Cardioprotection:
a promising role for metabolic agents
Marc Pini
Paris, France
Rationale for metabolic
cardioprotective intervention
Despite significant progress in recent years, coronary artery
disease remains a major health problem worldwide. The therapeutic
approach to the patient with acute myocardial infarction or unstable
angina has radically changed in recent times. The current strategy
is to consider reperfusion therapy, either catheter-based or fibrinolytic
(for myocardial infarction only), and to initiate it as soon as
possible. Appropriate therapy with aspirin, anticoagulants or
ß-blockers is prescribed to the majority of patients, since these
have been proved through randomized clinical trials to reduce
mortality. The pathophysiological mechanism is the acute rupture
of an atherosclerotic plaque in an epicardial coronary artery,
exposing endothelial tissue to a thrombogenic response and leading
to severe obstruction of the vessel. While the vessel is considered
to be the main target, there are multiple abnormalities in myocardial
energy metabolism that contribute to a poor prognosis, especially
in diabetic patients, despite the progress in revascularization
procedures. Cardiac metabolism has remained for many years the
lost child, despite accumulating evidence of its benefits in maintaining
myocardial viability in acute coronary syndromes.
The metabolic approach to treating coronary heart disease is based
on the concept that cardiac energy substrates can be manipulated
to optimize ATP production and enhance cardiac output. The efficacy
of this metabolic modulation in acute coronary syndromes has been
confirmed in two randomized trials. The DIGAMI (Diabetes Mellitus
Insulin-Glucose Infusion in Acute Myocardial Infarction) study
aimed to evaluate the impact on mortality of a glucose-insulin
infusion followed by multidose insulin treatment in diabetic patients
with acute myocardial infarction. [1] A total
of 620 diabetic patients were studied and the glucose-insulin
infusion produced a significant reduction in mortality at 1-year
follow-up (relative mortality reduction 29%, P = 0.027).
The ECLA (Estudios Cardiologicos Latina America) study was conducted
in 407 nondiabetic patients with suspected acute myocardial infarction,
who received either a glucose-insulin-potassium infusion (GIK)
or placebo.[2] At 1-year follow-up, a statistically
significant reduction in mortality (relative risk 0.34, 95% CI
0.15–0.78, 2P = 0.008) was observed in the GIK group vs. placebo
in patients who had undergone reperfusion with fibrinolysis.
Although a large-scale trial is necessary to reliably determine
the precise benefits of metabolic modulation, these studies have
highlighted the potential benefits of metabolic cardiac protection.
Cardioprotection with metabolic agents
Kantor et al [3] have recently clarified the
precise mechanism of action of Vastarel 20 mg, the first in a
new class of metabolic agents known as 3-KAT inhibitors. Vastarel
20 mg selectively inhibits a mitochondrial enzyme — the long-chain
3-ketoacyl CoA thiolase
(3-KAT) — thereby shifting cardiac metabolism away from fatty
acid b-oxidation and towards glucose oxidation, thus optimizing
energy production in the myocardial cell (Figure 1).[4]
 Figure 1. Mechanism of action of Vastarel
20. PDH, pyruvate dehydrogenase; ß-OX, ß-oxidation.
The cardioprotective effect of Vastarel 20 mg was
first demonstrated in experimental studies which confirmed that
it restores myocyte viability and ATP content in cardiomyocytes
exposed to hypoxia,[5] preserves the electrical
activity of the myocardial cell under ischemic conditions,[6]
reduces ischemic contracture, and improves functional recovery.[7]
In vivo animal studies have demonstrated the additive beneficial
effects of Vastarel 20 mg. Pretreatment with Vastarel 20 mg before
coronary ligation followed by reperfusion led to a reduction in
mean ST shift, a decrease in the size of the border area, and
a significant reduction in the extent of infarction.[8,9]
These encouraging results have been confirmed in several clinical
studies. During CABG, pretreatment with Vastarel 20 mg for 3 weeks,
followed by the addition of a Vastarel 20 mg solution to cardioplegic
solutions, resulted in a significant limitation of myocardial
injury.[10]
In addition to thrombolysis, pretreatment with Vastarel 20 mg
in 81 patients with anterior myocardial infarction recently produced
a significant reduction of ventricular arrhythmias (P < 0.05),
a smaller creatine kinase peak
(P = 0.012), and a smaller end-systolic volume (P = 0.037) compared
with pretreatment with placebo.[11] During
coronary angioplasty, intracoronary injection of Vastarel 20 mg
led to a marked reduction in ECG signs of ischemia and anginal
pain resulting from balloon inflation-induced ischemia during
angioplasty.[12,13]
Despite a higher initial value, an earlier and more marked return
to baseline ST-segment was observed in the Vastarel 20 mg group
(P = 0.014) in the LIST (Limitation of Infarct Size by Trimetazidine
Trial) (Figure 2).
