Download Trimetazidine and left ventricular ischaemic dysfunction: an

European Heart Journal Supplements (2001) 3 (Supplement O), O16–O20
Trimetazidine and left ventricular ischaemic
dysfunction: an overview of clinical evidence
S. L. Chierchia
The Division of Cardiology, Ospedale S. Martino e Cliniche, Universitarie Convenzionate, Genoa, Italy
The myocardial effects of trimetazidine, the prototypal agent of
the new class of 3-ketoacyl coenzyme A thiolase inhibitors, has
been assessed in three randomized, double-blind, placebocontrolled studies in patients with ischaemic cardiomyopathy,
stable angina or hibernating myocardium treated for periods
ranging from 15 days to 6 months.
Twenty patients with severe ischaemic cardiomyopathy (class
III and IV of the New York Heart Association [NYHA]) treated
with classic combination therapy were randomized to either
placebo or trimetazidine 20 mg three times daily. Ejection
fraction at rest was assessed by radionucleide angiography and
clinical symptoms both at baseline and after 6 months of
treatment. All patients treated with trimetazidine improved
clinically in that they gained one stage of NYHA classification,
whereas only one patient had improvement in the placebo
group (P < 0·001). Ejection fraction increased from
28·7 ± 3·8% to 29·6 ± 3·2% in the trimetazidine group, whereas
it decreased from 22·3 ± 2·4% to 18·6 ± 2·0% in the placebo
group (P = 0·002).
Fifteen patients with coronary artery disease confirmed by
angiography and a positive response to dobutamine testing
were treated with placebo or trimetazidine 20 mg three times
daily following a double-blind, cross over design. Stress
echocardiography was performed during baseline and after
both 2-week treatment periods. Compared with placebo,
treatment with trimetazidine significantly reduced the wall
motion score index in patients with a positive test (1·63 ± 0·40
versus 1·73 ± 0·46; P = 0·03). Furthermore, treatment with
trimetazidine increased the dobutamine infusion time
Introduction
In the cardiac muscle, energy production from available
substrates is obtained by step-by-step, enzymatically
controlled substrate metabolism and mitochondrial
oxidative phosphorylation, in which the energy content of
Correspondence: S.L. Chierchia, Division of Cardiology,
Monoblocco 7° Piano, Ospedale S. Martino, Largo R. Benzi 10,
Genoa, Italy.
1520-765X/01/0O0016 + 05 $35.00/0
(17·5 ± 4·9 min versus 15·2 ± 4·1 min; P = 0·04) and the
maximum dose of dobutamine administered to reach the
ischaemic threshold (27·9 ± 8·0 µg . kg – 1 . min – 1 versus
22·1 ± 5·8 µg . kg – 1 . min – 1; P = 0·006).
Forty-four patients with post-necrotic left ventricular
dysfunction (ejection fraction = 33 ± 5%) and multivessel
coronary artery disease were randomized to either placebo or
trimetazidine 20 mg three times daily and were treated over
8 weeks in combination with conventional antianginal
medications. Patients were assessed using low-dose dobutamine
(5–20 mg . kg – 1 . min – 1) echocardiography and symptomlimited cardiopulmonary exercise test. After trimetazidine, the
systolic wall thickening score index (SWTI) improved by 20·8%
(P < 0·001 versus control); ejection fraction at peak dobutamine
also increased (+14%; P < 0·001). Out of 14 patients who
showed improved SWTI, 11 had a concomitant increase in peak
VO2, wheras none of the five patients who had no improvement
in contractility showed an increased peak VO2.
In conclusion, treatment with the metabolic agent trimetazidine
is able to improve myocardial function in several situations
where left ventricular function is impaired. Improvement in
cardiac function occurs without haemodynamic change due to
a metabolic intra-mitochondrial effect within the myocyte.
Trimetazidine was very well tolerated in all three clinical trials.
(Eur Heart J Supplements 2001; 3 (Suppl O): O16–O20)
© 2001 The European Society of Cardiology
Key Words: Cardioprotection, ischaemia, metabolism,
myocardial dysfunction.
fuels is transferred to the high-energy phosphate bonds of
adenosine triphosphate (ATP). In turn, the energy necessary
to produce contractile work from hydrolysis of ATP is
produced primarily from the metabolism of carbohydrates
and free fatty acids (FFAs)[1,2]. Glucose metabolism is an
important source of energy. It consists of two main components: glycolysis and glucose oxidation. The former has the
advantage of producing ATP without requiring oxygen, but
only contributes 5–10% of the overall ATP supply of the
normal aerobic heart; it appears to play a special role in
maintaining ion homeostasis within the cardiac cell. For
© 2001 The European Society of Cardiology
Trimetazidine and left ventricular ischaemic dysfunction
glucose oxidation to occur, pyruvate, which is derived from
glycolysis, has to enter the mitochondria and to undergo
decarboxylation by the pyruvate–dehydrogenate complex.
