatty acid oxidation, elevated serum TG, hepatic
and cardiac insulin resistance, LVH, and systolic dysfunction
which is exacerbated by high fat feeding.12,76,82,83 These
studies suggest that long-term PPARa activation can be deleterious to the heart. On the other hand, pharmacological
activation of PPARa in rats with HF84 or in dogs or pigs
during the development of tachycardia-induced HF85,86 had
no adverse effects, suggesting that a modest increase in
activity is without major functional consequence in chronically stressed myocardium.
The adipose-derived hormone leptin produces satiety and
is positively correlated with percentage body fat. Genetic
deletion of leptin in rats and mice results in obesity, hyperlipidaemia, cardiac contractile dysfunction, and LV chamber
dilation. The leptin decient obese Zucker diabetic fatty
rats develop eccentric LV remodelling and systolic dysfunction with age concomitant with increased myocardial TG
content, accumulation of ceramides, and apoptosis compared with normal rats.67,87,88 A similar phenotype is
observed in obese leptin decient ob/ob mice.89,90 Due to
the obesity, hyperinsulinaemia, and diabetes that develops
in leptin-decient animal models, it is difcult to ascertain

Downloaded from http://cardiovascres.oxfordjournals.org/ by guest on April 8, 2012

acute ischaemic event.37,38 More recent studies showed

that elevated plasma FFA is a strong predictor of sudden
cardiac death in either patients undergoing coronary
angiography followed for 7 years39 or healthy middle-aged
men followed for 22 years.40 This association could be
due to deleterious effects on mitochondrial function41,42
or activation of Na or Ca2 channels, thereby triggering
ventricular arrhythmias.43
The uptake of fatty acids by the heart is primarily determined by the plasma FFA concentration, which is regulated
by the rate of lipolysis in adipose tissue.4446 In healthy
people, arterial FFA concentration varies 4-fold in a
normal day (~0.20.8 mM) but can increase rapidly to
.1.0 mM in response to adrenergic stimulation such as with
exercise, angina, or emotional stress. FFA levels increase
when insulin suppression of lipolysis is low, as with insulin
resistance (e.g. obesity, type 2 diabetes, or chronic physical
inactivity) or with low insulin levels (starvation, type 1 diabetes, exercise). Regulation of cardiac FFA metabolism is
complex (see reviews addressing this topic2,44,47). Once FFA
enter the cytosol, they are esteried to fatty acyl-CoA and
converted to TG or to long-chain fatty acyl-carnitine by carnitine palmitoyltransferase-I (CPT-I) (Figure 2A).44 Approximately 80% of long-chain fatty acids taken up by the heart
are immediately oxidized to CO2 and 20% enter the intracardiac TG pool.2,46 In healthy people, the myocardial content of
TG is low (3 mg g21 tissue)7 relative to the rate of FFA
uptake (3 mg g21 h21).48,49 Assuming that 20% of the FFA
uptake enters the intracardiac TG pool,44,46 the mean turnover time is 5 h, illustrating the dynamic nature of intracellular cardiac TG metabolism. Plasma FFA concentration
regulates cardiac TG content, as seen in recent NMR spectroscopy in healthy humans, which found a progressive
increase in myocardial TG stores with short-term food restriction (70% increase) or starvation (260% increase) corresponding with elevated plasma FFA.7
An important effect of elevated plasma FFA on the heart is
suppression of glucose and lactate uptake and oxidation
through inhibition of phosphofructokinase and pyruvate
dehydrogenase activity.50,51 Reducing plasma FFA with diet
or drugs rapidly decreases myocardial fatty acid oxidation
and increases pyruvate oxidation.2 In addition, high plasma
FFA and oxidation by the heart reduce myocardial mechanical efciency by increasing the energy expenditure for a
given rate of contractile power.5256 The mechanism for
this effect is unclear but could be due to both mitochondrial
uncoupling, accelerated futile cycle ux, or a lower ATP:O
ratio for fatty acids than pyruvate.2,53,54,5658 In addition
to these rapid acute effects, more sustained exposure of
the heart to high FFA levels will activate peroxisome
proliferator-activated receptor a (PPARa) and upregulate
the expression of pyruvate dehydrogenase kinase-4, which
inhibits the activity of pyruvate dehydrogenase (see
Section 3.1 below).2
Recently, attention has been placed on lipid accumulation
in the heart and the adverse effects on cardiac function and
clinical outcome, particularly in diabetic or obese
patients.59,60 Morbidly obese individuals frequently present
with hypertension, left ventricular hypertrophy (LVH), and
impaired contractility as a function of obesity duration
which might be due to toxic effects of lipid in the myocardium.6164 Septal TG levels, as assessed by magnetic
resonance spectroscopy,65,66 correlate positively with body

272

D.J. Chess and W.C. Stanley

Downloaded from http://cardiovascres.oxfordjournals.org/ by guest on April 8, 2012

Figure 2 Schematic depiction of myocardial metabolism under conditions of normal substrate concentrations (A) and elevated fatty acids (B) and glucose (C ).
GLUT, GLUT1 and GLUT4 glucose transporters; G 6-P, glucose 6-phosphate; PDHa, active pyruvate dehydrogenase; TCA cycle, tricarboxylic acid cycle; FATP, fatty
acid transport proteins; FFAs, free fatty acids; CPT-I, carnitine palmitoyltransferase-I; ETC, electron transport chain.

273

Diet and fuel overabundance in heart failure

3.2 Effects of high fat diets on the heart

Transgenic animal models, despite their utility, often represent supraphysiological conditions that rarely mimic
human pathologies. From a clinical perspective, it is more
relevant to assess the effects of substrate handling on
cardiac function and pathology on a normal genetic background in models of progressive HF. Thus, if lipotoxic
cardiomyopathy is an established clinical entity supported
by experimental evidence, it should be exacerbated by
increased fatty acid availability, such as upon consumption
of a high fat diet. However, as will be discussed below, it
appears that high fat diets are neutral or cardioprotective,
especially when high in v-3 polyunsaturated fatty acids.
Recent evidence suggests that consumption of a diet rich
in vegetable fat, specically polyunsaturated fatty acids,
decreases the risk for CHD (Figure 1). This observation has
prompted a paradigm shift in dietary recommendations for
prevention of CHD away from low fat/high carbohydrate
diets towards greater fat intake.36,99,100 However, there is
little information regarding the role of fat intake in the
development of HF. Epidemiological data show that high
intake of v-3 polyunsaturated fatty acids from sh is associated with a lower incidence of HF.101 A similar benet was
observed in rats with pressure overload-induced LVH and
dysfunction,102 suggesting that dietary intake of v-3 polyunsaturated fatty acids prevents the development of HF.
Additional animal studies indicate that a high fat diet comprised of either saturated or unsaturated fatty acids is not
deleterious to the heart. Normotensive rats fed a high fat