 Figure
2. Vectorcardiographic results obtained in the LIST study.
These results suggest an earlier and probably more complete myocardial
reperfusion with Vastarel 20 mg. Although randomized large-scale
studies are needed to confirm these promising results, the concept
of metabolic intervention in acute coronary syndromes appears
to be effective and is expected to improve the prognosis of patients
with coronary artery disease.
REFERENCES
-
Comment in:
 |
ACP J Club. 1996 Jan-Feb;124(1):1 |
Randomized trial of insulin-glucose infusion followed by
subcutaneous insulin treatment in diabetic patients with acute
myocardial infarction (DIGAMI study): effects on mortality at
1 year.
Malmberg K, Ryden L, Efendic S, Herlitz J, Nicol P, Waldenstrom
A, Wedel H, Welin L.
Department of Cardiology, Karolinska Hospital, Stockholm, Sweden.
OBJECTIVES. We tested how insulin-glucose infusion followed
by multidose insulin treatment in diabetic patients with acute
myocardial infarction affected mortality during the subsequent
12 months of follow-up. BACKGROUND. Despite significant improvements
in acute coronary care, diabetic patients with acute myocardial
infarction still have a high mortality rate. METHODS. A total
of 620 patients were studied: 306 randomized to treatment with
insulin-glucose infusion followed by multidose subcutaneous
insulin for > or = 3 months and 314 to conventional therapy.
RESULTS. The two groups were well matched for baseline characteristics.
Blood glucose decreased from 15.4 +/- 4.1 to 9.6 +/- 3.3 mmol/liter
(mean +/- SD) in the infusion group during the 1st 24 h, and
from 15.7 +/- 4.2 to 11.7 +/- 4.1 among control patients (p
< 0.0001). After 1 year 57 subjects (18.6%) in the infusion
group and 82 (26.1%) in the control group had died (relative
mortality reduction 29%, p = 0.027). The mortality reduction
was particularly evident in patients who had a low cardiovascular
risk profile and no previous insulin treatment (3-month mortality
rate 6.5% in the infusion group vs. 13.5% in the control group
[relative reduction 52%, p = 0.046]; 1-year mortality rate 8.6%
in the infusion group vs. 18.0% in the control group [relative
reduction 52%, p = 0.020]). CONCLUSIONS. Insulin-glucose infusion
followed by a multidose insulin regimen improved long-term prognosis
in diabetic patients with acute myocardial infarction.
Publication Types:
|
Clinical trial |
|
Randomized controlled trial |
PMID: 7797776 [PubMed - indexed for MEDLINE]
-
-
Metabolic modulation of acute myocardial infarction. The
ECLA (Estudios Cardiologicos Latinoamerica) Collaborative Group.
Diaz R, Paolasso EA, Piegas LS, Tajer CD, Moreno MG, Corvalan
R, Isea JE, Romero G.
Department of Cardiology, Instituto Cardiovascular de Rosario,
Rosario, Argentina.