The product of this reaction is acetyl coenzyme A (CoA),
which enters the Krebs cycle where the carbon groups are
further metabolized to carbon dioxide.
Fatty acid oxidation is the other major source of mitochondrial acetyl CoA production. This results from betaoxidation, which also provides reduced nicotinamide
adenine dinucleotide and reduced flavin adenine dinucleotide for the electron transport chain. An important factor is
that acetyl CoA originating from beta-oxidation competes
with glucose oxidation as a source of acetyl CoA for the
Krebs cycle; therefore, an increase in reduced nicotinamide
adenine dinucleotide from beta-oxidation further contributes to the decrease in glucose oxidation. As a result, a
high fatty acid oxidation rate will result in a marked
decrease in the glucose oxidation rate; furthermore,
although to a lesser extent, a high degree of fatty acid
oxidation also inhibit glycolysis.
Once acetyl CoA is produced it enters the Krebs cycle,
where it is further oxidized and used to produce substrates
for the electron transport chain. In the presence of oxygen,
the electron transport chain will facilitate the phosphorylation of adenosine diphosphate to ATP, a process termed
oxidative phosphorylation. This ATP then provides the
chemical energy to produce mechanical work.
Although the metabolism of fatty acids is a major source
of ATP production in the heart, fatty acids require more
oxygen than glucose to produce an equivalent amount of
ATP. As a result, fatty acids are not as efficient as glucose as
a source of energy because they require more oxygen.
Furthermore, as the contribution of fatty acid oxidation as a
source of acetyl CoA increases, the role of glucose oxidation decreases proportionately. Therefore, glucose oxidation
rates become substantially lower than glycolytic rates[3,4].
This is a particularly undesirable condition, especially
during and following myocardial ischaemia, because the
products of glycolysis (i.e. lactate and protons) can
accumulate and promote an increase in intracellular sodium
and calcium, which in turn require more ATP to re-establish
ionic homeostasis.
Ischaemic myocardial metabolism
During ischaemia, the oxidation of both fatty acids and
carbohydrates is limited by the lack of adequate supply of
oxygen to the muscle. Therefore, the relative contribution of
anaerobic glycolysis to ATP production increases, and high
concentrations of fatty acid further inhibit glucose
oxidation. Because fatty acids are a less efficient fuel, more
oxygen is required to produce equivalent amounts of ATP;
moreover, glycolysis becomes further uncoupled from
glucose oxidation, which increases the production of both
lactate and protons. Therefore, if fatty acids dominate as the
primary source of residual oxidative metabolism in
ischaemic heart muscle, then cardiac efficiency decreases
further and less energy is produced[5].
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Table 1 Cardioprotective metabolic modulators
Trimetazidine
Ranolazine
Etomoxir
Dichloroacetate
L-Carnitine
Propionyl L-carnitine
During reperfusion, fatty acid oxidation quickly recovers
and becomes the dominant source of ATP production[6].
This again occurs at the expense of glucose oxidation, the
result being that glucose metabolism can produce less than
10% of the total energy requirement of the heart. Therefore,
as for the ischaemic heart, also during reperfusion, high
rates of fatty acid oxidation contribute to a marked decrease
in the efficiency of energy utilization for producing
contractile work. It is now clear, however, that if glucose
oxidation is stimulated during reperfusion then cardiac
efficiency improves; this is reflected by a parallel
improvement in contractile function.
A number of direct and indirect strategies can be used to
optimize energy metabolism in the ischaemic heart. These
include directly inhibiting fatty acid oxidation, which will
indirectly stimulate glucose utilization. Another approach is
to stimulate glucose oxidation directly, for example by
directly stimulating the activity of pyruvate dehydrogenase.
Although most of these interventions have thus far been
limited to the experimental laboratory, recent evidence
obtained in humans indicates that pharmacological manipulation of ischaemic cardiac metabolism can also produce
objective improvements in the clinical situation; these
improvements can be measured clinically by assessing their
impact on global and regional ventricular function.
Stimulating glucose oxidation in
the ischaemic heart
A number of experimental and clinical studies have
provided promising evidence that pharmacological agents
that directly modify the utilization of energy substrates in
the heart can be used to reduce ischaemic injury. The
available agents are listed in Table 1. Of those agents
trimetazidine, and the piperazine derivatives in general, are
particularly interesting because their effects occur in the
complete absence of measurable haemodynamic changes
that could affect myocardial energy requirements and/or
improve myocardial perfusion.