diet (60% total energy from fat) for 8 weeks did not
develop LVH compared with a high carbohydrate/low fat
diet.103 Inhibition of CPT-I increased cardiac TG content
but did not lead to systolic dysfunction.104 Feeding a high
fat diet to hypertensive Dahl salt-sensitive rats attenuated
LVH, contractile dysfunction, and LV dilation compared
with a high carbohydrate chow.105,106
Hypertension in the Dahl rat is induced by high dietary salt
intake107 which, subsequently, may alter feeding behaviour
and macronutrient intake. Thus, studies have been performed in other models of pressure overload to eliminate
the confounding effects of elevated sodium. In a rat model
of abdominal aortic banding, a low carbohydrate/high fat
diet attenuated LVH and reduced LV remodelling and contractile dysfunction compared with a high carbohydrate/
low fat diet.108 The lower LV mass with a low carbohydrate/high fat diet was associated with decreased leptin
and insulin concentrations, consistent with the idea that
these hormones regulate cardiac growth.109 Furthermore,
LV end-systolic and end-diastolic volumes were inversely
correlated with plasma FFA concentration among banded
animals. These ndings are in agreement with recent epidemiological data (Figure 1), demonstrating that increased fat
consumption does not exacerbate the development of CHD.
The neutral effects of high fat feeding are not specic to
the rat. Mice subjected to transverse aortic constriction
(TAC) and a high fat diet (60% energy from fat) showed no
difference in body mass, heart weight, plasma TGs,
insulin, ventricular architecture, or ejection fraction compared with animals fed a high carbohydrate/low fat
diet.110 Furthermore, high fat feeding prevented a decrease
in both medium-chain acyl-CoA dehydrogenase and citrate
synthase activities in animals subjected to TAC, suggesting
maintenance of mitochondrial oxidative capacity in the
fat-fed animals.
The rat infarct model of HF displays a similar response. A
high fat diet had no adverse effects on LV remodelling or systolic function compared with a high carbohydrate/low fat
diet despite increases in plasma FFAs, TGs, and leptin in
animals subjected to coronary artery ligation.84,111 Myocardial TG and ceramide content were both increased but were
not associated with worse LV systolic function. In addition,
high fat feeding in infarcted animals increased state 3 and
state 4 mitochondrial respiration with lipid and non-lipid
substrates compared with animals on the high carbohydrate/low fat diet.111 Therefore, in this model, it
appears that increased exposure to fatty acids had no
toxic effects on the heart. Collectively, the pressure overload and infarct studies conict with data from transgenic
models of increased fatty acid uptake and oxidation. Thus,
in the context of a normal genetic background, high fat
feeding prevents LVH, LV dilation, and contractile dysfunction in rodent models of HF.

4. Glucotoxicity
The toxic effects of glucose overabundance on the heart are
not as well-dened as those for fatty acids. Recent data
showed that increased fasting plasma glucose is a predictor
of hospitalization for HF, suggesting that dysglycaemia
may exacerbate HF progression.112 Prospective studies
link hyperglycaemia to cardiovascular events and poor
outcome, as even modest increases in glycosylated

Downloaded from http://cardiovascres.oxfordjournals.org/ by guest on April 8, 2012

whether cardiac dysfunction is mediated directly by myocardial steatosis.91

As such, numerous transgenic mouse models have been
developed to alter myocardial fatty acid uptake or oxidation
independent of body mass or peripheral insulin resistance.
Mice with cardiomyocyte-specic overexpression of longchain acyl-CoA synthetase, an enzyme highly expressed in
the heart and responsible for catalyzing the rst step in
fatty acid metabolism, displayed myocardial neutral lipid
droplet formation and increased cytochrome c and ceramide
content.13 Similar results have been obtained in mice
with cardiomyocyte-restricted expression of lipoprotein
lipase.15 Associated with higher lipase activity was increased
heart weight to body weight ratio, LV dilation with systolic
dysfunction, and decreased survival. Furthermore, overexpression of fatty acid transport protein-1 produced LV and
atrial hypertrophy, diastolic dysfunction, and electrocardiographic abnormalities.14
TG storage in the heart also correlates with lipoprotein
synthesis. It has been well-documented that null mutations
in apolipoprotein B (apoB) and microsomal triglyceride
transfer protein (mtp)genes involved in lipoprotein assembly and secretionlead to substantial TG accumulation in
hepatocytes and enterocytes.92,93 ApoB and MTP are
expressed in the heart as well, suggesting that the heart
can export surplus lipids.94,95 Myocardial TG stores decrease
with cardiac-specic expression of human ApoB and increase
with MTP knockout.96 Lack of lipid accumulation in
ApoB-overexpressing mice prevents contractile dysfunction
in streptozotocin-induced diabetes.97 Similarly, ApoB production reduces lipotoxicity caused by lipoprotein lipase
overexpression and molecular markers of HF.98

274

D.J. Chess and W.C. Stanley

Additional work is needed to determine if increased glucose

ux is responsible for the cardiac pathology observed under
these conditions.8,9
Glucose may exert toxic effects through transcriptional
regulatory mechanisms. Glycosylation increases the stability
of the transcription factor Sp1, which is activated by
increased glucose availability124,125 and pressure overload117,126,127 and regulates reversion to the fetal isoform
programme during cardiac hypertrophy.128 Thus, increased
glucose metabolism indirectly may play a role in molecular
alterations associated with HF pathogenesis.

