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European Heart Journal Supplements (2001) 3 (Supplement O), O2–O7
Changes in cardiac metabolism: a critical step from
stable angina to ischaemic cardiomyopathy
W. C. Stanley
Department of Physiology and Biophysics, School of Medicine, Case Western Reserve University, Cleveland, Ohio, U.S.A.
Cardiac work requires a high rate of adenosine triphosphate
(ATP) breakdown. ATP is resynthesized in the mitochondria
with energy from the combustion of fatty acids, glucose and
lactate. Fatty acids are the main fuel for the heart, supplying
60–90% of the energy, with the balance (10–40%) from
pyruvate oxidation (formed from glycolysis and lactate). Fatty
acid oxidation inhibits pyruvate oxidation in the mitochondria.
During myocardial ischaemia, oxygen consumption and ATP
production is reduced, causing accelerated glycolysis and
lactate production; the pH falls and cell function is impaired.
Paradoxically, with a partial reduction in coronary flow, the
myocardium continues to derive most of its energy from the
oxidation of fatty acids despite a high rate of lactate
production; this fatty acid oxidation during ischaemia inhibits
pyruvate oxidation, and drives pyruvate conversion to lactate.
Partial inhibition of fatty acid oxidation in ischaemic
myocardium, such as with the long-chain 3-ketoacyl thiolase
inhibitor trimetazidine, reduces lactate production and H+
accumulation during ischaemia, and results in clinical benefit
in patients with angina pectoris.
(Eur Heart J Supplements 2001; 3 (Suppl O): O2–O7)
© 2001 The European Society of Cardiology
Introduction
theless, many patients with coronary artery disease continue
to have severe angina despite maximally tolerated traditional
therapy or following revascularization procedures. Such
patients would benefit from additional pharmacotherapy
that would reduce the symptoms of ischaemia without
further suppressing cardiac contractility, heart rate, or
arterial blood pressure.
An alternative or adjunctive treatment for myocardial
ischaemia is to reduce the production and release of anginaproducing stimuli, and lessen the ischaemic burden of the
patient by optimizing energy metabolism in the ischaemic
myocardium[2]. This approach differs from traditional
therapies (e.g. beta-adrenergic receptor antagonists, calcium
channel blockers, or long-acting nitrates) in that there are no
direct effects on coronary blood flow, heart rate, or
afterload. Rather, these agents alter the metabolism of the
ischaemic tissue so that there is less accumulation of lactate,
and a lesser fall in intracellular pH and ATP. The present
brief review presents the biochemical and physiological
rationale for this pharmacological approach to treatment of
chronic stable angina.
The pump function of cardiac muscle is supported by high
rates of myocardial blood flow, oxygen consumption, and
combustion of fat and carbohydrates (glucose and lactate).
Myocardial ischaemia occurs when there is a deficit between
the normal rate of oxygen delivery to the myocardium
required for a given heart rate, afterload and inotropic state,
and the actual rate of oxygen delivery to the myocardium.
The primary effect of ischaemia is mitochondrial metabolic
dysfunction caused by reduced aerobic formation of
adenosine triphosphate (ATP); this triggers accelerated
anaerobic glycolysis and disruption of normal cardiac cell
function[1,2].
Traditional therapies for ischaemia are aimed at restoring
the balance between oxygen delivery and ATP formation,
and the myocardial demand for ATP. This is achieved either
by increasing blood flow to the myocardium via coronary
vasodilatation, or by reducing the oxygen requirement of
the ischaemic tissue through decreasing heart rate, arterial
blood pressure and cardiac contractility. These haemodynamic approaches to the treatment of ischaemic heart
disease have proven relatively effective at reducing the
symptoms of angina and improving exercise time. NeverCorrespondence: William C. Stanley, PhD, Department of
Physiology and Biophysics, School of Medicine, Case Western
Reserve University, 10900 Euclid Avenue, Cleveland, OH 441064970, U.S.A.
1520-765X/01/0O0002 + 06 $35.00/0
Key Words: Angina pectoris, cardiac, coronary artery disease,
fatty acids, glucose, heart, lactate, metabolism, mitochondria.