The metabolic effect of trimetazidine is mediated by
inhibition of mitochondrial long-chain 3-ketoacyl CoA
thiolase, a fundamental enzyme that operates in the FFA
beta-oxidative chain[7]. As a result, myocardial glucose
oxidation is increased and substrate utilization is shifted
from fatty acid to carbohydrate metabolism. The effect
appears particularly desirable in the setting of decreased
oxygen supply, when the efficiency of substrate oxidation
and energy production is impaired by decreased glucose
oxidation and intracellular accumulation of FFAs.
Eur Heart J Supplements, Vol. 3 (Suppl O) November 2001
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S. L. Chierchia
Figure 1 Dobutamine infusion times (left) and doses (right) required to
elicit wall motion abnormalities during stress echocardiography performed
in patients receiving placebo (white) or trimetazidine (grey). Data are
expressed as mean ± standard deviation. From Lu et al.[10].
The metabolic effects of trimetazidine are reflected by the
cardioprotective properties of this agent. By decreasing
intracellular concentrations of protons, trimetazidine
prevents calcium and sodium overload; by reducing cytosol
concentrations of FFAs and hydrogen ions, it protects the
cell membrane from irreversible damage[8]. Therefore, both
the effects on cardiac metabolism and those that protect
cellular integrity may translate into improved cardiac
efficiency and cell survival.
Apart from the acute ischaemia–reperfusion situation, in
which the effect of trimetazidine may prove particularly
useful, another possible field of application of this agent is
represented by chronic ischaemic contractile dysfunction,
especially in those patients for whom surgical percutaneous
revascularization is not feasible. In fact, when the oxygen
supply is chronically and irreversibly limited, optimizing
cardiac metabolism may prove the only viable therapeutic
option.
Effect of trimetazidine in patients with
chronic ischaemic dysfunction
The first study of the effects of trimetazidine on severe
ischaemic cardiomyopathy was reported over 10 years ago
by Brottier et al.[9]. In a group of patients with ischaemic
congestive cardiomyopathy and severely depressed ventricular ejection fraction, those investigators administered oral
trimetazidine at the usual therapeutic dosage (20 mg three
times daily). By the end of the 6-month treatment period,
radionuclide ejection fraction had increased by more than
9%, in relative terms, and functional capacity had improved.
As expected, the improvement occurred in the absence of
obvious haemodynamic changes, and Brottier et al.
concluded that the effect was most likely attributable to
improved myocardial ischaemic metabolism.
The demonstration that trimetazidine can indeed delay
the onset of ischaemic myocardial dysfunction and reduce
its severity, in the presence of increased myocardial
Eur Heart J Supplements, Vol. 3 (Suppl O) November 2001
demand, came from another study conducted by our
group[10]. In 15 patients with documented chronic coronary
artery disease, moderately reduced left ventricular function
and a positive response to dobutamine stress echocardiography, we administered oral trimetazidine at a dosage of
20 mg three times daily for 2 weeks. The study was
conducted according to a double-blind, placebo-controlled,
crossover design. End-points were improvement in the
ischaemic threshold as measured by dobutamine dose and
infusion time, and improvement in left ventricular function
as assessed by changes in wall motion score index at rest
and at peak dobutamine stress.
After an initial wash-out period, patients were randomly
assigned to receive either trimetazidine (20 mg three times
daily) or matching placebo. The duration of the trial was
30 days, and crossover took place after 15 days. During
the study period, patients continued their usual
concomitant antianginal medication. However, nitrates
and calcium channel blockers were withdrawn 48 h and
beta-blockers were stopped 72 h before dobutamine stress
testing. All patients underwent dobutamine echocardiography (5–40 µg . kg – 1 . min – 1) at the end of the wash-out
period, as well as at days 15 and 30 of the trial. At each visit,
the dobutamine infusion time and dose to the onset of new
or worsening of pre-existing regional wall motion
abnormalities were recorded, as was wall motion score
index. The latter was calculated as the mean value of the
total of all the scores recorded in each of the 16 left
ventricular segments considered for the analysis. A low
score indicates that the wall motion and systolic function
are satisfactory. At each visit, heart rate, systolic blood
pressure and rate × pressure product were measured at rest
and at peak dobutamine infusion.
The mean dobutamine infusion time required to elicit new
or worsening of pre-existing dysfunction was 15·2 ± 4·1 min
with placebo and 17·5 ± 4·9 min with trimetazidine (P = 0·04;
Fig. 1). The mean dobutamine dose required to induce wall
motion abnormalities was 22·1 ± 5·8 µg . kg – 1 . min – 1
with placebo and 27·9 ± 8·0 µg . kg – 1 . min – 1 with
trimetazidine (P = 0·018; Fig. 1). Both under resting
Trimetazidine and left ventricular ischaemic dysfunction
Figure 2 Wall motion score index (WMSI) recorded at
rest (left two columns) and at peak dobutamine
infusion (right two columns) during placebo (white) or
trimetazidine (grey) administration. Data are
expressed as mean ± standard deviation. From Lu et
al.[10].
conditions and at peak dobutamine infusion, the wall
motion score index was significantly lower during
trimetazidine administration. At rest, the index was
1·34 ± 0·37 versus 1·4 ± 0·4 (P = 0·013); at peak infusion it
was 1·61 ± 0·4 versus 1·71 ± 0·45 (P = 0·018; Fig. 2). As in
previous studies, the heart rate, systolic blood pressure and
rate × pressure product were not significantly different in
the two trial phases.