4.1 Cellular mechanisms

4.3 Effects of high carbohydrate diets on the heart

Similar to fatty acids, glucose mediates its toxic effects when

there is a disconnect between uptake and oxidation. High
sugar intake and/or insulin resistance would overexpose the
heart to glucose and chronically activate insulin signalling
pathways, which would induce cardiomyocyte protein synthesis and LVH109,115 (Figure 2C). Chronic hyperglycaemia
increases ux through the hexosamine biosynthetic pathway
and N-acetyl-glucosamine production, which induces insulin
resistance, cardiomyocyte hypertrophy and apoptosis, myocardial brosis, and ROS production.16,116118
Another potential mediator of oxidative damage is the
oxidative pentose phosphate pathway, of which glucose 6phosphate dehydrogenase (G6PDH) is a rate-controlling
enzyme. Normally, this pathway serves to provide cytosolic
NADPH and generate ribose 6-phosphate for de novo
purine nucleotide synthesis. However, under hyperglycaemic
conditions, glucose ux through this pathway may be
increased and fuel paradoxical ROS production via NADPH
oxidases and uncoupled nitric oxide synthase.8,9

Recent studies in rats and mice with arterial hypertension

suggest that a high carbohydrate diet, particularly one
high in sugar, increases the incidence and/or severity of
HF compared with a low carbohydrate/high fat diet. Hypertensive Dahl rats fed a high fructose diet (60% energy
derived from fructose) had signicantly increased mortality
(Figure 3), decreased LV hemodynamics, and ejection fraction reduction compared with animals fed a low carbohydrate/high fat diet.105 Similarly, rats subjected to
abdominal aortic banding and fed a high sucrose diet (62%
energy from sucrose) exhibited greater LVH and ventricular
remodelling compared with the low carbohydrate/high fat
group.108 Multivariate regression analyses indicated that
plasma insulin concentration was positively associated with
both end-systolic and end-diastolic volumes. Mice subjected
to TAC and fed a high fructose diet (61% energy derived from
fructose) exhibited signicantly increased mortality compared with a high starch diet.129 Fructose-fed TAC mice
had increased end-systolic diameter and decreased ejection
fraction compared with sham, effects which were completely prevented with a high starch diet. Interestingly, high
fructose decreased the activities of medium-chain
acyl-CoA dehydrogenase and citrate synthase and dramatically upregulated mhcb with TAC compared with animals
fed either a high starch or high fat diet (Figure 4). These
ndings suggest that carbohydrate composition may have
an even greater impact than that of fat and concur with
evidence linking increased glycaemic load to risk for CHD
(Figure 1).

4.2 Evidence from animal and human studies

Mice with an 80% reduction in G6PDH activity presented with
reduced vascular oxidative stress and less atherogenesis.119
Aortic tissue from these mice displayed low NADPH concentration and protection against angiotensin-II-induced oxidative stress.120 Moreover, humans with G6PDH deciency,
the most common enzymopathy in the world, exhibit lower
atherosclerosis-associated
cardiovascular
mortality.121
Conversely, LV homogenates from a canine model of HF or
from HF patients have upregulated G6PDH activity, high
levels of NADPH, and increased superoxide levels which
are normalized by G6PDH inhibition.8,9 Thus, oxidative
stress via the pentose phosphate pathway may be a culprit
in the severely hypertrophied or failing heart where
glucose oxidation is upregulated,2 particularly if a high
carbohydrate/low fat diet is consumed. The exact role of
this pathway in the pathogenesis of HF requires further
investigation.
Cardiac glucotoxicity could occur under conditions where
there is chronically decreased myocardial fatty acid metabolism, resulting in reciprocal acceleration of glucose metabolism.8,9 Mice with heart-specic deletion of lipoprotein
lipase had increased myocardial glucose oxidation.122
Associated with increased glucose metabolism was intolerance to pressure overload, increased interstitial and
perivascular collagen content, and impaired age-related
cardiac function. Similarly, increased cardiomyocyte
glucose uptake caused by PPARg overexpression leads to
cardiac hypertrophy, LV dilation, and systolic dysfunction.123

Figure 3 Cumulative mortality in hypertensive Dahl salt-sensitive rats fed a

high fat (fat, 60% total energy from fat, 20% carbohydrate), fat sugar (45%
fat, 25% fructose), complex carb (57% starch, 10% fat), and fructose (52%
fructose, 10% fat) for 12 weeks. P , 0.05 compared with all other diets.
Figure drawn from data published in Sharma et al.105

Downloaded from http://cardiovascres.oxfordjournals.org/ by guest on April 8, 2012

haemoglobin or glycaemia are associated with increased risk

of myocardial infarction, angina, and ischaemic heart
disease and cardiovascular death.113,114 Prolonged insulin
resistance and accompanying increases in plasma glucose
and insulin concentration may lead to LVH and contribute
to the development of HF.109 While the focus of this
review is on the cardiotoxic effects of substrate overabundance, it is important to recognize that activation of
cardiac insulin signalling induced by hyperinsulinaemia
likely contributes to cardiac hypertrophy and pathology in
hypertension or following myocardial infarction.109,115

275

Diet and fuel overabundance in heart failure

be to (i) maintain low body fat content and high insulin

sensitivity through restricted food intake and daily physical
activity, (ii) eat a relatively low carbohydrate diet (4055%
of energy intake from carbohydrate) comprised of foods
with a low glycaemic index,135 and (iii) consume fat of
vegetable and marine origin that is rich in mono- and polyunsaturated fatty acids (30 to 40% of energy intake).
Clearly, extensive interventional studies are needed before
incorporating this strategy into clinical dietary guidelines.

7. Conclusion

5. Glucolipotoxicity: the worst of both worlds

The convergence of gluco- and lipotoxicity has been well
established in pancreatic b-cells both in vitro and in vivo,
where elevated FFA and hyperglycaemia synergize to cause
greater b-cell damage than is observed with either component alone.130132 Though one study has shown similar
effects in isolated cardiomyocytes,133 there is a lack of evidence for this phenomenon in cardiac pathologies. Elevated
glucose and fatty acid levels set up a dangerous environment
for the heart: increased fatty acid uptake inhibits pyruvate
dehydrogenase, thereby reducing glucose oxidation and
displacing glucose to non-glycolytic and/or non-oxidative
pathways
leading
to
noxious
derivatives
(e.g.
N-acetylglucosamine, ROS). Thus, elevated plasma FFA concentrations should exacerbate the toxic effects of hyperglycaemia on the heart. This situation is particularly relevant
in patients with the metabolic syndrome or type 2 diabetes,
where elevated plasma FFA levels and hyperglycaemia
are accompanied by hyperinsulinaemia, which stimulates
cardiac glucose uptake in the face of sustained FFA uptake.134

6. Dietary macronutrient recommendations

for prevention and treatment of heart failure
The evidence presented above raises an important question:
in the clinical situation, should a low carbohydrate/high fat
diet be recommended to patients at risk for or with established HF? The answer is not clear, as epidemiological
studies have assessed development of CHD in healthy
people and not in those with established HF or in patients
at risk for developing HF. Furthermore, management
of co-morbidities such as hypertension, dyslipidaemia,
obesity, and diabetes complicate dietary recommendations.
In any case, it appears that increased intake of mono- and
polyunsaturated fat and restricted intake of rened carbohydrate reduces the risk for CHD and could have a similar
benecial effect in reducing the incidence of HF. Thus, for
the prevention and treatment of HF, the overall goal is to
expose the heart to normal circulating concentrations of
free fatty acids and glucose and low levels of insulin and
leptin. To accomplish these goals, the best strategy would

Conict of interest: none declared.

