Download the role of fatty acid oxidation in cardiac ischemia and reperfusion

REVIEW
THE ROLE OF FATTY ACID OXIDATION IN CARDIAC ISCHEMIA
AND REPERFUSION
—
T
Gary Lopaschuk, PhD*
ABSTRACT
The heart has high energy demands and utilizes free fatty acids and glucose as the primary
substrates for the production of adenosine triphosphate (ATP). Most of the ATP required by the heart
is generated via oxidation of fatty acids during
aerobic or mild ischemic conditions. Fatty acid oxidation requires more oxygen than does glucose
oxidation to produce the same amount of ATP.
Over a wide range of workloads, the heart maintains a “metabolic homeostasis” of metabolites
and energy flux that is controlled by a complex
cytosolic and mitochondrial network. Fatty acids
are transported across the mitochondrial membrane via a complex process involving carnitine
and malonyl coenzyme A as 2 of the critical components. Alterations in metabolism result in
increased levels of fatty acid oxidation after an
ischemic event and during reperfusion. The heightened consumption of fatty acids in an oxygen-poor
environment results in greater oxygen consumption, reduced ATP production, and alteration in
ionic homeostasis. The result is mitochondrial damage and a loss of cardiac efficiency. Ischemic heart
disease is a metabolic problem. Manipulation of
cardiac metabolism provides promise for the treatment of ischemic heart disease. An overview of
fatty acid oxidation’s role in cardiac ischemia and
reperfusion is reviewed.
(Adv Stud Med. 2004;4(10B):S803-S807)
*Professor, Departments of Pediatrics and Pharmacology,
Cardiovascular Research Group, University of Alberta,
Edmonton, Alberta, Canada.
Address correspondence to: Gary Lopaschuk, PhD,
Cardiovascular Research Group, 423 Heritage Medical
Research Centre, University of Alberta, Edmonton, Alberta,
Canada T6G 2S2. E-mail: [email protected].
Advanced Studies in Medicine
n
he heart has high energy demands to
maintain contractility, ion homeostasis,
and associated phenomena and is capable
of utilizing a variety of substrates to meet
these needs including free fatty acids, glucose, lactate, pyruvate, ketone bodies, and amino acids.1,2
Although free fatty acids and glucose are the major
sources of energy, in the form of adenosine triphosphate
(ATP), under normal conditions, the preferred substrate
is dependent upon arterial concentrations, hormonal
factors, and workload.3 More than 60 years ago, the
importance of fatty acids as a fuel for the heart was initially reported.4 Later research elucidated that the majority of oxygen consumption accounted for fatty acid
oxidation while only a minor part was used for carbohydrate oxidation.5 However, ATP production via fatty acid
oxidation is less efficient, in terms of oxygen consumption, than is glucose oxidation. While fatty acids are the
major source of acetyl-coenzyme A (acetyl-CoA) for the
Krebs cycle and of the oxidative production of ATP
under normal conditions, carbohydrate oxidation can
also be an important source of ATP production.
Carbohydrates are used for energy via glucose oxidation
and glycolysis, with the former being the main source of
ATP production from glucose. Glycolysis, accounting
for only about 5% of the heart’s energy needs, converts
glucose to pyruvate.
The energy demands of the heart are dependent
upon adequate oxygenation and oxidizable substrates
to generate enough ATP.6 ATP is in turn used to perform cardiac work, namely contraction and to a lesser
degree, ionic homeostasis.2 The production of ATP
meets the demands of the heart and more than the
total amount of ATP in the myocyte is consumed in
under 10 seconds. Due to this rapid consumption of
energy, the pathways involved in the synthesis of ATP
are well controlled and are normally able to quickly
respond to changes in energy demand. Although the
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REVIEW
exact mechanisms involved in the control of cellular
respiration have been debated, the direct relationship
between oxygen consumption and cardiac work has
been well documented.
Cardiac metabolism is primarily aerobic and most of
the energy (ATP) is supplied via oxidative phosphorylation.6 During a mild ischemic episode (such as during an
anginal attack), oxidative metabolism decreases in proportion to the decrease in oxygen supply, although fatty
acid oxidation remains the primary source of residual
metabolism. Nonetheless, the production of ATP via
glycolysis increases during ischemia. Anaerobic glycolysis
may be able to maintain contractility but cellular integrity is sacrificed due to increased tissue concentrations of
lactate and hydrogen ions. The following review provides
an overview of the role of fatty acid oxidation in cardiac
ischemia and reperfusion.
