(Circulation. 1998;97:2278-2279.)
© 1998 American Heart Association, Inc.
Glucose-Insulin-Potassium Therapy for Treatment of Acute Myocardial Infarction
Pertti Ebeling, MD;
; Veikko A. Koivisto, MD
Department of Medicine,
Helsinki University Hospital,
Helsinki, Finland
To the Editor:
The meta-analysis of Fath-Ordoubadi and
Beatt1 suggests a beneficial role for
glucose-insulin-potassium therapy for treatment of acute myocardial
infarction in nondiabetic patients, a result in accordance with the
recently reported beneficial effect in diabetic
patients.2
Although the exact mechanisms behind the improvement of prognosis are
unclear, we would like to stress the importance of reducing free fatty
acids (FAs) as a myocardial fuel by insulin administration. Normally,
FA oxidation and cardiac work are closely associated. In
ischemic hearts, the proportion of energy produced from FAs
increases. Kudo and coworkers3 induced global
ischemia of 30 minutes followed by aerobic reperfusion of 60
minutes in isolated working rat hearts. Although cardiac work after
reperfusion was reduced to only 16% of aerobic values, palmitate
oxidation increased to 136%. The reduced cardiac efficiency in
ischemia may depend on the excessive entrance of FAs into
mitochondria, leading to uncoupling of mechanical function from FA
oxidation. The same phenomenon is seen with medium-chain FAs with free
entrance into mitochondria.4 Normally, the access
of long-chain FAs, the great majority of FAs, into mitochondria is
inhibited by malonyl-CoA through carnitine palmitoyl transferase I. In
the work of Kudo et al,3 acetyl-CoA, substrate
for malonyl-CoA, and malonyl-CoA levels were reduced in concert after
ischemia. However, malonyl-CoA levels were much further reduced
during aerobic reperfusion, although acetyl-CoA levels did not decrease
further. The level of malonyl-CoA after reperfusion was only 
1% of
aerobic level. Thus, FAs probably had almost uncontrolled access into
mitochondria. The activity of acetyl coenzyme-A carboxylase (ACC), the
enzyme converting acetyl-CoA to malonyl-CoA, was reduced in
ischemic hearts during reperfusion, explaining the lowered
malonyl-CoA level after reperfusion. Cardiac dysfunction may lead to
greater myocardial injury. Because glucose and insulin increase the
concentration of malonyl-CoA5 by stimulating
ACC,6 they inhibit entrance of FAs into
mitochondria and consequently restrict the damage caused by the
uncoupling of FA oxidation and the myocardium contraction.
Thus, intensive insulin therapy both reduces FA availability by
inhibiting lipolysis and prevents excessive FA entrance into
mitochondria, both mechanisms that reduce FA toxicity in the
ischemic heart.
References
1.
Fath-Ordoubadi F, Beatt KJ. Glucose-insulin-potassium
therapy for treatment of acute myocardial infarction: an overview of
randomized placebo-controlled trials. Circulation. 1997;96:1152–1156.[Abstract/Free Full Text]
2.
Malmberg K, for the DIGAMI Study Group. Prospective
randomized study of intensive insulin treatment on long-term survival
after acute myocardial infarction in patients with diabetes mellitus.
BMJ. 1997;314:1512–1515.[Abstract/Free Full Text]
3.
Kudo N, Barr AJ, Barr RL, Desai S, Lopaschuck GD. High
rates of fatty acid oxidation during reperfusion of ischemic
hearts are associated with a decrease in malonyl-CoA levels due to an
increase in 5'-AMP-activated protein kinase inhibition of
acetyl-CoA carboxylase. J Biol Chem. 1995;270:17513–17520.[Abstract/Free Full Text]
4.
Schönfeld P, Wojtczak AB, Geelen MJH, Kunz W,
Wojtczak L. On the mechanism of the so-called uncoupling effect of
medium- and short-chain fatty acids. Biochim Biophys
Acta. 1988;936:280–288.[Medline]
[Order article via Infotrieve]
5.
Duan C, Winder WW. Control of malonyl CoA by glucose
and insulin in perfused skeletal muscle. J Appl
Physiol. 1993;74:2543–2547.[Abstract/Free Full Text]
6.