Funding
This work was supported by NIH grant HL074237.

References
1. Bing RJ. The metabolism of the heart. Harvey Lect 1955;50:2770.
2. Stanley WC, Recchia FA, Lopaschuk GD. Myocardial substrate metabolism in the normal and failing heart. Physiol Rev 2005;85:10931129.
3. Wisneski JA, Stanley WC, Neese RA, Gertz EW. Effects of acute hyperglycemia on myocardial glycolytic activity in humans. J Clin Invest 1990;
85:16481656.
4. Gertz EW, Wisneski JA, Stanley WC, Neese RA. Myocardial substrate utilization during exercise in humans. Dual carbon-labeled carbohydrate
isotope experiments. J Clin Invest 1988;82:20172025.
5. Denton RM, Randle PJ. Concentrations of glycerides and phospholipids in
rat heart and gastrocnemius muscles. Effects of alloxan-diabetes and
perfusion. Biochem J 1967;104:416422.
6. Opie LH, Evans JR, Shipp JC. Effect of fasting on glucose and palmitate
metabolism of perfused rat heart. Am J Physiol 1963;205:12031208.
7. Hammer S, van der Meer RW, Lamb HJ, Schar M, de Roos A, Smit JW
et al. Progressive caloric restriction induces dose dependent changes
in myocardial triglyceride content and diastolic function in healthy
men. J Clin Endocrinol Metab 2007;93:497503.
8. Gupte SA, Levine RJ, Gupte RS, Young ME, Lionetti V, Labinskyy V et al.
Glucose-6-phosphate dehydrogenase-derived NADPH fuels superoxide
production in the failing heart. J Mol Cell Cardiol 2006;41:340349.
9. Gupte RS, Vijay V, Marks B, Levine RJ, Sabbah HN, Wolin MS et al. Upregulation of glucose-6-phosphate dehydrogenase and NAD(P)H oxidase
activity increases oxidative stress in failing human heart. J Card Fail
2007;13:497506.
10. Smyth MJ, Obeid LM, Hannun YA. Ceramide: a novel lipid mediator of
apoptosis. Adv Pharmacol 1997;41:133154.
11. Schaffer JE. Lipotoxicity: when tissues overeat. Curr Opin Lipidol 2003;
14:281287.
12. Finck BN, Lehman JJ, Leone TC, Welch MJ, Bennett MJ, Kovacs A et al.
The cardiac phenotype induced by PPARalpha overexpression mimics
that caused by diabetes mellitus. J Clin Invest 2002;109:121130.
13. Chiu HC, Kovacs A, Ford DA, Hsu FF, Garcia R, Herrero P et al. A novel
mouse model of lipotoxic cardiomyopathy. J Clin Invest 2001;107:
813822.

Downloaded from http://cardiovascres.oxfordjournals.org/ by guest on April 8, 2012

Figure 4 Ratio of myosin heavy chain (MHC) b to MHCa mRNA expression in

mice subjected to either transverse aortic constriction (TAC) or sham surgery.
Starch (58% total energy from starch, 10% fat), fat (60% fat, 20% carbohydrate),
and fructose (61% fructose, 20% carbohydrate) diets were maintained for 16
weeks. Data are means + SEM. *P , 0.05 compared with sham animals on the
same diet; P , 0.05 compared with TAC animals on the fat and starch diets.
Figure drawn from data published in Chess et al.110,129

There is strong evidence that substrate overabundance

contributes to the development and progression of HF. The
myocardium can adapt to these metabolic changes but
may lose this exibility with continued stress. With the
worldwide epidemic in metabolic disorders and resultant
heart disease, additional emphasis should be placed on preventing substrate excess through weight control, physical
exercise, and proper diet. Emerging data suggest that HF
may be prevented or slowed by maintaining low body fat
and high insulin sensitivity and consuming a diet of low
glycaemic load that is high in mono- and polyunsaturated
fatty acids.

