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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]. O17 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 O18 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 O20 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 References [1] Neely JR, Morgan HE. Relationship between carbohydrate and lipid metabolism and the energy balance of heart muscle. Annu Rev Physiol 1974; 36: 413–59. [2] Lopaschuk GD, Belke DD, Gamble J et al. Regulation of fatty acid oxidation in the mammalian heart in health and disease. Biochim Biophys Acta 1994; 1213: 263–76. [3] Wisnesky JA, Stanley WC, Neese RA et al. Effects of acute hyperglycaemia on myocardial glycolytic activity in humans. J Clin Invest 1990; 85: 1648–56. [4] Lopaschuk GD, Stanley WC. Glucose metabolism in the ischaemic heart. Circulation 1997; 95: 313–5. [5] Liedtke AJ, DeMaison L, Eggelston AM et al. Changes in substrate metabolism and effects of excess fatty acids in reperfused myocardium. Circ Res 1988; 62: 535–42. [6] Lopaschuk GD, Spafford M, Davies NJ et al. Glucose and palmitate oxidation in isolated working rat hearts reperfused following a period of transient global ischaemia. Circ Res 1990; 66: 656–63. [7] Kantor PF, Lucien A, Kozak R, Lopaschuk GD. 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. Circ Res 2000; 86: 580–8. [8] Renaud JF. Internal pH, Na+ and Ca++ regulation by trimetazidine during cardiac cell acidosis. Cardiovasc Drugs Ther 1988; 1: 677–86. [9] Brottier L, Barat JL, Combe C, Boussens B, Bonnet J, Bricaud H. Therapeutic value of a cardioprotective agent in patients with severe ischaemic cardiomyopathy. Eur Heart J 1990; 11: 207–12. [10] Lu C, Dabrowsky P, Fragasso G, Chierchia S. Effects of trimetazidine on ischemic left ventricular dysfunction in patients with coronary artery disease. Am J Cardiol 1998; 82: 898–901. [11] Belardinelli R, Purcaro A. Effects of trimetazidine on the contractile response of chronically dysfunctional myocardium to lowdose dobutamine in ischaemic cardiomyopathy. Eur Heart J 2001 (in press).