Cardioprotection during myocardial revascularization:
benefit of a metabolic intervention
Ioana Holban, MD
Abstract
Revascularization procedures such as PCI or CABG currently
represent a widely used therapeutic option for treating coronary
patients.
While improving the prognosis of patients, these techniques
still trigger myocardial damage as they induce transient and
profound ischemia.
Therefore, myocardial protection during such interventions
remains an important therapeutic target. Conventional hemodynamic
agents (b-blockers, calcium antagonists and long-acting nitrates)
do not seem to provide patients with strong benefits in terms
of cardioprotection.
A new therapeutic approach, derived from a better understanding
of cardiac metabolism alterations during ischemia, has provided
myocardial protection during revascularization procedures
through a direct action on myocyte metabolism. Trimetazidine
(Vastarel 20), the first of a new class of metabolic agents,
known as 3-KAT inhibitors, acts on a critical step in cardiac
metabolism: fatty acid oxidation. Through a decrease in fatty
acid oxidation, secondary to the selective inhibition of an
enzyme (the 3-KetoAcyl CoA Thiolase), trimetazidine significantly
reduces ischemia-induced metabolic injury. Recent randomized
clinical trials illustrate the anti-ischemic benefits of this
agent during primary angioplasty (LIST study) or during surgery
(Fabiani study). In both situations, trimetazidine was shown
to prevent ischemia-reperfusion damage.
- Heart Metabol. 2002;16:23–25.
Key words: Cardioprotection,
PTCA, CABG, metabolic intervention, trimetazidine
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In patients with stable angina, angiography and
revascularization of all stenoses, irrespective of prognostic
stratification, are unwarranted. Establishment of an appropriate
risk profile, including noninvasive investigation of left ventricular
function, reversible ischemia, exercise tolerance, and response
to pharmacological therapy, is a sensitive, cost-effective, and
responsible use of resources [1].
Nonetheless, cardiology entered a new era in the late 1970s when
heart specialists performed the first therapeutic catheterization
procedures. In September 1977, in Switzerland, Grüntzig performed
the first PTCA procedure for the treatment of angina [2].
Angioplasty revolutionized cardiology, especially for the treatment
of acute coronary syndromes.
Angiography plays a pivotal role in establishing the advisability
and need for revascularization. If the patient is in a high-risk
group, revascularization techniques should be considered. Patients
with significant left main artery stenosis or triple-vessel coronary
disease are best managed with CABG surgery, particularly if they
are diabetic [3].
Controversy has accompanied the development of stenting procedures,
which permit a significantly lower rate of restenosis, compared
with PTCA, and improve clinical outcomes in acute myocardial infarction.
Stenting must therefore be compared with surgery in large-scale,
randomized trials in patients with three-vessel disease or left
main artery stenosis.
Despite the significant improvement in prognosis due to the development
of revascularization procedures, myocardial injury during PTCA
and stenting is an important determinant of clinical outcome.
Protection of the myocardial tissue during such procedures should
therefore be an important target. Randomized studies, however,
have shown limited benefits for cardioprotection using traditional
hemodynamic agents (b-blockers, nitrates, and calcium antagonists).
However, better understanding of the sequences of the ischemic
cascade have led to the development of a metabolic approach using
new pharmacologic agents. Much attention has been given to metabolic
agents that are capable of acting directly on myocyte metabolism.
Among these agents, trimetazidine (Vastarel 20 mg) is the first
3-KAT inhibitor to be used worldwide due to its well-documented
anti-ischemic cardioprotective properties in patients with angina
pectoris; while other agents, such as sodium-hydrogen exchange
inhibitors, remain under evaluation.
Recent studies with trimetazidine have raised new hopes for cardioprotection
during revascularization procedures due to the originality of
its mechanism of action. Trimetazidine significantly reduces metabolic
damage caused by ischemia, by acting on a critical step in cardiac
metabolism: fatty acid b-oxidation. This is due to selective inhibition
of an enzyme, the long-chain 3-ketoacyl-CoA-thiolase (3-KAT)
[4]. The beneficial effects of trimetazidine during revascularization
procedures were recently illustrated in randomized clinical trials.
