Circulation Research. 2000;86:487-489
(Circulation Research. 2000;86:487.)
© 2000 American Heart Association, Inc.
Metabolic Mechanisms Associated With Antianginal Therapy
E. Douglas Lewandowski
From the Metabolic Research Laboratory, Department of Radiology,
Massachusetts General Hospital and Harvard Medical School, Boston, Mass.
Correspondence to E. Douglas Lewandowski, PhD, Department of Radiology, Room 2301, Massachusetts General Hospital, Bldg 149, 13th St, Charlestown, MA 02129. E-mail doug{at}nmr.mgh.harvard.edu
Key Words: myocardial ischemia fatty acids mitochondria glycolysis metabolism
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Introduction
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Laboratory investigations into preserving viability
of the ischemic
myocardium or to promote recovery
during reperfusion have often
focused on the intermediary pathways of
energy metabolism. However,
in the clinical treatment of
angina, the application of metabolic
therapies has
generally lagged behind or has been incidental
to other approaches,
such as a vasodilators, calcium antagonists,
and negative
inotropes. A study published in this issue of
Circulation
Research has demonstrated that the antianginal agent trimetazidine
(1-[2,3,4-trimethoxybenzyl]
piperazine dihydrochloride [TMZ])
inhibits the activity of one
of the enzymes of the ß-oxidation
pathway in cardiac mitochondria
with direct increases in glucose
oxidation.
1 These findings
confirm in an intact,
functioning heart model the well-documented,
anti-ischemic
properties of TMZ
2 3 4 and the inhibitory
effects
of TMZ on long-chain fatty acid oxidation
5 with
reciprocal
enhancement of glucose uptake.
6 The study
localizes the inhibition
of ß-oxidation to a specific enzyme, the
mitochondrial
long-chain 3-ketoacyl coenzyme A (CoA) thiolase. The
suggestion
by the authors is that the effectiveness of TMZ as an
antianginal
agent is directly linked to this inhibitory
effect on long-chain
fatty acid oxidation.
Although studies on the isolated heart preparation can neither
specifically nor conclusively identify an antianginal mechanism, the
findings of the University of Alberta group1 are
consistent with the known effectiveness of TMZ as an
antianginal agent7 8 9 that reduces long-chain fatty acid
oxidation, while lacking both vasodilator activity and negative
inotropic effects.9 The inhibitory effects of
TMZ on long-chain fatty acid transport into rat heart mitochondria, via
inhibition of carnitine palmitoyltransferase 1 (CPT 1) enzyme, have
already been demonstrated, but TMZ was also found to be much less
potent than two other proven antianginal drugs, perhexiline and
amiodarone.5 10 However, TMZ does not induce the
confounding vasoactive, inotropic and chronotropic responses of these
other agents. Thus, the data suggesting that TMZ inhibits the
long-chain 3-ketoactyl CoA thiolase, downstream from CPT 1, add to the
argument for a purely metabolic mechanism of antianginal
therapy. The implied effectiveness of pharmacological changes in the
oxidative pathways of mitochondria in treating stable angina warrants a
heightened awareness of metabolic enzyme activity and
mitochondrial function as targets for clinical therapeutics.
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Shifting the Balance of Fuels for Energy Production
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The ischemic and reperfused myocardium
benefits from a shift
away from fatty acid oxidation to that of
carbohydrates.
11 12 13 The ability of anaerobic
glycolysis to support the ischemic
myocardium is
well established,
14 but the benefits of glucose
oxidation
over that of fatty acid oxidation in the flow-limited
myocardium
are only now being realized.
1 A
shift toward glucose oxidation,
which is a more efficient mode of ATP
production per mole of
oxygen used, is likely to benefit
hypoperfused myocardium.
An agent that promotes carbohydrate oxidation via activation of
pyruvate dehydrogenase (PDH), dichloroacetate, has improved left
ventricular function in patients with coronary
artery disease.15 Other agents, such as oxfenecine,
etomoxir, and methylplamoxirate inhibit the oxidation of fatty acids.
Among the inhibitors of long-chain fatty acid oxidation,
TMZ and ranolazine, both have antianginal effects. Despite a growing
body of evidence that enhancing carbohydrate oxidation, but not
necessarily glycolysis, and reducing fatty acid oxidation are
beneficial to the ischemic and reperfused heart, clinical
studies of such metabolic protocols remain limited.
Noting the paucity of clinical data on metabolic support
strategies is not to imply that the notion has not been a longstanding
consideration. The use of glucose-insulin-potassium (GIK) solution as
an adjunctive therapy for acute myocardial infarction is one of the
first examples of an approach to intervene on cardiac substrate
utilization.16 The bottom line to this approach is to
maintain high-energy phosphate stores in ischemic
myocardium. However, even on
revascularization and the restoration of cellular
energy charge, the postischemic heart remains abnormal and
benefits from additional metabolic interventions that are
shown experimentally to counter myocardial stunning. Thus, the observed
changes in fatty acid and carbohydrate oxidation induced by TMZ, and
related antianginal compounds, aid recovery during myocardial
reperfusion.