Witters LA, Kemp BE. Insulin activation of acetyl-CoA
carboxylase accompanied by inhibition of the 5'-AMP-activated
protein kinase. J Biol Chem. 1992;267:2864–2867.[Abstract/Free Full Text]
Response
Farzin Fath-Ordoubadi, BSc MB BCh MRCP;
; Kevin J. Beatt, PhD, FESC, FACC
Hammersmith Hospital,
London, UK
We agree with Dr Ebeling and Dr Koivisto and do believe that one
of the main beneficial effects of GIK during ischemia, as
mentioned in our article,1 is to reduce the
circulating level of free fatty acids (FFAs) and inhibit their uptake
and utilization by myocardial cells. The theoretical evidence for this
beneficial effect is strong. However, in the clinical setting it would
be very difficult to separate out the relative importance of different
properties of glucose-insulin-potassium (GIK) therapy because these
effects occur simultaneously and are complementary. There
are several pointers indicating the importance of lowering FFAs. In our
meta-analysis,1 pooled data from trials
of high-dose intravenous GIK therapy, which is associated
with greater reduction of circulating FFAs, showed a greater reduction
in mortality after myocardial infarction than pooled results of all the
trials including those using low-dose therapy. Inadequate suppression
of FFAs by low-dose GIK therapy may be the reason behind the
disappointing results of the recent post–myocardial infarction Polish
GIK study.2 ß-Blockers reduce the rate of
sudden death during myocardial infarction. This action of ß-blockers
may be explained at least in part by their ability to reduce
circulating FFAs by blunting the action of sympathetic activity during
ischemia. Nicotinic acid analogues lower plasma
FFAs,3 and this action is associated with
reduction of extent of ST-segment depression at rest and during
exercise.4 Hearts perfused with fatty acids are
less able to recover after reperfusion than hearts perfused with
glucose.5 The clinical implications from these
points are that during ischemia, the FFA level needs to be
reduced quickly and adequately. For best results, FFA levels should be
reduced before reperfusion has occurred to improve the chance of
myocardial recovery after reperfusion and to prevent reperfusion
injury. When one uses Rackley's high-dose intravenous
regimen (infusion of 50 U of insulin and 80 mmol of potassium in 1
L of 30% glucose, administered at a rate of 
1.5 mL ·
kg-1 ·
h-1),6 adequate
suppression of circulating FFAs can be achieved within 30 minutes.
However, an initial bolus therapy followed by high-dose
intravenous infusion may lead to even quicker suppression
of FFAs. Finally, GIK therapy not only has a complementary role with
reperfusion strategies such as thrombolysis, but its
actions should also be enhanced by ß-blockers. Early use of these 3
agents together may therefore have the greatest impact in reducing
cardiac mortality after an acute myocardial infarction.
References
1.
Fath-Ordoubadi F, Beatt KJ. Glucose-insulin-potassium
therapy for treatment of acute myocardial infarction: an overview of
randomized placebo-controlled trials. Circulation. 1997;96:1152–1156.
2.
Ceremuzynski L, Budaj A, Czepiel A, Achremczyk P,
Smielak-Korombel W, Maciejewicz J. Low-dose polarizing mixture
(glucose-insulin-kalium) in acute myocardial infarction: Pol-GIK
multicenter trial. Circulation. 1997;96(suppl I):I-206.
Abstract.
3.
Russell DC, Oliver MF. Effect of antilipolytic therapy
on ST segment elevation during myocardial ischaemia in man. Br
Heart J.. 1978;40:117–123.[Free Full Text]
4.
Luxton MR, Miller NE, Oliver MF. Antilipolytic
treatment in angina pectoris. Br Heart J. 1976;38:1204–1208.[Abstract/Free Full Text]
5.
Coleman GM, Gradinac S, Taegtmeyer H, Sweeney M,
Frazier OH. Efficacy of metabolic support with
glucose-insulin-potassium for left ventricular pump failure
after aortocoronary bypass surgery. Circulation.
1989;80(suppl I):91–96.
6.
Rackley CE, Russell RO, Rogers WJ, Mantle JA,
McDaniel HG, Papapietro SE. Clinical experience with
glucose-insulin-potassium therapy in acute myocardial infarction.
Am Heart J. 1981;102:1038–1049.[Medline]
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