276

41. Chua BH, Shrago E. Reversible inhibition of adenine nucleotide translocation by long chain acyl-CoA esters in bovine heart mitochondria and
inverted submitochondrial particles. Comparison with atractylate and
bongkrekic acid. J Biol Chem 1977;252:67116714.
42. Korge P, Honda HM, Weiss JN. Effects of fatty acids in isolated mitochondria: implications for ischemic injury and cardioprotection. Am J Physiol
Heart Circ Physiol 2003;285:259269.
43. Corr PB, Yamada KA. Selected metabolic alterations in the ischemic
heart and their contributions to arrhythmogenesis. Herz 1995;20:
156168.
44. Lopaschuk GD, Belke DD, Gamble J, Itoi T, Schonekess BO. Regulation of
fatty acid oxidation in the mammalian heart in health and disease.
Biochim Biophys Acta 1994;1213:263276.
45. Bing RJ, Siegel A, Ungar I, Gilbert M. Metabolism of the human heart II.
Studies on fat, ketone and amino acid metabolism. Am J Med 1954;16:
504515.
46. Wisneski JA, Gertz EW, Neese RA, Mayr M. Myocardial metabolism of
free fatty acids. Studies with 14C-labeled substrates in humans. J Clin
Invest 1987;79:359366.
47. Lopaschuk GD, Folmes CD, Stanley WC. Cardiac energy metabolism in
obesity. Circ Res 2007;101:335347.
48. Neglia D, De Caterina A, Marraccini P, Natali A, Ciardetti M, Vecoli C
et al. Impaired myocardial metabolic reserve and substrate
selection exibility during stress in patients with idiopathic dilated
cardiomyopathy. Am J Physiol Heart Circ Physiol 2007;293:32703278.
49. Davila-Roman VG, Vedala G, Herrero P, de las Fuentes L, Rogers JG,
Kelly DP et al. Altered myocardial fatty acid and glucose metabolism
in idiopathic dilated cardiomyopathy. J Am Coll Cardiol 2002;40:
271277.
50. Randle PJ. Fuel selection in animals. Biochem Soc Trans 1986;14:
799806.
51. Randle PJ, Garland PB, Hales CN, Newsholme EA. The glucose fatty-acid
cycle. Its role in insulin sensitivity and the metabolic disturbances of
diabetes mellitus. Lancet 1963;1:785789.
52. Zhou L, Huang H, Yuan CL, Keung W, Lopaschuk GD, Stanley WC. Metabolic response to an acute jump in cardiac workload: effects on
malonyl-CoA, mechanical efciency, and fatty acid oxidation. Am J
Physiol Heart Circ Physiol 2008;294:954960.
53. Kjekshus JK, Mjos OD. Effect of free fatty acids on myocardial function
and metabolism in the ischemic dog heart. J Clin Invest 1972;51:
17671776.
54. Mjos OD. Effect of free fatty acids on myocardial function and oxygen
consumption in intact dogs. J Clin Invest 1971;50:13861389.
55. Liedtke AJ, Nellis SH, Mjos OD. Effects of reducing fatty acid metabolism on mechanical function in regionally ischemic hearts. Am J
Physiol 1984;247:387394.
56. Simonsen S, Kjekshus JK. The effect of free fatty acids on myocardial
oxygen consumption during atrial pacing and catecholamine infusion
in man. Circulation 1978;58:484491.
57. Mjos OD, Kjekshus J. Increased local metabolic rate by free fatty acids
in the intact dog heart. Scand J Clin Lab Invest 1971;28:389393.
58. Korvald C, Elvenes OP, Myrmel T. Myocardial substrate metabolism
inuences left ventricular energetics in vivo. Am J Physiol Heart Circ
Physiol 2000;278:13451351.
59. McGavock JM, Lingvay I, Zib I, Tillery T, Salas N, Unger R et al. Cardiac
steatosis in diabetes mellitus: a 1H-magnetic resonance spectroscopy
study. Circulation 2007;116:11701175.
60. Sharma S, Adrogue JV, Golfman L, Uray I, Lemm J, Youker K et al. Intramyocardial lipid accumulation in the failing human heart resembles the
lipotoxic rat heart. FASEB J 2004;18:16921700.
61. Alpert MA, Singh A, Terry BE, Kelly DL, el Deane MS, Mukerji V et al.
Effect of exercise and cavity size on right ventricular function in
morbid obesity. Am J Cardiol 1989;64:13611365.
62. Alpert MA, Lambert CR, Panayiotou H, Terry BE, Cohen MV, Massey CV
et al. Relation of duration of morbid obesity to left ventricular mass,
systolic function, and diastolic lling, and effect of weight loss. Am J
Cardiol 1995;76:11941197.
63. Alpert MA, Lambert CR, Terry BE, Cohen MV, Mukerji V, Massey CV et al.
Interrelationship of left ventricular mass, systolic function and diastolic
lling in normotensive morbidly obese patients. Int J Obes Relat Metab
Disord 1995;19:550557.
64. Alpert MA, Hashimi MW. Obesity and the heart. Am J Med Sci 1993;306:
117123.
65. Szczepaniak LS, Nurenberg P, Leonard D, Browning JD, Reingold JS,
Grundy S et al. Magnetic resonance spectroscopy to measure hepatic

Downloaded from http://cardiovascres.oxfordjournals.org/ by guest on April 8, 2012

14. Chiu HC, Kovacs A, Blanton RM, Han X, Courtois M, Weinheimer CJ et al.
Transgenic expression of fatty acid transport protein 1 in the heart
causes lipotoxic cardiomyopathy. Circ Res 2005;96:225233.
15. Yagyu H, Chen G, Yokoyama M, Hirata K, Augustus A, Kako Y et al. Lipoprotein lipase (LpL) on the surface of cardiomyocytes increases lipid
uptake and produces a cardiomyopathy. J Clin Invest 2003;111:
419426.
16. Fulop N, Marchase RB, Chatham JC. Role of protein O-linked
N-acetyl-glucosamine in mediating cell function and survival in the
cardiovascular system. Cardiovasc Res 2007;73:288297.
17. Herrmann G, Decherd GM. The chemical nature of heart failure. Ann
Intern Med 1939;12:12331244.
18. Wollenberger A. On the energy-rich phosphate supply of the failing
heart. Am J Physiol 1947;150:733736.
19. Olson RE, Schwartz WB. Myocardial metabolism in congestive heart
failure. Medicine (Baltimore) 1951;30:2141.
20. Olson RE. Myocardial metabolism in congestive heart failure. J Chronic
Dis 1959;9:442464.
21. van Bilsen M, Smeets PJ, Gilde AJ, van der Vusse GJ. Metabolic remodelling of the failing heart: the cardiac burn-out syndrome? Cardiovasc Res
2004;61:218226.
22. Neubauer S. The failing heartan engine out of fuel. N Engl J Med 2007;
356:11401151.
23. Sparagna GC, Chicco AJ, Murphy RC, Bristow MR, Johnson CA, Rees ML
et al. Loss of cardiac tetralinoleoyl cardiolipin in human and experimental heart failure. J Lipid Res 2007;48:15591570.
24. Chicco AJ, Sparagna GC. Role of cardiolipin alterations in mitochondrial
dysfunction and disease. Am J Physiol Cell Physiol 2007;292:3344.
25. Lei B, Lionetti V, Young ME, Chandler MP, DAgostino C, Kang E et al.
Paradoxical downregulation of the glucose oxidation pathway despite
enhanced ux in severe heart failure. J Mol Cell Cardiol 2004;36:
567576.
26. Hu FB, Willett WC. Optimal diets for prevention of coronary heart
disease. JAMA 2002;288:25692578.
27. Saltiel AR. New perspectives into the molecular pathogenesis and
treatment of type 2 diabetes. Cell 2001;104:517529.
28. King H, Aubert RE, Herman WH. Global burden of diabetes, 19952025:
prevalence, numerical estimates, and projections. Diabetes Care 1998;
21:14141431.
29. Liu S, Willett WC, Stampfer MJ, Hu FB, Franz M, Sampson L et al. A prospective study of dietary glycemic load, carbohydrate intake, and risk of
coronary heart disease in US women. Am J Clin Nutr 2000;71:
14551461.
30. Halton TL, Willett WC, Liu S, Manson JE, Albert CM, Rexrode K et al.
Low-carbohydrate-diet score and the risk of coronary heart disease in
women. N Engl J Med 2006;355:19912002.
31. Beulens JW, de Bruijne LM, Stolk RP, Peeters PH, Bots ML, Grobbee DE
et al. High dietary glycemic load and glycemic index increase risk of cardiovascular disease among middle-aged women: a population-based
follow-up study. J Am Coll Cardiol 2007;50:1421.
32. Liu S, Stampfer MJ, Hu FB, Giovannucci E, Rimm E, Manson JE et al.
Whole-grain consumption and risk of coronary heart disease: results
from the Nurses Health Study. Am J Clin Nutr 1999;70:412419.
33. Kris-Etherton PM, Harris WS, Appel LJ. Fish consumption, sh oil,
omega-3 fatty acids, and cardiovascular disease. Arterioscler Thromb
Vasc Biol 2003;23:2030.
34. Howard BV, Van Horn L, Hsia J, Manson JE, Stefanick ML,
Wassertheil-Smoller S et al. Low-fat dietary pattern and risk of cardiovascular disease: the Womens Health Initiative Randomized Controlled
Dietary Modication Trial. JAMA 2006;295:655666.
35. Arora SK, McFarlane SI. The case for low carbohydrate diets in diabetes
management. Nutr Metab (Lond) 2005;2:16.
36. Hu FB. Diet and cardiovascular disease prevention the need for a paradigm shift. J Am Coll Cardiol 2007;50:2224.
37. Oliver MF, Opie LH. Effects of glucose and fatty acids on myocardial
ischaemia and arrhythmias. Lancet 1994;343:155158.
38. Oliver MF, Kurien VA, Greenwood TW. Relation between
serum-free-fatty acids and arrhythmias and death after acute
myocardial infarction. Lancet 1968;1:710714.
39. Pilz S, Scharnagl H, Tiran B, Wellnitz B, Seelhorst U, Boehm BO et al.
Elevated plasma free fatty acids predict sudden cardiac death: a
6.85-year follow-up of 3315 patients after coronary angiography. Eur
Heart J 2007;28:27632769.
40. Jouven X, Charles MA, Desnos M, Ducimetiere P. Circulating nonesteried fatty acid level as a predictive risk factor for sudden death in the
population. Circulation 2001;104:756761.