METABOLIC HOMEOSTASIS
Cells in the heart are able to rapidly alter overall
energy input and output in relationship to energy
demands.7 Dramatic changes in energy demands are
met while maintaining a near constant level of
metabolites in the cytoplasm and mitochondria. The
mechanics responsible for this equilibrium have been
studied for decades and it is still a somewhat controversial issue. Once thought to be due to a simple feedback loop, it is now accepted that the orchestration of
this remarkably rapid flux of metabolites and energy is
controlled by a much more complex systems and
involves a “metabolic homeostasis” of metabolites used
for energy consumption in the cytoplasm. Such equilibrium exists over a range of workloads and is thought
to be controlled by a complex cytoplasmic and mitochondrial network that regulates the rate of ATP production. The heart’s ability to maintain this balance of
energy metabolism and output is compromised when
a condition that impairs cardiac energy metabolism
exists, such as in the case of ischemia.
state (during angina, after acute myocardial infarction, or
during cardiac surgery), the circulating levels of fatty
acids increase.8,10-13 Fatty acids are hydrophobic and
depend upon a complex process for transport across the
mitochondrial membrane (Figure 1).8,14 The first compound required for this process is carnitine. Carnitine
makes the transport of long-chain fatty acids through the
inner mitochondrial membrane possible. Carnitine
palmitoyltransferase is an enzyme that, in the presence of
carnitine, transfers fatty acyl groups from acyl CoA to
carnitine thereby forming acyl carnitine. The acyl carnitine is then able to enter the mitochondrial matrix,
where it is converted back to acyl CoA and enters the
fatty acid beta oxidative pathway to produce acetyl-CoA.
Another compound critical in the regulation of
fatty acid transport is malonyl CoA.8,14 Malonyl CoA is
an important endogenous inhibitor of fatty acid oxidation and acts in opposition to carnitine.
Simplistically speaking, carnitine acts to increase fatty
acids available for beta oxidation while malonyl CoA
acts to decrease it. The enzyme involved in the synthesis of malonyl CoA is acetyl-CoA carboxylase (ACC),
which is in turn regulated by adenosine monophosphate (AMP)-activated protein kinase (AMPK). A
third enzyme, malonyl CoA decarboxylase, acts to
convert malonyl CoA back to acetyl-CoA.
Figure 1. Uptake of Fatty Acids into the
Mitochondria Through the Carnitine Shuttle
CYTOSOL
MALONYL CoA
Fatty acyl CoA
—
Fatty acyl carnitine
CPT-1
CPT-2
Translocase
INCREASE IN FATTY ACID LEVELS FOLLOWING
ACUTE EVENT
Fatty acyl
carnitine
AN
In order to meet energy requirements, the heart regulates the production of acetyl-CoA. Acetyl-CoA is a
substrate used in the tricarboxylic acid cycle (Krebs cycle)
in the generation of ATP.8,9 The beta oxidation of fatty
acids is a major source of acetyl-CoA. In the ischemic
S804
Fatty acyl CoA
MITOCHONDRIA
CPT = carnitine palmitoyl transferase.
Reprinted with permission from Hopkins et al. AMP-activated protein
kinase regulation of fatty acid oxidation in the ischaemic heart. Biochem
Soc Trans. 2003;31(pt 1):207-212.14
Vol. 4 (10B)
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November 2004
REVIEW
Figure 2. Effect of Ischemia on Fatty Acid Metabolism
COMPARISON OF FATTY ACID
GLUCOSE METABOLISM
AND
ATP
EFFECTS ON ATP PRODUCTION AND
IONIC HOMEOSTASIS
Enhanced
Activated
malonyl-CoA
ischemic
The metabolic pathway for fatty acids and
AMP
AMPK
levels
injury
glucose
in the heart under aerobic conditions
ACC-P
(less activated)
is shown in Figure 3.9 As previously mentioned, the heart derives most of its energy
ATP = adenosine triphosphate; AMP = adenosine monophosphate; ACC = acetyl-CoA carboxylase; ACC-P-acetyl-CoA carboxylase phosphorylation; AMPK = AMP-activated protein
from the oxidation of fatty acids over the use
kinase; CPT-1 = carnitine palmitoyl transferase-1.
of carbohydrates; however, fatty acid oxidation
Reprinted with permission from Lopaschuk. Regulation of carbohydrate metabolism in
ischemia and reperfusion. Am Heart J. 2000;139(2, pt 3):S115-S119.