Metabolism in healthy myocardium
Before considering myocardial metabolism during
ischaemia, it is important to have an understanding of
metabolism in the normal healthy heart.
© 2001 The European Society of Cardiology
Myocardial metabolism in chronic stable angina
O3
Cardiac function is maintained by the
synthesis and breakdown of adenosine
triphosphate
Under conditions of normal coronary blood flow, ATP is
broken down by myosin ATPase, releasing energy that fuels
tension development and systolic work (Fig. 1). ATP
breakdown is also employed by the sarcoplasmic reticulum
Ca2+-ATPase to remove Ca2+ from the cytosol at the end of
systole and allow for diastolic relaxation. Approximately
two-thirds of the ATP used by the heart goes to contractile
shortening, and the remaining one-third is used for the
sarcoplasmic reticulum Ca2+-ATPase and other ion
pumps[1,2]. ATP is constantly resynthesized from adenosine
diphosphate and inorganic phosphate in the mitochondria by
oxidative phosphorylation. In the healthy heart the processes
of ATP synthesis and breakdown are exquisitely matched
such that there is never a significant fall in ATP concentration,
even with large increases in cardiac power output[3].
Fatty acids are the predominant fuel
for the heart
Fatty acids supply approximately 60–90% of the energy
used to synthesize ATP in the healthy human heart
(Fig. 1)[1–7]. The rate of fatty acid uptake by the heart is
primarily determined by the concentration of fatty acids in
the plasma[6], which varies widely between 0·1 and
approximately 1·5 mmol . l – 1. Plasma fatty acids come
from the breakdown of triglyceride in fat cells, and the
broad range in plasma concentration is due to the hormonal
control of hormone-sensitive lipase by insulin and
noradrenaline (norepinephrine) in this tissue. Insulin
suppresses fatty acid levels, and thus fatty acid levels are
low when insulin levels are high after a meal. On the other
hand, noradrenaline increases fatty acid release from fat
cells so that fatty acid levels are elevated under times of
stress, such as physical exercise, fasting, or myocardial
ischaemia. Diabetic patients (both types 1 and 2) have high
fatty acid levels because of low insulin levels and/or
resistance to the normal insulin-induced suppression of fatty
acid release from fat cells. Thus, during times of stress,
when catecholamines are high and insulin is low, the heart
is faced with a high plasma free fatty acid concentration,
and fatty acid oxidation by the heart is high.
Fatty acids are oxidized in the mitochondria, where they
release energy in the form of reduced nicotinamide adenine
dinucleotide (NADH) and reduced flavin adenine
dinucleotide (FADH2) for the electron transport chain and
the subsequent formation of ATP by oxidative
phosphorylation (Fig. 2)[8]. On entering the cell, fatty acids
are esterified to fatty acyl-coenzyme A (CoA), which makes
the fatty acid more water-soluble. In order to cross the inner
mitochondrial membrane, the fatty acid must be converted
to fatty acylcarnitine by the enzyme carnitine palmitoyl
transferase[8]. Once in the mitochondrion the fatty acid
undergoes beta-oxidation, a process that repeatedly cleaves
off two carbon acetyl-CoA units, generating NADH and
Figure 1 Cardiac energy metabolism under normal
aerobic conditions. Fatty acids are the primary source of
energy for the heart, supplying 60–90% of the energy for
adenosine triphosphate (ATP) synthesis. The balance
(10–40%) comes from the oxidation of pyruvate formed
from glycolysis and lactate oxidation. Almost all of the
ATP formation comes from oxidative phosphorylation in
the mitochondria; only a trivial amount of ATP (<2% of
the total) is synthesized by glycolysis. ADP=adenosine
diphosphate; SR=sarcoplasmic reticulum.
FADH2 in the process. The acetyl-CoA is further oxidized
to CO2 in the citric acid cycle. The rate of fatty acid betaoxidation is primarily regulated by the concentration of free
fatty acids in the plasma, the activity of the carnitine
transferase/translocase system on the mitochondrial
membranes, and the activity of a series of enzymes that
catalyze the multiple steps of fatty acid beta-oxidation
(Fig. 2)[8].