D.J. Chess and W.C. Stanley

277

Diet and fuel overabundance in heart failure

66.

67.

68.
69.

70.

71.

72.

74.

75.
76.

77.

78.

79.

80.

81.

82.

83.

84.

85.

86.

87.

88.

89.

90.

91.
92.

93.

94.

95.
96.

97.

98.

99.

100.

101.

102.

103.

104.

105.

106.

107.

of the left ventricular dysfunction in porcine tachycardia-induced

cardiomyopathy. J Cardiovasc Pharmacol 2007;49:408415.
Paradise NF, Pilati CF, Payne WR, Finkelstein JA. Left ventricular function of the isolated, genetically obese rats heart. Am J Physiol 1985;
248:438444.
Young ME, Guthrie PH, Razeghi P, Leighton B, Abbasi S, Patil S et al.
Impaired long-chain fatty acid oxidation and contractile dysfunction in
the obese Zucker rat heart. Diabetes 2002;51:25872595.
Barouch LA, Gao D, Chen L, Miller KL, Xu W, Phan AC et al. Cardiac
myocyte apoptosis is associated with increased DNA damage and
decreased survival in murine models of obesity. Circ Res 2006;98:
119124.
Barouch LA, Berkowitz DE, Harrison RW, Odonnell CP, Hare JM. Disruption of leptin signaling contributes to cardiac hypertrophy independently of body weight in mice. Circulation 2003;108:754759.
McGavock JM, Victor RG, Unger RH, Szczepaniak LS. Adiposity of the
heart, revisited. Ann Intern Med 2006;144:517524.
Raabe M, Veniant MM, Sullivan MA, Zlot CH, Bjorkegren J, Nielsen LB
et al. Analysis of the role of microsomal triglyceride transfer protein
in the liver of tissue-specic knockout mice. J Clin Invest 1999;103:
12871298.
Young SG, Cham CM, Pitas RE, Burri BJ, Connolly A, Flynn L et al. A
genetic model for absent chylomicron formation: mice producing apolipoprotein B in the liver, but not in the intestine. J Clin Invest 1995;96:
29322946.
Nielsen LB, Veniant M, Boren J, Raabe M, Wong JS, Tam C et al. Genes
for apolipoprotein B and microsomal triglyceride transfer protein are
expressed in the heart: evidence that the heart has the capacity to
synthesize and secrete lipoproteins. Circulation 1998;98:1316.
Boren J, Veniant MM, Young SG. Apo B100-containing lipoproteins are
secreted by the heart. J Clin Invest 1998;101:11971202.
Bjorkegren J, Veniant M, Kim SK, Withycombe SK, Wood PA,
Hellerstein MK et al. Lipoprotein secretion and triglyceride stores in
the heart. J Biol Chem 2001;276:3851138517.
Nielsen LB, Bartels ED, Bollano E. Overexpression of apolipoprotein B in
the heart impedes cardiac triglyceride accumulation and development
of cardiac dysfunction in diabetic mice. J Biol Chem 2002;277:
2701427020.
Yokoyama M, Yagyu H, Hu Y, Seo T, Hirata K, Homma S et al. Apolipoprotein B production reduces lipotoxic cardiomyopathy: studies in heart
specic lipoprotein lipase transgenic mouse. J Biol Chem 2003;279:
42044211.
Lichtenstein AH, Appel LJ, Brands M, Carnethon M, Daniels S, Franch HA
et al. Diet and lifestyle recommendations revision 2006: a scientic
statement from the American Heart Association Nutrition Committee.
Circulation 2006;114:8296.
Griel AE, Ruder EH, Kris-Etherton PM. The changing roles of dietary
carbohydrates: from simple to complex. Arterioscler Thromb Vasc Biol
2006;26:19581965.
Mozaffarian D, Bryson CL, Lemaitre RN, Burke GL, Siscovick DS. Fish
intake and risk of incident heart failure. J Am Coll Cardiol 2005;45:
20152021.
Duda MK, OShea KM, Lei B, Barrows BR, Azimzadeh AM, McElfresh TE
et al. Dietary supplementation with omega-3 PUFA increases adiponectin and attenuates ventricular remodeling and dysfunction with pressure
overload. Cardiovasc Res 2007;76:303310.
Okere IC, Chandler MP, McElfresh TA, Rennison JH, Sharov V, Sabbah HN
et al. Differential effects of saturated and unsaturated fatty acid diets
on cardiomyocyte apoptosis, adipose distribution, and serum leptin. Am
J Physiol Heart Circ Physiol 2006;291:3844.
Okere IC, Chandler MP, McElfresh TA, Rennison JH, Kung TA, Hoit BD
et al. Carnitine palmitoyl transferase-I inhibition is not associated
with cardiac hypertrophy in rats fed a high-fat diet. Clin Exp Pharmacol
Physiol 2007;34:113119.
Sharma N, Okere IC, Duda MK, Johnson J, Yuan CL, Chandler MP et al.
High fructose diet increases mortality in hypertensive rats compared
to a complex carbohydrate or high fat diet. Am J Hypertens 2007;20:
403409.
Okere IC, Young ME, McElfresh TA, Chess DJ, Sharov VG, Sabbah HN et al.
Low carbohydrate/high-fat diet attenuates cardiac hypertrophy, remodeling, and altered gene expression in hypertension. Hypertension
2006;48:11161123.
Kang PM, Yue P, Liu Z, Tarnavski O, Bodyak N, Izumo S. Alterations in
apoptosis regulatory factors during hypertrophy and heart failure. Am
J Physiol Heart Circ Physiol 2004;287:7280.