BACKGROUND: Several trials have been performed in the past using
glucose, insulin, and potassium infusion (GIK) for the treatment
of acute myocardial infarction (AMI). Because of continuing
uncertainty about the potential role of this therapeutic intervention,
we conducted a randomized trial to evaluate the impact of a
GIK solution during the first hours of AMI. METHODS AND RESULTS:
Four hundred seven patients with suspected AMI admitted within
24 hours of symptoms onset were enrolled. In a ratio of 2:1,
268 patients were allocated to receive GIK (high- or low-dose)
and 139 to receive control. Phlebitis and serum changes in the
plasma concentration of glucose or potassium were observed more
often with GIK. A trend toward a nonsignificant reduction in
major and minor in-hospital events was observed in patients
allocated to GIK. In 252 patients (61.9%) treated with reperfusion
strategies, a statistically significant reduction in mortality
(relative risk [RR] 0.34; 95% CI: 0.15 to 0.78; 2P=0.008) and
a consistent trend toward fewer in-hospital events in the GIK
group were observed. CONCLUSIONS: Our results confirm that a
metabolic modulation strategy in the first hours of an AMI is
feasible, applicable worldwide, and has mild side effects. The
statistically significant mortality reduction in patients who
underwent a reperfusion strategy might have important implications
for the management of AMI patients. It is now essential to perform
a large-scale trial to reliably determine the magnitude of benefit.
Publication Types:
|
Clinical trial |
|
Multicenter study |
|
Randomized controlled trial |
PMID: 9867443 [PubMed - indexed for MEDLINE]
-
-
Comment in:
|
Circ Res. 2000 Mar 17;86(5):487-9 |
The antianginal drug trimetazidine shifts cardiac energy
metabolism from fatty acid oxidation to glucose oxidation by
inhibiting mitochondrial long-chain 3-ketoacyl coenzyme A thiolase.
Kantor PF, Lucien A, Kozak R, Lopaschuk GD.
Cardiovascular Research Group and the Division of Pediatric
Cardiology, University of Alberta, Edmonton, Canada.
Trimetazidine is a clinically effective antianginal agent that
has no negative inotropic or vasodilator properties. Although
it is thought to have direct cytoprotective actions on the myocardium,
the mechanism(s) by which this occurs is as yet undefined. In
this study, we determined what effects trimetazidine has on
both fatty acid and glucose metabolism in isolated working rat
hearts and on the activities of various enzymes involved in
fatty acid oxidation. Hearts were perfused with Krebs-Henseleit
solution containing 100 microU/mL insulin, 3% albumin, 5 mmol/L
glucose, and fatty acids of different chain lengths. Both glucose
and fatty acids were appropriately radiolabeled with either
(3)H or (14)C for measurement of glycolysis, glucose oxidation,
and fatty acid oxidation. Trimetazidine had no effect on myocardial
oxygen consumption or cardiac work under any aerobic perfusion
condition used. In hearts perfused with 5 mmol/L glucose and
0.4 mmol/L palmitate, trimetazidine decreased the rate of palmitate
oxidation from 488+/-24 to 408+/-15 nmol x g dry weight(-1)
x minute(-1) (P<0.05), whereas it increased rates of glucose
oxidation from 1889+/-119 to 2378+/-166 nmol x g dry weight(-1)
x minute(-1) (P<0.05). In hearts subjected to low-flow ischemia,
trimetazidine resulted in a 210% increase in glucose oxidation
rates. In both aerobic and ischemic hearts, glycolytic rates
were unaltered by trimetazidine. The effects of trimetazidine
on glucose oxidation were accompanied by a 37% increase in the
active form of pyruvate dehydrogenase, the rate-limiting enzyme
for glucose oxidation. No effect of trimetazidine was observed
on glycolysis, glucose oxidation, fatty acid oxidation, or active
pyruvate dehydrogenase when palmitate was substituted with 0.8
mmol/L octanoate or 1.6 mmol/L butyrate, suggesting that trimetazidine
directly inhibits long-chain fatty acid oxidation. This reduction
in fatty acid oxidation was accompanied by a significant decrease
in the activity of the long-chain isoform of the last enzyme
involved in fatty acid beta-oxidation, 3-ketoacyl coenzyme A
(CoA) thiolase activity (IC(50) of 75 nmol/L). In contrast,
concentrations of trimetazidine in excess of 10 and 100 micromol/L
were needed to inhibit the medium- and short-chain forms of
3-ketoacyl CoA thiolase, respectively. Previous studies have
shown that inhibition of fatty acid oxidation and stimulation
of glucose oxidation can protect the ischemic heart. Therefore,
our data suggest that the antianginal effects of trimetazidine
may occur because of an inhibition of long-chain 3-ketoacyl
CoA thiolase activity, which results in a reduction in fatty
acid oxidation and a stimulation of glucose oxidation.