Glucose and lactate metabolism
Glucose and lactate supply between approximately 10% and
40% of the energy requirement of the heart (Fig. 1)[1,2,4,5,7].
Glucose is taken up by the myocardium and is either stored
as glycogen, or broken down by glycolysis to pyruvate in
the cytosol of the cell (Fig. 2). Lactate is extracted from the
blood, converted to pyruvate in the cytosol, and further
oxidized to acetyl-CoA in the mitochondrial matrix. In the
normal healthy human heart, pyruvate is derived in
approximately equal proportions from glycolysis and
lactate uptake[4,5,7]. Pyruvate is oxidized to acetyl-CoA in
the mitochondria by the enzyme pyruvate dehydrogenase
(PDH; Fig. 3). The rate of flux of pyruvate to acetyl-CoA is
determined by the amount of active enzyme present in the
tissue and the concentration of the substrates (CoA,
nicotinamide adenine dinucleotide [NAD+] and pyruvate),
and the products (acetyl-CoA and NADH)[2,9].
Fatty acid oxidation inhibits glucose
and lactate oxidation
Oxidation of glucose and lactate is strongly inhibited by high
rates of fatty acid oxidation in the heart[1,2,5,7,10,11]. Lowering
plasma fatty acid concentration by pharmacological means
(e.g. with niacin[12,13]), or directly inhibiting fatty acid
Eur Heart J Supplements, Vol. 3 (Suppl O) November 2001
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W. C. Stanley
Figure 2 Mitochondrial energy metabolism. Reduced
nicotinamide adenine dinucleotide (NADH) and reduced
flavin adenine dinucleotide (not shown) transfer
electrons from fatty acids, glucose and lactate to the
electron transport chain. The process of oxidative
phosphorylation is driven by the electron transport
chain, which takes the energy from the oxidation of fatty
acids, glucose and lactate, primarily via NADH.
ADP=adenosine diphosphate; ATP=adenosine triphosphate; CoA=coenzyme A; NAD+= nicotinamide adenine
dinucleotide.
oxidation in the mitochondria (e.g. with a carnitine
palmitoyltransferase I inhibitor[14,15] or with the 3-ketoacyl
thiolase [3-KAT] inhibitor trimetazidine[16]) will result in an
increase in the rates of glucose and/or lactate uptake and
oxidation. The molecular site of fatty acid inhibition of
pyruvate oxidation (and thus glucose and lactate oxidation)
is at the level of PDH. PDH and beta-oxidation of fatty acids
yield the common products acetyl-CoA and NADH. Flux of
pyruvate to acetyl-CoA is inhibited by acetyl-CoA and
NADH, and thus high rates of fatty acid oxidation result in
elevated NADH : NAD+ and acetyl-CoA : free CoA ratios,
which strongly inhibit flux through PDH (Fig. 3)[2,9]. The
amount of active enzyme is also under acute allosteric
control by PDH kinase, which phosphorylates and inhibits
PDH[2,9–11]. The activity of PDH kinase is stimulated by
increases in the NADH : NAD+ and acetyl-CoA : free CoA
ratios, and thus high rates of fatty acid oxidation stimulate
PDH kinase and inhibit the rate of glucose and lactate
oxidation by the heart. Studies conducted in humans and
large animals have demonstrated that pharmacological
inhibition of the rate of fatty acid oxidation by the heart
accelerates the flux of pyruvate through PDH, and the uptake
and oxidation of glucose and lactate by the heart[2,12,13,15].
Energy metabolism during ischaemia
Accelerated glycolysis, lactate production
and a fall in pH
The primary result of ischaemia is mitochondrial metabolic
dysfunction caused by reduced oxygen delivery to the
Eur Heart J Supplements, Vol. 3 (Suppl O) November 2001
Figure 3
Regulation of pyruvate oxidation under
normal aerobic conditions. Pyruvate is formed in the
cytosol from glycolysis and lactate oxidation, and is
converted to acetyl-coenzyme A (CoA) in the mitochondria by pyruvate dehydrogenase (PDH). The
acetyl-CoA and reduced nicotinamide adenine dinucleotide (NADH) generated by fatty acid oxidation
inhibit flux through PDH. Pharmacological inhibition
of the rate of fatty acid oxidation removes inhibition of
flux through PDH by NADH and acetyl-CoA, and
results in more pyruvate oxidation and thus more
glucose and lactate uptake.