consumes about 10% more oxygen than
required by glucose metabolism to produce the
same amount of ATP. ATP produced by fatty
acid metabolism or glucose oxidation is depenMETABOLIC CHANGES IN ISCHEMIA AND REPERFUSION
dent on the presence of oxygen. On the other hand,
Although we know that the metabolic pathways durATP produced via glycolysis is not oxygen dependent.
ing ischemia and reperfusion of the heart are drastically
These factors contribute to making fatty acids less effialtered, the exact molecular mechanisms essential to
cient than glucose as a source of energy regarding conthese changes have not been fully delineated.15 It has
sumption of oxygen.
been suggested that AMPK has a pivotal role in the
Ischemia of the myocardium results in dramatic
mediation of fatty acid and glucose metabolism and has
alteration of fuel metabolism and the effects of ischemia
even been called “a metabolic master switch.”
on fatty acid metabolism are shown in Figure 2.8 Low
Restrictions in oxygen supply to the cardiac tissue result
levels of oxygen during ischemia alter the normal oxidain a decrease in both fatty acid and glucose oxidation.
tive processes for production of ATP shifting more
During ischemia, AMP accumulates and in turn stimuimportance to glycolysis as a source of ATP. However,
lates AMPK (Figure 2).8 ACC is phosphorylated by
pyruvate generated from glycolysis is converted to lactate
AMPK resulting in a decrease in ACC activity and
decreased synthesis of malonyl CoA. This decrease in the
synthesis of malonyl CoA is coupled with the mainteFigure 3. Metabolic Pathway for Fatty Acids and
nance of malonyl CoA degradation by malonyl CoA
Glucose in the Well-Oxygenated Heart
decarboxylase, the consequence of which is a dramatic
decrease in malonyl CoA levels during reperfusion of
ischemic hearts. The end result is a loss in the control of
Glucose
mitochondrial fatty acid uptake and increased levels of
Fatty acids
Glycolysis
fatty acids available for oxidation.
ADP
Glycolysis
ATP
Human and animal models of cardiac ischemia
β-oxidation
Pyruvate
spiral
have demonstrated that after myocardial ischemia and
Fatty
acid
Lactate
Pyruvate
Glucose
reperfusion, the rate of fatty acid oxidation in the heart
oxidation
dehydrogenase
oxidation
increases rapidly and meets or exceeds preischemic
Acetyl-CoA
Acetyl-CoA
rates.8,16-18 These high rates of fatty acid consumption
Krebs
cycle
after ischemia and reperfusion are associated with an
O
HO
increase in oxygen consumption and a net loss of carElectron
Contractile function
diac efficiency. Thus, high plasma fatty acid concentransport
basal metabolism
chain
tration and alterations in the control mitochondrial
ADP
ATP
fatty acid uptake result in an increased severity of
ADP = adenosine diphosphate; ATP = adenosine triphosphate.
ischemic damage. As a result, the reduction, not
Reprinted with permission from Lopaschuk. Optimizing cardiac energy metaboincrease, of fatty acids available after reperfusion is
lism: how can fatty acid and carbohydrate metabolism be manipulated? Coron
associated with an improvement in recovery.
Artery Dis. 2001;12(suppl 1):S8-S11.
Ischemia
CPT-I
(more active) fatty acid
oxidation
(during
reperfusion)
CPT-I
(less active)
ACC
8
2
2
9
Advanced Studies in Medicine
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REVIEW
rather than being completely metabolized to CO2 and
H2O in the mitochondria.15,19-21 The resultant increased
production of lactate and protons in the setting of
ischemia results in a decrease in contractile work and a
dramatic disruption in cellular homeostasis.19,20
Changes in ionic homeostasis in the cell, such as
high levels of cytosolic calcium, result from the
impaired generation of ATP during ischemia.22 The
sarcoplasmic reticulum is unable to take up calcium at
normal rates in the setting of decreased ATP. The
resultant increase in cytoplasmic calcium has 4 primary metabolic consequences for the heart: (1) ischemic
contracture is promoted resulting in a further fall in
the already low ischemic blood flow, (2) calcium overload of the mitochondria promotes the depletion of
ATP, (3) some phospholipases are activated and thereby assist in the destruction of cell membranes and
accumulation of harmful detergent lysolecithins, and
(4) the stage is set for a predisposition to calciummediated arrhythmias.