PMID: 10720420 [PubMed - indexed for MEDLINE]
-
Effects of trimetazidine on metabolic and functional recovery
of postischemic rat hearts.
Allibardi S, Chierchia SL, Margonato V, Merati G, Neri G,
Dell'Antonio G, Samaja M.
Dipartimento di Scienze e Technologie Biomediche, Universita
degli Studi di Milano, Italy.
The objective of this study was to test the hypothesis that
the beneficial effect of trimetazidine during reflow of ischemic
hearts is mediated by energy sparing and ATP pool preservation
during ischemia. Isolated rat hearts (controls and rats treated
with 10(-6) M trimetazidine, n = 17 per group) underwent the
following protocol: baseline perfusion at normal coronary flow
(20 minutes), low-flow ischemia at 10% flow (60 minutes), and
reflow (20 minutes). We measured contractile function, O2 uptake,
lactate release, venous pH and PCO2, and the tissue content
of high-energy phosphates and their metabolites. During baseline,
trimetazidine induced higher venous pH and lower PCO2 without
influencing performance and metabolism. During low-flow ischemia,
trimetazidine reduced myocardial performance (P = 0.04) and
ATP turnover (P = 0.02). During reflow, trimetazidine improved
performance (91 +/- 6% versus. 55 +/- 6% of baseline), prevented
the development of diastolic contracture and coronary resistance,
and reduced myocardial depletion of adenine nucleotides and
purines. ATP turnover during low-flow ischemia was inversely
related to recovery of the rate-pressure product (P = 0.002),
end-diastolic pressure (P = 0.007), and perfusion pressure (P
= 0.05). We conclude that trimetazidine-induced protection of
ischemic-reperfused hearts is also mediated by energy sparing
during ischemia, which presumably preserves the ATP pool during
reflow.
PMID: 10410824 [PubMed - indexed for MEDLINE]
5. Honore E, Adamantidis M, Challice
CE, Dupuis BA. Cardioprotection by calcium antagonists, piridoxilate
and Vastarel 20 mg. IRCS Med Sci. 1986;14:938–939.
6. Drake-Holland AJ, Belcher PR, Hynd J, Noble
MIM. Infarct size in rabbits: a modified method illustrated by
the effects of propranolol and Vastarel 20 mg. Basic Res Cardiol.
1993;88:250–258.
Trimetazidine inhibits neutrophil accumulation after myocardial
ischaemia and reperfusion in rabbits.
Williams FM, Tanda K, Kus M, Williams TJ.
Department of Applied Pharmacology, National Heart & Lung
Institute, London, England.
Interventions that inhibit neutrophil infiltration into myocardial
tissue after ischaemia and reperfusion are reported to reduce
the size of the infarct. We examined whether administration
of trimetazidine, which is reported to reduce myocardial infarct
size, affects this process. [111In]Neutrophils and [125I]albumin
were administered intravenously (i.v.) to anaesthetized rabbits
to allow measurement of cell accumulation and changes in microvascular
plasma protein leakage. A 30-min period of coronary artery occlusion
followed by 3-h reperfusion was used, and the area at risk (AR)
myocardium was defined by dye exclusion. Twelve rabbits received
2.5 mg/kg trimetazidine i.v., 10 min before coronary artery
occlusion; the 13 controls received saline. In the control group,
the number of [111In]neutrophils/g tissue in the AR (30,591
+/- 6,725) was significantly greater than in the normal zone
(NZ, 11,519 +/- 1,605, p < 0.01). In the trimetazidine-treated
group, the number of [111In]neutrophils in the AR was significantly
lower than in the control group (12,717 +/- 1,958 [111In]neutrophils/g,
p < 0.01). There was no significant difference in neutrophil
content of the NZ (7,832 +/- 1,117 [111In]neutrophils/g) in
treated animals as compared with that in control. Accumulation
of [111In]neutrophils in response to intradermal administration
of leukotriene B4, interleukin-8 (IL-8), or zymosan-activated
plasma was not affected by the drug. The effect of trimetazidine
on neutrophil accumulation into post-ischaemic reperfused myocardium
therefore does not appear to result from a direct action on
the neutrophil.
PMID: 7509900 [PubMed - indexed for MEDLINE]
Effects of trimetazidine on ischemic contracture in isolated
perfused rat hearts.