tissue, resulting in a decrease in ATP formation by oxidative
phosphorylation (Fig. 4)[1,2,17]. The reduction in aerobic
ATP formation stimulates glycolysis, and an increase in
myocardial glucose uptake and glycogen breakdown
occurs[1,2]. Unlike under conditions of normal blood flow,
however, during ischaemia pyruvate produced by glycolysis
is not so readily oxidized in the mitochondria, and there is a
high rate of conversion of pyruvate to lactate in the cytosol,
and a rise in tissue lactate content. Instead of the normal
uptake of lactate from the blood, the ischaemic myocardium
switches to production of lactate. Cell homeostatis is
dramatically disrupted; there is accumulation of lactate and
H+, a fall in intracellular pH, and a reduction in contractile
work (Fig. 4). Thus, during ischaemia there is accelerated
glycolysis and pyruvate formation concurrent with impaired
pyruvate oxidation in the mitochondria, which results in
lactate accumulation in the tissue.
The ischaemia-induced fall in intracellular pH has several
negative effects on the ability of cardiac muscle to maintain
Ca2+ homeostatis and use the energy released from the
breakdown of ATP to perform contractile work. First, the
amount of ATP required by the sarcoplasmic Ca2+ pump is
greater when pH is decreased[18]. Second, the Ca2+
concentration for a given amount of force generation is
greater at a lower pH, and thus a higher cytosolic Ca2+
concentration is required during systole to produce a given
amount of mechanical power[18]. Thus, at low pH, for a
given rate of ATP synthesis, more of the energy released
from ATP breakdown contributes to the ‘chemical work’ of
regulating Ca2+ content in the cytosol, and less to contractile
work. In addition, the efflux of H+ from the cardiomyocyte
Myocardial metabolism in chronic stable angina
O5
High rates of fatty acid oxidation inhibit
pyruvate oxidation during ischaemia
Figure 4 Cardiac energy metabolism during ischaemia
of moderate severity (approximately 40% of normal
blood flow). The up and down arrows indicate the
changes compared with normal aerobic conditions.
Relative to aerobic conditions, ischaemia results in an
increase in glycolysis without an increase in the rate of
pyruvate oxidation, thus causing lactate to accumulate
in the cell. Despite accelerated glycolysis and lactate
production, the relatively high rate of residual oxygen
consumption is fuelled primarily by the oxidation of
fatty acids. ADP=adenosine diphosphate; ATP=
adenosine triphosphate; Pi=inorganic phosphate.
that occurs in exchange for Na+ leads to a greater Na+–Ca2+
exchange across the cell membrane, and further wasting of
ATP in order to maintain Ca2+ homeostasis[19].
Fatty acids are the main fuel for the
mitochondria during partial ischaemia
During moderate myocardial ischaemia, the residual
oxygen consumption is largely supported by the oxidation
of fatty acids (Fig. 4)[2,8,17,20]. In fact, the relative contribution of fatty acids to the energy requirement of the myocardium is not significantly affected by ischaemia of
moderate severity[2,17,20]. Studies conducted in large animal
models show that reductions in coronary blood flow of
30–60% do not affect the relative contribution of fatty acids
to mitochondrial oxygen consumption, despite a dramatic
switch to lactate production. In studies conducted in swine
and dogs using isotopically labelled glucose and fatty acid
tracers, there was a continued high rate of fatty acid
oxidation with an increase in the relative contribution of
glucose to mitochondrial oxidative metabolism when
coronary blood flow was reduced by 30–60%[2,17,20]. Even
though there was a switch from lactate uptake to lactate
production and a decrease in myocardial ATP content
during ischaemia, fatty acid continued to be the predominant fuel for the heart. It is important to note that
patients undergoing myocardial ischaemia have very high
plasma free fatty acid concentrations (>1·0 mmol . l – 1)
because of activation of the peripheral sympathetic nervous
system[21], which would fuel a high relative contribution of
fatty acid to myocardial substrate oxidation.