EXACERBATION OF MYOCYTE NECROSIS
During aerobic conditions, the mitochondria produce large amounts of ATP.23 During anaerobic conditions, the integrity of the mitochondrial membrane
begins to break down as production of ATP is reduced.
A simplistic view of cell death in ischemia involves the
concept of a critical level of ATP required for life and
suggests that once levels of ATP drop below this level,
vital functions cease, and all is lost.1 Although a reduction in ATP is a sign of metabolic deterioration and
poor prognosis, myocyte death in ischemia is not this
simple. Rather, cardiac cell death involves not only
necrosis but also apoptosis, which is not dependent on
ATP depletion. A key component of this process is the
release of cytochrome C from mitochondria damaged
due to a variety of stimuli, one of which is ischemia.
Mitochondria are vital mediators of myocyte damage during ischemia and reperfusion.24 Functional and
ultrastructural mitochondrial injury occurs early in the
course of ischemia and damage progresses as the duration of ischemia increases. After 10 to 20 minutes of
severe ischemia, the mitochondrial oxidative function
and cardiac contractile function are able to recover. If
ischemia is sustained for longer periods, such as for 30
to 45 minutes, irreversible myocyte damage begins due
to irreversible defects to the distal electron transport
chain. The result is myocyte death.
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MECHANISMS OF DIMINISHED CARDIAC EFFICIENCY
Profound metabolic sequelae result from ischemia
making the unbalanced utilization of fatty acids and carbohydrates even more important in the poorly oxygenated heart. High levels of fatty acids following an
ischemic event have detrimental effects on the mechanical and electrophysiologic characteristics of the heart
after reperfusion. The excessive production of protons in
the heart due to glycolysis can result in accumulation of
sodium and calcium ions. This overload in calcium may
contribute to reperfusion injury by inducing excessive
myofilament activation at the time of re-oxygenation
and by causing an increase in mitochondrial calcium.25,26
When mitochondrial calcium levels increase, the
ability to generate ATP is subsequently decreased limiting the metabolic recovery of the myocyte. Lastly,
calcium-activated proteases can act to destroy critical
intracellular structures.25,27 During reperfusion, the
heart is a relatively inefficient pump as it is required to
spend much of the limited ATP on re-establishing a
normal intracellular pH and not on contractility.1
High fatty acid oxidation rates exacerbate this inefficiency, primarily by inhibiting glucose oxidation.8,18
CONCLUSIONS
The well-oxygenated heart consumes substrates to
produce power and heat. The metabolism of fatty
acids is important as a source of ATP and accounts for
50% to 70% of the total energy required for cardiac
function while much of the rest is generated from carbohydrates via glucose oxidation and glycolysis. Levels
of fatty acids increase dramatically during and following ischemia. This combined with alterations in intracellular control of fatty acid oxidation keep fatty acids
the predominant fuel during and following ischemia.
This high fatty acid oxidation inhibits glucose oxidation contributing to the excess production of lactate
and protons. Consequently, ionic homeostasis is eventually disrupted resulting in myocyte necrosis and
decreased cardiac efficiency.
Ischemic heart disease is a metabolic problem.
Manipulation of cardiac metabolism may hasten functional recovery from ischemic events. Therapies aimed
towards direct or indirect stimulation of myocardial
glucose metabolism, a more oxygen-efficient form of
ATP production than fatty acid oxidation, provide
promise for the treatment of ischemic heart disease.
Vol. 4 (10B)
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REFERENCES
1. Opie LH, Lopaschuk GD. Fuels: aerobic and anaerobic
metabolism. In: Opie LH, ed. Heart Physiology from Cell to
Circulation. 4th ed. Philadelphia, Pa: Lippincott Williams &
Wilkins; 2004:306-354.
2. Jafri MS, Dudycha SJ, O’Rourke B. Cardiac energy metabolism: models of cellular respiration. Annu Rev Biomed Eng.
2001;3:57-81.
3. Visser FC. Imaging of cardiac metabolism using radiolabelled glucose, fatty acids, and acetate. Coron Artery Dis.
2001;12(suppl 1):S12-S18.
4. Cruikshank EW, Kosterlitz HW. Utilization of fat by aglycaemic mammalian heart. J Physiol. 1941;99:208-223.
5. 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(4):504-515.
6. Carvajal K, Moreno-Sánchez R. Heart metabolic disturbances in cardiovascular diseases. Arch Med Res. 2003;
34(2):89-99.
