Trimetazidine in AMI.

I read with interest the paper by the EMIP-FR Group published in issue 18, Vol. 21, of the European Heart Journal, as well as the accompanying editorial by Dr Giani Tognoni. The paper by the EMIP-PR Group investigated whether 48 h i.v. use of trimetazidine alters the shortand long-term outcome of patients with an acute myocardial infarction. The results of this large prospective multicentred trial demonstrate that trimetazidine reduces mortality in nonthrombolyzed patients, but not in the thrombolyzed patients. This study was criticized in the Tognoni editorial due, in part, to a rationalization that the supposed free radical antagonizing effects of trimetazidine are not consistent with a lack of benefit of trimetazidine in the thrombolyzed group. Presumably inhibition of free radical production should be most beneficial under conditions of reperfusion (i.e. thrombolysis) where free radical production is greatest (i.e. reperfusion injury). It is clear that Dr Tognoni is not a strong proponent of the concept of ‘reperfusion injury’ and points out the disappointing clinical experience with free radical modification in the setting of reperfusion following an acute myocardial infarction. While I do not disagree with Dr Tognoni on this point, I would like to point out that it is unlikely that the mechanism of action of trimetazidine is related to an inhibition of free radical production. Trimetazidine is an effective antiischaemic agent which acts independent of haemodynamic effects (see for review). Until recently, the mechanism of action of trimetazidine was not understood, although it was clear it had direct cytoprotective effects on the heart. While early studies suggested that trimetazidine may protect the heart against free radical-induced membrane damage, it is unlikely that this can explain the antiischaemic properties of trimetazidine at clinically relevant concentrations. Recent studies have demonstrated that the beneficial effects of trimetazidine can be explained by an optimization of energy metabolism in the heart. We have shown that trimetazidine acts by inhibition of myocardial fatty acid oxidation, secondary to inhibition of long chain 3-ketoacyl CoA thiolase. This results in an increase in glucose oxidation, resulting in an improved coupling between glycolysis and glucose oxidation. This decreases proton production from uncoupled glucose metabolism, resulting in a decrease in intracellular acidosis, and a decrease in intracellular Na+ accumulation. These effects of trimetazidine on myocardial energy metabolism have the potential to markedly improve cardiac efficiency both during the following ischaemia (see for review). The EMIP-FR group originally began their clinical study, which examined the effects of trimetazidine on the outcome of patients with acute myocardial infarction, assuming that trimetazidine acts by inhibiting free radical production. Indeed, the acronym ‘EMIP-FR’ stands for ‘European Myocardial Infarction Project-Free Radicals’. Unfortunately, the EMIPFR Group paper does not cite recent studies demonstrating that trimetazidine is unlikely to act as an inhibitor of free radical production, but rather acts as a ‘metabolic modulator’ that optimizes energy metabolism in the heart. I believe this omission led Dr Tognoni to assume in his editorial that the lack of benefit of trimetazidine in thrombolyzed patients was inconsistent with trimetazidine acting as an inhibitor of free radical production. The benefits observed with trimetazidine in non-thrombolyzed AMI patients is consistent with the actions of trimetazidine acting as a ‘metabolic modulator’. Previous studies in AMI patients have shown that metabolic therapy with glucose-insulinpotassium (GIK) can benefit patients in the absence of thrombolysis (see for review of clinical trials). Furthermore, the mechanism of action of trimetazidine is consistent with trimetazidine having a beneficial effect on jeoparidized ischaemic myocardium in the absence of reperfusion. While Dr Tognoni also points out other deficiencies in the EMIP-FR Group study related to subanalysis procedures, I do not agree with Dr Tognoni that the results of the EMIP-FR study demonstrate the lack of biological relevance of free radical scavenging approach to treating AMI. Since trimetazidine does not act as an inhibitor of free radical production, this question is still unresolved. However, the promising results showing trimetazidine decreases mortality in non-thrombolyzed AMI patients, combined with recent success of ‘metabolic modulation’ using GIK in AMI patients, suggests that the concept of optimizing energy metabolism in the heart warrants further investigation as a clinical approach to treating patients with AMI.