The impaired pyruvate oxidation during ischaemia of
moderate severity is due to the rise in mitochondrial NADH
secondary to the fall in oxygen consumption and to the high
rates of fatty acid oxidation. During moderate ischaemia,
there is a build-up of NADH and a rise in the NADH : NAD+
ratio in the mitochondria, which feedback and inhibit flux
through PDH via product inhibition (Fig. 5). The build-up
of NADH during ischaemia is the result of the decrease in
oxygen consumption and electron transport chain flux,
resulting in a back-up of NADH oxidation and a fall in
NAD+ content. Studies conducted in pigs and dogs showed
that ischaemia does not decrease the degree of direct PDH
inhibition by phosphorylation[2,22,23], suggesting that the
impairment in the in vivo rate of pyruvate oxidation during
ischaemia is not due to deactivation of the enzyme, but
rather to product inhibition by an increase in the
NADH : NAD+ ratio.
Optimization of energy metabolism
during ischaemia
Myocardial ischaemia is treated with drugs that are aimed
at restoring normal metabolism by the following
mechanisms: delivering more oxygen to the tissue via
coronary vasodilatation; decreasing the demand for mitochondrial oxygen consumption by reducing arterial blood
pressure, contractility and heart rate; or optimizing myocardial metabolism by decreasing fatty acid oxidation and
stimulating pyruvate oxidation in the mitochondria (e.g. by
the use of glucose–insulin–potassium therapy for acute
myocardial infarction, or trimetazidine for stable
angina)[1,2].
Metabolic agents that suppress fatty acid oxidation and
increase the oxidation of pyruvate by PDH in the
mitochondria will reduce the ischaemia-induced disruption
in cardiac metabolism[2]. In other words, inhibiting cardiac
fatty acid oxidation and increasing the oxidation of pyruvate
results in less lactate production and less of a fall in cell pH,
with clinical benefit to the ischaemic patient[2,24–27]. This
direct metabolic approach is optimally suited to conditions
in which there is sufficient residual oxygen delivery to the
myocardium to support pyruvate oxidation in the
mitochondria. In other words, it is important that there be a
sufficient rate of acetyl-CoA oxidation and oxygen
consumption so that increasing the rate of pyruvate
oxidation has a meaningful effect on the rate of lactate
production. Metabolic interventions clearly work well with
demand-induced ischaemia (e.g. exercise-induced angina),
as has been observed in several positive trials with the 3KAT inhibitors trimetazidine and ranolazine, which partly
reduce fatty acid oxidation[25–27]. Those agents show clear
clinical benefit, as reflected in improved exercise duration,
without eliciting any direct effects on heart rate or blood
pressure.
Eur Heart J Supplements, Vol. 3 (Suppl O) November 2001
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W. C. Stanley
Figure 5 Pyruvate oxidation during ischaemia. There is
accelerated glycolysis and lactate production in the
cytosol. In the mitochondria there is a rise in the ratio of
reduced nicotinamide adenine dinucleotide (NADH) to
oxidized nicotinamide adenine dinucleotide (NAD+) due
to a decrease in oxygen consumption and continued fatty
acid oxidation. Pharmacologically inhibiting fatty acid
oxidation (e.g. with the 3-ketoacyl thiolase inhibitor
trimetazidine) during ischaemia removes inhibition of
pyruvate dehydrogenase (PDH) by NADH and acetylcoenzyme A (CoA), and results in more pyruvate
oxidation and reduced symptoms of angina.
Conclusion
Myocardial ischaemia of moderate severity dramatically
alters fuel metabolism, reducing the rate of oxygen
consumption and ATP production. This leads to a fall in
ATP content, high rates of glycolysis, pyruvate formation
and lactate accumulation, and a fall in intracellular pH. The
myocardium continues to derive most of its energy
(50–70%) from the oxidation of fatty acids. Despite the high
rate of lactate production during ischaemia, pyruvate
oxidation is inhibited by fatty acid oxidation, which
contributes to the accelerated lactate production, intracellular acidosis and general disruption to cell homeostatis.
Ischaemia-induced dysfunction can be minimized by
metabolic agents that partly inhibit fatty acid oxidation, and
increase the combustion of glucose and lactate.
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