7. Balaban RS. Cardiac energy metabolism homeostasis:
role of cytosolic calcium. J Mol Cell Cardiol. 2002;
34(10):1259-1271.
8. Lopaschuk G. Regulation of carbohydrate metabolism in
ischemia and reperfusion. Am Heart J. 2000;139(2, pt
3):S115-S119.
9. Lopaschuk GD. Optimizing cardiac energy metabolism:
how can fatty acid and carbohydrate metabolism be
manipulated? Coron Artery Dis. 2001;12(suppl 1):S8-S11.
10. Lopaschuk GD. Treating ischemic heart disease by pharmacologically improving cardiac energy metabolism. Am J
Cardiol. 1998;82(5A):14K-17K.
11. Lopaschuk GD, Collins-Nakai R, Olley PM, et al. Plasma
fatty acid levels in infants and adults after myocardial
ischemia. Am Heart J. 1994;128(1):61-67.
12. Mueller HS, Ayres SM. Metabolic response of the heart in
acute myocardial infarction in man. Am J Cardiol. 1978;
42(3):363-371.
13. Wolff AA, Rotmensch HH, Stanley WC, Ferrari R.
Metabolic approaches to the treatment of ischemic heart
disease: the clinicians’ perspective. Heart Fail Rev. 2002;
7(2):187-203.
14. Hopkins TA, Dyck JR, Lopaschuk GD. AMP-activated protein
kinase regulation of fatty acid oxidation in the ischaemic
heart. Biochem Soc Trans. 2003;31(pt 1):207-212.
Advanced Studies in Medicine
n
15. Sambandam N, Lopaschuk GD. AMP-activated protein
kinase (AMPK) control of fatty acid and glucose metabolism in
the ischemic heart. Prog Lipid Res. 2003;42(3):238-256.
16. Liedtke AJ, Renstrom B, Nellis SH, Hall JL, Stanley WC.
Mechanical and metabolic functions in pig hearts after 4
days of chronic coronary stenosis. J Am Coll Cardiol.
1995;26(3):815-825.
17. Liedtke AJ, Nellis SH, Mjos OD. Effects of reducing fatty
acid metabolism on mechanical function in regionally ischemic
hearts. Am J Physiol. 1984;247(3, pt 2):H387-H394.
18. Lopaschuk GD, Belke DD, Gamble J, Itoi T, Schönekess
BO. Regulation of fatty acid oxidation in the mammalian
heart in health and disease. Biochim Biophys Acta.
1994;1213(3):263-276.
19. Stanley WC. Cardiac energetics during ischaemia and
the rationale for metabolic interventions. Coron Artery Dis.
2001;12(suppl 1):S3-S7.
20. Das DK, Engelman RM, Rousou JA, Breyer RH. Aerobic vs
anaerobic metabolism during ischemia in heart muscle.
Ann Chir Gynaecol. 1987;76(1):68-76.
21. Renstrom B, Nellis SH, Liedtke AJ. Metabolic oxidation of
pyruvate and lactate during early myocardial reperfusion.
Circ Res. 1990;66(2):282-288.
22. Opie LH. The mechanism of myocyte death in ischemia.
Eur Heart J. 1993;14(suppl G):31-33.
23. Opie LH, Sack MN. Metabolic plasticity and the promotion
of cardiac protection in ischemia and ischemic preconditioning. J Mol Cell Cardiol. 2002;34(9):1077-1089.
24. Lesnefsky EJ, Moghaddas S, Tandler B, Kerner J, Hoppel
CL. Mitochondrial dysfunction in cardiac disease: ischemia
- reperfusion, aging, and heart failure. J Mol Cell Cardiol.
2001;33(6):1065-1089.
25. Wang QD, Pernow J, Sjoquist PO, Ryden L. Pharmacological
possibilities for protection against myocardial reperfusion
injury. Cardiovasc Res. 2002;55(1):25-37.
26. Stanley WC, Lopaschuk GD, Hall JL, McCormack JG.
Regulation of myocardial carbohydrate metabolism under normal and ischaemic conditions. Potential for pharmacological
interventions. Cardiovasc Res. 1997;33(2):243-257.
27. Xie GH, Rah SY, Yi KS, et al. Increase of intracellular Ca
(2+) during ischemia/reperfusion injury of heart is mediated
by cyclic ADP-ribose. Biochem Biophys Res Commun.
2003;307(3):713-718.
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