PTCA and stenting represent a typical model of transient profound
myocardial ischemia. In a controlled, randomized trial, intracoronary
trimetazidine was shown to delay ST-segment shift and reduce it
by more than 40% during balloon inflation (Figure 1)
[5].
Figure 1. Change in ST-segment shift and extent with trimetazidine
vs placebo during balloon inflation [5]. D1, first inflation 5
min after successful dilatation; D2, second inflation 5 min after
D1.
These results agree with the findings of the LIST
study [6]. This randomized, double-blind, placebo-controlled
study assessed the value of trimetazidine in patients undergoing
primary angioplasty following acute myocardial infarction
[6]. Ninety-four patients with acute myocardial infarction
were randomized to trimetazidine (40 mg bolus followed by 60 mg/day
intravenously for 48 h) or placebo (n = 50), starting prior to
recanalization of the infarcted vessel. Patients underwent continuous
ST-segment monitoring to evaluate the return of the ST-segment
deviation to baseline and the 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. The results showed an earlier and more marked return towards
baseline within the first 6 h in the trimetazidine group compared
with placebo (P = 0.014), despite higher initial ST deviation
from baseline in the trimetazidine group. The clinical outcomes
were similar in both groups, which may probably be related to
the relatively small size of the study as well as to the selection
of a low-risk patient population and the relatively short follow-up
time.
In view of the LIST study, we can conclude that trimetazidine,
compared with placebo, leads to earlier resolution of ST-segment
elevation in patients undergoing PTCA following acute myocardial
infarction. This confirms the anti-ischemic effect of the drug.
Other metabolic agents, for example cariporide used in the GUARDIAN
study, failed to demonstrate any benefits in comparison with placebo
on the composite end point of death and myocardial infarction
in patients undergoing high-risk PTCA [7].
Trimetazidine has also been shown to possess cardioprotective
benefits during CABG. In a double-blind, placebo-controlled study,
19 patients were randomized to either trimetazidine or placebo,
3 weeks before CABG [8]. Metabolic assessments
showed that the increase in malondialdehyde measured in the coronary
sinus after reperfusion was significantly reduced by trimetazidine
compared with placebo (P = 0.014). Myosin level was lower with
trimetazidine (P = 0.036), and ventricular function also improved
(P = 0.01). Trimetazidine seems to reduce ischemia-reperfusion
damage during cardiac surgery, since pretreatment with trimetazidine
prior to CABG allows the patient to undergo the procedure with
preserved left ventricular function.
Conclusion
Prevention of myocardial injury during revascularization
procedures (PTCA, stent, CABG) is an important goal that has important
clinical consequences in the prognosis of patients with coronary
artery disease. Following initial experimental data and recent
randomized clinical trials using the anti-ischemic agent trimetazidine,
metabolic intervention appears to be a promising means of reducing
myocardial ischemia and injury. Large-scale trials
will confirm the long-term clinical benefits of trimetazidine
in these specific situations.
REFERENCES
1. 1997 Heart and Stroke Statistical
Update. Dallas, Tx: American Heart Association; 1996.
Transluminal dilatation of coronary-artery
stenosis.
Gruntzig A.
Publication Types:
PMID: 74678 [PubMed - indexed for MEDLINE]
Comment in:
Medical care costs and quality of life after
randomization to coronary angioplasty or coronary bypass surgery.
Bypass Angioplasty Revascularization Investigation (BARI)
Investigators.
Hlatky MA, Rogers WJ, Johnstone I, Boothroyd D, Brooks MM, Pitt
B, Reeder G, Ryan T, Smith H, Whitlow P, Wiens R, Mark DB.
Stanford University School of Medicine, CA 94305-5092, USA.