Boucher FR, Hearse DJ, Opie LH.
URA CNRS 1287, Universite Joseph Fourier, Grenoble, France.
Trimetazidine (1-[2,3,4-trimethoxibenzyl)]-piperazine, TMZ)
is a drug with a proposed metabolically based antiischemic action.
Because ischemic contracture is a serious complication of ischemia
and is considered metabolic in origin, we studied the effect
of trimetazidine (TMZ) on development of ischemic contracture
in experimental low-flow ischemia. TMZ was either added to the
perfusion fluid or given as pretreatment to the donor rats.
Langendorff-perfused isolated rat hearts were submitted to 30-min
subtotal global ischemia (residual flow = 0.2 ml/min, n = 6
per group) (normal flow = 12.4 +/- 0.8 ml/min, heart fresh weight
= 0.9 +/- 0.3 g). Ischemic contracture was measured by a water-filled
intraventricular balloon. Thereafter, the hearts were reperfused
for 20 min and recovery of intraventricular pressure was monitored.
Furthermore, because the mechanisms of action of TMZ may involve
cellular energy metabolism, we assessed throughout glycolytic
flux by collecting the coronary effluent every 5 min during
control perfusion, ischemia, and reperfusion periods. Animals
from the pretreated groups received TMZ [3 mg/kg orally (p.o.)
twice daily] for 5 days. Animals from the control group received
placebo for the same time period. Concentrations of 10(-6) and
10(-4) M were used when the drug was added to the perfusate.
In our experimental conditions, TMZ pretreatment alone had no
measurable cardioprotective effect, but addition to the perfusate
of TMZ 10(-6) M, approximately a therapeutic concentration in
humans, reduced ischemic contracture in both pretreated and
control groups and improved postischemic recovery of developed
pressure.(ABSTRACT TRUNCATED AT 250 WORDS)
PMID: 7521488 [PubMed - indexed for MEDLINE]-
-
Cardioprotective effect of trimetazidine during coronary
artery graft surgery.
Fabiani JN, Ponzio O, Emerit I, Massonet-Castel S, Paris
M, Chevalier P, Jebara V, Carpentier A.
Cardiovascular Surgery Department, Hopital Broussais, Paris,
France.
Reperfusion injury remains the most uncontrolled phenomenon
during cardiac surgery. Potential myocardial protection by trimetazidine
was tested in a double blind placebo controlled study on 19
patients undergoing aorto-coronary bypass surgery. The trimetazidine
group was composed of 10 patients and the placebo group of 9
patients. Pretreatment was started three weeks before surgery
with 1 tablet (trimetazidine 20 mg) t.i.d. and the same drug
was added to the cardioplegic solutions (trimetazidine: 10(-6)
M). The cross clamping time was 41.1 +/- 3.8 minutes in the
trimetazidine group and 39.8 +/- 2.3 minutes in the placebo
group. Metabolic measurements showed that the increase of malondialdehyde
measured in the coronary sinus 20 minutes after reperfusion
was significantly (p = 0.014) less in the trimetazidine group
(from 1.60 +/- 0.11 to 1.79 +/- 0.2 mumol/L-1) than in the placebo
group (from 1.17 +/- 0.11 to 2.84 +/- 0.58 mumol/L-1). Myosin
was present 4 hours after surgery in all patients in the placebo
group and in 5 of the 10 of the trimetazidine group (p = 0.036).
Haemodynamic measurements showed that patients pretreated with
trimetazidine had a better ventricular function, as assessed
by the stroke work index (SWI) significantly (p = 0.01) higher
in the trimetazidine group (0.0391 +/- 0.0029 g/min/m2/beta)
than in the placebo group (0.0282 +/- 0.0026 g/min/m2/beat),
the evolution of SWI during surgery was not significantly different
between the two groups. Thus trimetazidine seems to reduce ischaemia-reperfusion
damage during cardiac surgery; moreover pretreatment with trimetazidine
allows the patient to face the operation with better ventricular
function.
Publication Types:
|
Clinical trial |
|
Randomized controlled trial |
PMID: 1527157 [PubMed - indexed for MEDLINE]
-
-
Myocardial protection during percutaneous transluminal coronary
angioplasty: effects of trimetazidine.