Downloaded from http://cardiovascres.oxfordjournals.org/ by guest on April 8, 2012

73.

triglyceride content: prevalence of hepatic steatosis in the general

population. Am J Physiol Endocrinol Metab 2005;288:462468.
Szczepaniak LS, Dobbins RL, Metzger GJ, Sartoni-DAmbrosia G,
Arbique D, Vongpatanasin W et al. Myocardial triglycerides and systolic
function in humans: in vivo evaluation by localized proton spectroscopy
and cardiac imaging. Magn Reson Med 2003;49:417423.
Zhou YT, Grayburn P, Karim A, Shimabukuro M, Higa M, Baetens D et al.
Lipotoxic heart disease in obese rats: implications for human obesity.
Proc Natl Acad Sci USA 2000;97:17841789.
Unger RH. Lipotoxic diseases. Annu Rev Med 2002;53:319336.
Wakasaki H, Koya D, Schoen FJ, Jirousek MR, Ways DK, Hoit BD et al. Targeted overexpression of protein kinase C beta2 isoform in myocardium
causes cardiomyopathy. Proc Natl Acad Sci USA 1997;94:93209325.
Furuno T, Kanno T, Arita K, Asami M, Utsumi T, Doi Y et al. Roles of long
chain fatty acids and carnitine in mitochondrial membrane permeability
transition. Biochem Pharmacol 2001;62:10371046.
Scorrano L, Penzo D, Petronilli V, Pagano F, Bernardi P. Arachidonic acid
causes cell death through the mitochondrial permeability transition.
Implications for tumor necrosis factor-alpha aopototic signaling. J Biol
Chem 2001;276:1203512040.
Penzo D, Petronilli V, Angelin A, Cusan C, Colonna R, Scorrano L et al.
Arachidonic acid released by phospholipase A(2) activation triggers
Ca(2)-dependent apoptosis through the mitochondrial pathway.
J Biol Chem 2004;279:2521925225.
Wrede CE, Dickson LM, Lingohr MK, Briaud I, Rhodes CJ. Protein kinase
B/Akt prevents fatty acid-induced apoptosis in pancreatic beta-cells
(INS-1). J Biol Chem 2002;277:4967649684.
Kong JY, Rabkin SW. Palmitate-induced cardiac apoptosis is mediated
through CPT-1 but not inuenced by glucose and insulin. Am J Physiol
Heart Circ Physiol 2002;282:717725.
Huss JM, Kelly DP. Nuclear receptor signaling and cardiac energetics.
Circ Res 2004;95:568578.
Finck BN, Han X, Courtois M, Aimond F, Nerbonne JM, Kovacs A et al. A
critical role for PPARalpha-mediated lipotoxicity in the pathogenesis of
diabetic cardiomyopathy: modulation by dietary fat content. Proc Natl
Acad Sci USA 2003;100:12261231.
Gilde AJ, Van Der Lee KA, Willemsen PH, Chinetti G, Van Der Leij FR, van
der Vusse GJ et al. Peroxisome proliferator-activated receptor (PPAR)
{alpha} and PPAR{beta}/{delta}, but not PPAR{gamma}, modulate the
expression of genes involved in cardiac lipid metabolism. Circ Res
2003;92:518524.
Cheng L, Ding G, Qin Q, Xiao Y, Woods D, Chen YE et al. Peroxisome
proliferator-activated receptor delta activates fatty acid oxidation in
cultured neonatal and adult cardiomyocytes. Biochem Biophys Res
Commun 2004;313:277286.
DeLuca JG, Doebber TW, Kelly LJ, Kemp RK, Molon-Noblot S, Sahoo SP
et al. Evidence for peroxisome proliferator-activated receptor
(PPAR)alpha-independent peroxisome proliferation: effects of PPARgamma/delta-specic agonists in PPARalpha-null mice. Mol Pharmacol
2000;58:470476.
Barak Y, Nelson MC, Ong ES, Jones YZ, Ruiz-Lozano P, Chien KR et al.
PPAR gamma is required for placental, cardiac, and adipose tissue
development. Mol Cell 1999;4:585595.
Miyazaki Y, Mahankali A, Matsuda M, Glass L, Mahankali S, Ferrannini E
et al. Improved glycemic control and enhanced insulin sensitivity in
type 2 diabetic subjects treated with pioglitazone. Diabetes Care
2001;24:710719.
Park SY, Cho YR, Finck BN, Kim HJ, Higashimori T, Hong EG et al.
Cardiac-specic overexpression of peroxisome proliferator-activated
receptor-alpha causes insulin resistance in heart and liver. Diabetes
2005;54:25142524.
Burkart EM, Sambandam N, Han X, Gross RW, Courtois M, Gierasch CM
et al. Nuclear receptors PPARbeta/delta and PPARalpha direct distinct
metabolic regulatory programs in the mouse heart. J Clin Invest 2007;
117:39303939.
Morgan EE, Rennison JH, Young ME, McElfresh TA, Kung TA, Tserng KY
et al. Effects of chronic activation of peroxisome proliferator-activated
receptor-alpha or high-fat feeding in a rat infarct model of heart
failure. Am J Physiol Heart Circ Physiol 2006;290:18991904.
Labinskyy V, Bellomo M, Chandler MP, Young ME, Lionetti V, Qanud K
et al. Chronic activation of PPAR{alpha} with fenobrate prevents
alterations in cardiac metabolic phenotype without changing the
onset of decompensation in pacing-induced heart failure. J Pharmacol
Exp Ther 2007;321:165171.
Brigadeau F, Gele P, Wibaux M, Marquie C, Martin-Nizard F, Torpier G
et al. The PPARalpha activator fenobrate slows down the progression