BACKGROUND: Randomized trials comparing coronary angioplasty with
bypass surgery in patients with multivessel coronary disease have
shown no significant differences in overall rates of death and
myocardial infarction. We compared quality of life, employment,
and medical care costs during five years of follow-up among
patients treated with angioplasty or bypass surgery. METHODS: A
total of 934 of the 1829 patients enrolled in the randomized
Bypass Angioplasty Revascularization Investigation participated in
this study. Detailed data on quality of life were collected
annually, and economic data were collected quarterly. RESULTS:
During the first three years of follow-up, functional-status
scores on the Duke Activity Status Index, which measures the
ability to perform common activities of daily living, improved
more in patients assigned to surgery than in those assigned to
angioplasty (P<0.05). Other measures of quality of life improved
equally in both groups throughout the follow-up period. Patients
in the angioplasty group returned to work five weeks sooner than
did patients in the surgery group (P<0.001). The initial mean cost
of angioplasty was 65 percent that of surgery ($21,113 vs.
$32,347, P<0.001), but after five years the total medical cost of
angioplasty was 95 percent that of surgery ($56,225 vs. $58,889),
a difference of $2,664 (P = 0.047). The five-year cost of
angioplasty was significantly lower than that of surgery among
patients with two-vessel disease ($52,930 vs. $58,498, P<0.05),
but not among patients with three-vessel disease ($60,918 vs.
$59,430). After five years of follow-up, surgery had an overall
cost-effectiveness ratio of $26,117 per year of life added, but
unacceptable ratios of $100,000 or more per year of life added
could not be excluded (P=0.13). Surgery appeared particularly cost
effective in treating diabetic patients because of their
significantly improved survival. CONCLUSIONS: In patients with
multivessel coronary disease, coronary-artery bypass surgery is
associated with a better quality of life for three years than
coronary angioplasty, after the initial morbidity caused by the
procedure. Coronary angioplasty has a lower five-year cost than
bypass surgery only in patients with two-vessel coronary disease.
Publication Types:
- Clinical Trial
- Randomized Controlled Trial
PMID: 8988886 [PubMed - indexed for MEDLINE]
Comment in:
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]
Comment in:
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]
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]
Inhibition of the sodium-hydrogen exchanger
with cariporide to prevent myocardial infarction in high-risk
ischemic situations. Main results of the GUARDIAN trial. Guard
during ischemia against necrosis (GUARDIAN) Investigators.
Theroux P, Chaitman BR, Danchin N, Erhardt L, Meinertz T,
Schroeder JS, Tognoni G, White HD, Willerson JT, Jessel A.
BACKGROUND: The transmembrane sodium/hydrogen exchanger maintains
myocardial cell pH integrity during myocardial ischemia but
paradoxically may precipitate cell necrosis. The development of
cariporide, a potent and specific inhibitor of the exchanger,
prompted this investigation of the potential of the drug to
prevent myocardial cell necrosis. METHODS AND RESULTS: A total of
11 590 patients with unstable angina or non-ST-elevation
myocardial infarction (MI) or undergoing high-risk percutaneous or
surgical revascularization were randomized to receive placebo or 1
of 3 doses of cariporide for the period of risk. The trial failed
to document benefit of cariporide over placebo on the primary end
point of death or MI assessed after 36 days. Doses of 20 and 80 mg
every 8 hours had no effect, whereas a dose of 120 mg was
associated with a 10% risk reduction (98% CI 5.5% to 23.4%,
P=0.12). With this dose, benefit was limited to patients
undergoing bypass surgery (risk reduction 25%, 95% CI 3.1% to
41.5%, P=0.03) and was maintained after 6 months. No effect was
seen on mortality. The rate of Q-wave MI was reduced by 32% across
all entry diagnostic groups (2.6% versus 1.8%, P=0.03), but the
rate of non-Q-wave MI was reduced only in patients undergoing
surgery (7.1% versus 3.8%, P=0.005). There were no increases in
clinically serious adverse events. CONCLUSIONS: No significant
benefit of cariporide could be demonstrated across a wide range of
clinical situations of risk. The trial documented safety of the
drug and suggested that a high degree of inhibition of the
exchanger could prevent cell necrosis in settings of
ischemia-reperfusion.
Publication Types:
- Clinical Trial
- Randomized Controlled Trial
PMID: 11120691 [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]
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