Kober G, Buck T, Sievert H, Vallbracht C.
Clinic Nordrhein, Bad Nauheim, Germany.
Trimetazidine (TMZ) has recently been shown to improve anginal
symptoms without altering haemodynamic variables. A randomized,
double-blind, placebo-controlled study was conducted in 20 patients
to study the effects of TMZ on the severity of myocardial ischaemia
during PTCA of the left anterior descending coronary artery.
Five minutes after a first successful dilatation (D0), a control
balloon inflation (D1) was performed until onset of ischaemic
signs on both the intracoronary (i.c.) and precordial ECG. Two
minutes later, patients received either TMZ 6 mg or placebo
i.c. Another inflation (D2) was performed 5 min after D1. No
differences were found between the two groups regarding responses
in heart rate, systemic and i.c. pressures during the study.
TMZ decreased the maximum ST-segment shift at D2 compared with
D1 (0.8 +/- 0.1 vs 1.4 +/- 0.3 mV, P = 0.023) and delayed its
onset (46 +/- 4 vs 36 +/- 5 s, P = 0.024). TMZ also decreased
maximum T-wave changes (1.06 +/- 0.24 vs 2.19 +/- 0.3 mV, P
= 0.001), and significantly reduced the area under the curve
(mv s-1) of the i.c. ST-segment and T-wave changes during balloon
inflation (P = 0.042 and P = 0.009 respectively). The placebo
had no effect on these parameters. These results support the
hypothesis that trimetazidine has a direct anti-ischaemic effect
on human myocardial cells.
Publication Types:
|
Clinical trial |
|
Randomized controlled trial |
PMID: 1505561 [PubMed - indexed for MEDLINE]
-
-
Effects of trimetazidine administration before thrombolysis
in patients with anterior myocardial infarction: short-term
and long-term results.
Di Pasquale P, Lo Verso P, Bucca V, Cannizzaro S, Scalzo
S, Maringhini G, Rizzo R, Paterna S.
Division of Cardiology Paolo Borsellino, G.F. Ingrassia Hospital
Palermo, Italy.
Reperfusion may prevent or reduce the development and extent
of necrosis, but may also lead to an increase in reperfusion
damage. Experimental studies performed in various animal models
of myocardial ischemia have demonstrated the anti-ischemic properties
of trimetazidine (TMZ) and have suggested that TMZ has antioxidant
properties, without any direct hemodynamic effects. Our study
was aimed at investigating the effects of TMZ before thrombolysis
in acute anterior myocardial infarction and included 81 patients,
hospitalized within 4 hours of the onset of symptoms. Patients
were randomly (double-blind) subdivided in two groups The first
group (40 patients, Group A, TMZ-pretreatment), received 40
mg TMZ orally about 15 minute before thrombolysis and, subsequently,
20 mg every 8 hours. The second group (41 patients, Group B)
received placebo before thrombolysis. Ventricular arrhythmias
(VA) due to reperfusion were evaluated in the first 2 hours.
VA occurred in 15 of patients in group A, versus 29 in group
B, p<0.05. Creatine kinase (CK) normalization time was achieved
after 55.7+/-12.5 hours in group A, versus 61.2+/-12.1 hour
in group B, p = 0.048. CK peak was 1772+/-890 in group A vs.
2285+/-910 Ul/l in group B, (p = 0.012). In the follow-up (range
6-22 months), there were 4 deaths, two patients in each group.
After 180 days from treatment, the TMZ group showed a smaller
end systolic volume than the placebo group (echocardiographic
data), 46.2+/-12 and 52.8+/-13 ml/m2, respectively, p = 0.037.
Our data suggest that TMZ probably reduces reperfusion damage
and/or infarct size in patients with anterior AMI subjected
to thrombolysis and affects the post-AMI remodeling. Our data
must be interpreted with caution because of the selection of
patients. These findings require further extensive trials.
Publication Types:
|
Clinical trial |
|
Randomized controlled trial |
PMID: 10547222 [PubMed - indexed for MEDLINE]
-
-
Effects of trimetazidine on heart rate variability and left
ventricular systolic performance in patients with coronary artery
disease after percutaneous transluminal angioplasty.
Birand A, Kudaiberdieva GZ, Batyraliev TA, Akgul F, Usal
A.