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Mechanisms of Substrate Utilization
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The effectiveness of direct strategies to shift the balance
from
fatty acid oxidation toward glucose oxidation in the reperfused
myocardium
now appears to be linked to both the recovery of
intracellular
pH and the cytosolic redox state of the
myocytes.
11 17 These
two factors, pH and redox state, are
linked to proton production
due to the counterbalance between
coupling of glycolysis to
the oxidation rate of glycolytic end
products and the production
and oxidation of
lactate.
11 17 18 However, beneficial effects
of a more
carbohydrate-based, oxidative energy metabolism are
not
uniquely dependent on glycolytic flux. Indeed, improved
contractile
recovery during reperfusion is more associated with
the stimulation of
pyruvate oxidation, as opposed to the nonoxidative
metabolism
of glycolytic end products that forms
alanine and lactate in
the cytosol.
19 This balance between
oxidative and nonoxidative
pyruvate metabolism is central
to the recovery of pH and cytosolic
redox state that are both
associated with postischemic contractile
function.
Regulating the balance between the oxidation of fatty acids and
pyruvate is the enzyme complex PDH. During early reperfusion, PDH is
primarily in the inactive, phosphorylated
state.20 Activating PDH is effective in improving the
recovery of reperfused myocardium.11 17 19 21
However, such protocols on animal models have not proven effective
during conditions of low-flow ischemia,22 when PDH
remains in the active form.
The activity of PDH is also influenced by fatty acid oxidation rates.
Thus, reductions in fatty acid oxidation, such as those produced by
TMZ, increase the fraction of active PDH to produce an increase in
carbohydrate oxidation. On the reciprocal end, when PDH activity is
stimulated, as with inhibitors of PDH kinase, fatty acid
oxidation becomes reduced.
Other mechanisms for reducing fatty acid oxidation hold potential for
therapeutic use. A strong influence on the reduction in fatty acid
oxidation is the inhibitory effect of malonyl CoA on CPT
1.23 Malonyl CoA is produced in the cytosol from the
action of the enzyme acetyl CoA carboxylase on acetyl CoA. Thus,
increased production of acetyl CoA has the effect of reducing
long-chain fatty acid oxidation. Different isoform distributions of CPT
1 have the potential to mediate its responsiveness to malonyl CoA, in
particular during pathophysiological
changes.24 However, at different fatty acid oxidation
rates in the heart, changes in CPT 1 activity have not yet been noted
in the absence of a change in malonyl CoA level. This finding suggests
that the modulation of CPT 1 responsiveness to malonyl CoA is not a
strong regulatory factor in the normal myocyte.13 Thus,
beyond pharmacological strategies, it remains to be seen whether
differential expression of enzyme isoforms will prove effective in
inducing similar therapeutic changes in cardiac
metabolism.
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Ischemic Stress and Protein Activation
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Can the activity of one single enzyme, or the flux rate through
one
specific metabolic pathway be responsible for angina?
Such an
overly simplified scenario is unlikely the case, but the
necessity
of minimizing confounding variables in an experimental
protocol
may suggest such oversimplification. On the other hand, a less
direct,
but intriguing, notion is to target stress-activated
proteins.
The increased production and activation of enzymes
that respond
to pathophysiology can trigger a cascade of events,
including
metabolic changes that influence cell function
and viability
(Figure

).

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Figure 1. Schematic of regulatory pathways as metabolic
targets for drug action. Solid lines are metabolic
pathways. Dashed lines are regulatory effects, with - for
inhibition and + for stimulation. TMZ indicates trimetazidine
(1-[2,3,4-trimethoxybenzyl] piperazine dihydrochloride); DCA,
dichloroacetate; LCFA, long-chain fatty acid; ACC, acetyl CoA
carboxylase; AMPK, 5' AMP-activated protein kinase; PDH,
pyruvate dehydrogenase; PDHK, pyruvate dehydrogenase kinase; CPT 1,
carnitine palmitoyltransferase 1; and GLUT, glucose transporter.
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Such an example is the activation of stress proteins during
ischemia, which leads to changes in glucose uptake and fatty
acid oxidation. As a specific example, the glucose transporters GLUT-4
and GLUT-1 are translocated from the intracellular membranes to the
sarcolemma in response to the low-energy, state-linked activation of 5'
AMP-activated protein kinase (AMPK) in the ischemic
heart.25 26 Interestingly, the activity of AMPK also
inactivates acetyl CoA carboxylase, with the net result of
decreasing malonyl CoA levels.27 Thus, other regulating
factors upstream from the enzymes of the metabolic pathways
are potential targets for therapeutic approaches to improving the
energy balance of the ischemic myocardium.
The efficacy of antianginal drugs, such as TMZ, that invoke a direct
metabolic effect underscores the need for further
elucidation of metabolic regulatory mechanisms that
influence myocyte function and viability. Many of these mechanisms can
be induced by protein production responses to ischemic
stress, which is, in part, the product of impaired energy
metabolism. Thus, we come full circle in the intervention
of cardiac metabolism in ischemic and reperfused
myocardium. The challenge then is to detect these
metabolic changes in the functioning organ, where the
physiological consequences can be elucidated.
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Footnotes
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The opinions expressed in this editorial are not necessarily
those of the editors or of the American Heart Association.
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