The results of our study indicate that trimetazidine not only
prevents or delays ischaemic myocardial dysfunction induced
by excessive cardiac work in the presence of limited coronary
flow reserve, but also improves resting left ventricular
function in patients with chronic coronary artery disease.
The specific question regarding whether the drug can
improve myocardial dysfunction in patients with coronary
artery disease and severely depressed left ventricular
ejection fraction was addressed in a recent study conducted
by Belardinelli and Purcaro[11]. Those investigators studied
38 patients with severe ischaemic cardiomyopathy, who
were randomly assigned to receive either trimetazidine
O19
(20 mg three times daily, n = 19) or placebo (n = 19) for
2 months. All patients had a history of chronic stable
coronary artery disease, documented anatomical obstruction
and severely depressed ejection fraction (mean 33%). In all
patients, the presence of previous myocardial infarction was
documented. At the end of the 2-month treatment period,
patients underwent echocardiography both at rest and
during low-dose dobutamine infusion, as well as a
cardiopulmonary exercise test.
In trimetazidine-treated patients resting ejection fraction
increased from 33·1 ± 4·5% to 39·5 ± 5·9% (P = 0·001); left
ventricular systolic volume decreased from 121·8 ± 9·2 ml to
110·2 ± 13 ml (P = 0·003); and the number of dysfunctional
segments was reduced from 147 to 137 (Fig. 3). Low-dose
(5–20 µg . kg – 1 . min – 1) dobutamine improved contractility
in 99 out of 179 segments (a 30% increase, relative to the
initial study), whereas no significant changes (relative to the
control study) were observed in patients receiving placebo.
Finally, peak oxygen consumption significantly increased from
16·4 ± 1·4 ml . kg – 1 . min – 1 to 18·9 ± 1·7 ml . kg – 1 . min – 1
only in those patients who received the active medication.
Belardinelli and Purcaro concluded that, in patients with
severe ischaemic dysfunction, trimetazidine improves
resting contractile function as well as the contractile
response to inotropic stimulation by low-dose dobutamine.
Conclusion
The evidence obtained in the trials summarized in the
present review indicates that trimetazidine improves resting
ventricular function in patients with coronary artery disease
and various degrees of contractile impairment. The agent
also appears to prevent or delay regional myocardial dysfunction when metabolic requirements exceed the possible
increase in blood supply. Furthermore, the drug improves
the contractile response to moderate inotropic stimulation as
well as functional capacity, as assessed by cardiopulmonary
stress testing.
Figure 3 Ejection fraction (left) and end-systolic volume (right) recorded
during placebo (white) or trimetazidine (grey) administration. Data are
expressed as mean ± standard deviation. From Belardinelli and Purcaro[11].
Eur Heart J Supplements, Vol. 3 (Suppl O) November 2001
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S. L. Chierchia
There are several explanations for the data summarized
here. Certainly, in the presence of severe limitation of
coronary flow reserve, better utilization of available
substrates can improve myocardial efficiency and increase
the production of mechanical work. This can translate into a
greater ejection fraction and improved functional status, as
well as preserve residual viability of ‘chronically’
ischaemic, potentially hibernating myocardium. The
positive response to low-dose dobutamine exhibited by
patients with low ejection fraction treated with
trimetazidine lends support to this hypothesis.
The improvement in contractility induced by
trimetazidine has potential prognostic and therapeutic
implications. Apart from allowing a more active lifestyle
and improving functional capacity, improved myocardial
contractility and stroke volume could improve peripheral
perfusion and decrease neurohumoral activation, thereby
resetting the sympathovagal balance toward a more
favourable condition. This could translate into improved
prognosis and decreased arrhythmogenic risk.
Such a contention will have to be substantiated by
specifically designed trials and by population studies that
are large enough to address the issue of prognosis. In the
meantime, trimetazidine should be considered as a valuable
therapeutic adjunct to be used on top of other more
traditional available agents, especially in patients with
severe, chronic ischaemic dysfunction, particularly if this is
not amenable to revascularization. In this regard the agent
appears particularly interesting for use in diabetic patients,
whose anatomy is frequently not suitable for surgical or
percutaneous intervention and whose metabolism (severely
disturbed by impaired utilization of carbohydrate fuels and
preferentially directed toward lipid oxidation) would appear
the ideal target for this drug.
Eur Heart J Supplements, Vol. 3 (Suppl O) November 2001
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