Cardiology Department, Cukurova University, Medical Faculty,
Balcali Hospital, Adana, Turkey.
Fifty-one patients (mean age 51.6 +/- 7.1 years) with angiographically
proven coronary artery disease (CAD) entered the study. In 26
patients (Group I), trimetazidine treatment started twenty-four
hours after percutaneous transluminal coronary angioplasty (PTCA).
Another 25 patients (Group II) without trimetazidine treatment
were kept as controls. The groups were comparable by age, gender,
risk factors of CAD, coronary anatomy, left ventricular performance,
and heart rate variability indices at baseline state. Power
spectral analysis of heart rate variability and two-dimensional
and Doppler echocardiographic examinations were performed before
PTCA, and twenty-four hours, ten days, thirty days, and three
months after PTCA. A statistically significant improvement of
left ventricular systolic performance (P < 0.001), augmentation
of the parasympathetic band of heart rate variability (P <
0.001), and decline of P1/P2 ratio (P < 0.01) were evident
in patients treated with trimetazidine, while no apparent changes
were observed in controls. The intergroup analysis also showed
marked difference between groups as recorded on the day 30 and
month 3 of observation (P < 0.001). During follow-up period
recurrences of angina pectoris and ischemia were registered
in Group II, while no evidence of ischemia was discerned in
Group I patients. In conclusion, trimetazidine modulates the
autonomic control of heart rate, ie, reduces sympathetic overactivity
and augments vagal influences, improves left ventricular contractility,
and diminishes the clinical manifestations of ischemia in patients
with CAD after PTCA.
Publication Types:
|
Clinical trial |
|
Randomized controlled trial |
PMID: 9158385 [PubMed - indexed for MEDLINE]
-
-
A randomized double-blind trial of intravenous trimetazidine
as adjunctive therapy to primary angioplasty for acute myocardial
infarction.
Steg PG, Grollier G, Gallay P, Morice M, Karrillon GJ, Benamer
H, Kempf C, Laperche T, Arnaud P, Sellier P, Bourguignon C,
Harpey C; LIST Study Group.
Cardiologie, Hopital Bichat, 46 rue Henri Huchard, 75877 Cedex
18, Paris, France. gabriel.steg@bch.ap-hop-paris.fr
BACKGROUND: Despite high patency rates, primary angioplasty
for myocardial infarction does not necessarily result in optimal
myocardial reperfusion and limitation of infarct size. Experimentally,
trimetazidine limits infarct size, decreases platelet aggregation,
and reduces leukocyte influx into the infarct zone. To assess
trimetazidine as adjunctive therapy to primary angioplasty for
acute myocardial infarction a prospective, double-blind, placebo-controlled
pilot trial was performed. METHODS: 94 patients with acute myocardial
infarction were randomized to receive trimetazidine (40 mg bolus
followed by 60 mg/day intravenously for 48 h) (n=44) or placebo
(n=50), starting before recanalization of the infarct vessel
by primary angioplasty. Patients underwent continuous ST-segment
monitoring to assess return of ST-segment deviation to baseline
and presence of ST-segment exacerbation at the time of vessel
recanalization. Infarct size was measured enzymatically from
serial myoglobin measurements. Left ventricular angiography
was performed before treatment and repeated at day 14. RESULTS:
Blinded ST segment analysis showed that despite higher initial
ST deviation from baseline in the trimetazidine group (355 (32)
vs. 278 (29) microV, P=0.07), there was an earlier and more
marked return towards baseline within the first 6 h than in
the placebo group (P=0.014) (change: 245 (30) vs. 156 (31) microV
respectively, P=0.044). There was a trend towards less frequent
exacerbation of ST deviation at the time of recanalization in
the trimetazidine group (23.3 vs. 42.2%, P=0.11). There was
no difference in left ventricular wall motion at day 14, or
in enzymatic infarct size. There was no side effect from treatment.
Clinical outcomes were similar between groups. CONCLUSION: Trimetazidine
was safe and led to earlier resolution of ST-segment elevation
in patients treated by primary angioplasty for acute myocardial
infarction.
Publication Types:
|
Clinical trial |
|
Multicenter study |
|
Randomized controlled trial |
PMID: 11182191 [PubMed - indexed for MEDLINE]
|