278

122. Augustus AS, Buchanan J, Park TS, Hirata K, Noh HL, Sun J et al. Loss of
lipoprotein lipase-derived fatty acids leads to increased cardiac glucose
metabolism and heart dysfunction. J Biol Chem 2006;281:87168723.
123. Son NH, Park TS, Yamashita H, Yokoyama M, Huggins LA, Okajima K et al.
Cardiomyocyte expression of PPARgamma leads to cardiac dysfunction
in mice. J Clin Invest 2007;117:27912801.
124. Han I, Kudlow JE. Reduced O glycosylation of Sp1 is associated with
increased proteasome susceptibility. Mol Cell Biol 1997;17:25502558.
125. Daniel S, Kim KH. Sp1 mediates glucose activation of the acetyl-CoA
carboxylase promoter. J Biol Chem 1996;271:13851392.
126. Karns LR, Kariya K, Simpson PC. M-CAT, CArG, and Sp1 elements are
required for alpha 1-adrenergic induction of the skeletal alpha-actin
promoter during cardiac myocyte hypertrophy. Transcriptional enhancer
factor-1 and protein kinase C as conserved transducers of the fetal
program in cardiac growth. J Biol Chem 1995;270:410417.
127. Izumo S, Nadal-Ginard B, Mahdavi V. Protooncogene induction and
reprogramming of cardiac gene expression produced by pressure
overload. Proc Natl Acad Sci USA 1988;85:339343.
128. Sack MN, Disch DL, Rockman HA, Kelly DP. A role for Sp and nuclear
receptor transcription factors in a cardiac hypertrophic growth
program. Proc Natl Acad Sci USA 1997;94:64386443.
129. Chess DJ, Lei B, Hoit BD, Azimzadeh AM, Stanley WC. Deleterious effects
of sugar and protective effects of starch on cardiac remodeling, contractile dysfunction, and mortality in response to pressure overload.
Am J Physiol Heart Circ Physiol 2007;293:18531860.
130. Prentki M, Joly E, El Assaad W, Roduit R. Malonyl-CoA signaling, lipid
partitioning, and glucolipotoxicity: role in beta-cell adaptation and
failure in the etiology of diabetes. Diabetes 2002;51:405413.
131. Poitout V, Robertson RP. Minireview: Secondary beta-cell failure in type
2 diabetesa convergence of glucotoxicity and lipotoxicity. Endocrinology 2002;143:339342.
132. Poitout V, Robertson RP. Glucolipotoxicity: fuel excess and {beta}-cell
dysfunction. Endocr Rev 2007
133. Dyntar D, Eppenberger-Eberhardt M, Maedler K, Pruschy M,
Eppenberger HM, Spinas GA et al. Glucose and palmitic acid induce
degeneration of myobrils and modulate apoptosis in rat adult cardiomyocytes. Diabetes 2001;50:21052113.
134. Jagasia D, Whiting JM, Concato J, Pfau S, McNulty PH. Effect of
non-insulin-dependent diabetes mellitus on myocardial insulin responsiveness in patients with ischemic heart disease. Circulation 2001;
103:17341739.
135. Leeds AR. Glycemic index and heart disease. Am J Clin Nutr 2002;76:
286289.

Downloaded from http://cardiovascres.oxfordjournals.org/ by guest on April 8, 2012

108. Duda MK, OShea KM, Lei B, Barrows BR, Azimzadeh AM, McElfresh TA
et al. Low carbohydrate/high fat diet attenuates pressure overload
induced ventricular remodeling and dysfunction. J Card Fail 2008
109. Sharma N, Okere IC, Duda MK, Chess DJ, OShea KM, Stanley WC. Potential impact of carbohydrate and fat intake on pathological left ventricular hypertrophy. Cardiovasc Res 2007;73:257268.
110. Chess DJ, Lei B, Hoit BD, Azimzadeh AM, Stanley WC. Effects of a high
saturated fat diet on cardiac hypertrophy and dysfunction in response
to pressure overload. J Card Fail 2008;14:8288.
111. Rennison JH, McElfresh TA, Okere IC, Vazquez EJ, Patel HV, Foster AB
et al. High-fat diet postinfarction enhances mitochondrial function
and does not exacerbate left ventricular dysfunction. Am J Physiol
Heart Circ Physiol 2007;292:14981506.
112. Held C, Gerstein HC, Yusuf S, Zhao F, Hilbrich L, Anderson C et al.
Glucose levels predict hospitalization for congestive heart failure in
patients at high cardiovascular risk. Circulation 2007;115:13711375.
113. Gerstein HC, Capes SE. Dysglycemia: a key cardiovascular risk factor.
Semin Vasc Med 2002;2:165174.
114. Deedwania P, Kosiborod M, Barrett E, Ceriello A, Isley W, Mazzone T
et al. Hyperglycemia and acute coronary syndrome. A scientic statement from the american heart association diabetes committee of the
council on nutrition, physical activity, and metabolism. Circulation 2008
115. Shiojima I, Yefremashvili M, Luo Z, Kureishi Y, Takahashi A, Tao J et al.
Akt signaling mediates postnatal heart growth in response to insulin and
nutritional status. J Biol Chem 2002;277:3767037677.
116. Zachara NE, Hart GW. O-GlcNAc a sensor of cellular state: the role of
nucleocytoplasmic glycosylation in modulating cellular function in
response to nutrition and stress. Biochim Biophys Acta 2004;1673:
1328.
117. Wells L, Vosseller K, Hart GW. Glycosylation of nucleocytoplasmic proteins: signal transduction and O-GlcNAc. Science 2001;291:23762378.
118. Wells L, Hart GW. O-GlcNAc turns twenty: functional implications for
post-translational modication of nuclear and cytosolic proteins with
a sugar. FEBS Lett 2003;546:154158.
119. Matsui R, Xu S, Maitland KA, Mastroianni R, Leopold JA, Handy DE et al.
Glucose-6-phosphate dehydrogenase deciency decreases vascular
superoxide and atherosclerotic lesions in apolipoprotein E(2/2)
mice. Arterioscler Thromb Vasc Biol 2006;26:910916.
120. Matsui R, Xu S, Maitland KA, Hayes A, Leopold JA, Handy DE et al.
Glucose-6 phosphate dehydrogenase deciency decreases the vascular
response to angiotensin II. Circulation 2005;112:257263.
121. Cocco P, Todde P, Fornera S, Manca MB, Manca P, Sias AR. Mortality in a
cohort of men expressing the glucose-6-phosphate dehydrogenase
deciency. Blood 1998;91:706709.

D.J. Chess and W.C. Stanley