Effects of metabolic modulation by trimetazidine on left ventricular function and phosphocreatine/adenosine triphosphate ratio in patients with heart failure.
AIMS: The addition of trimetazidine to standard treatment has been shown to improve left ventricular (LV) function in patients with heart failure. The aim of this study is to non-invasively assess, by means of in vivo 31P-magnetic resonance spectroscopy (31P-MRS), the effects of trimetazidine on LV cardiac phosphocreatine and adenosine triphosphate (PCr/ATP) ratio in patients with heart failure. METHODS AND RESULTS: Twelve heart failure patients were randomized in a double-blind, cross-over study to placebo or trimetazidine (20 mg t.i.d.) for two periods of 90 days. At the end of each period, all patients underwent exercise testing, 2D echocardiography, and MRS. New York Heart Association (NYHA) class, ejection fraction (EF), maximal rate-pressure product, and metabolic equivalent system (METS) were evaluated. Relative concentrations of PCr and ATP were determined by cardiac 31P-MRS. On trimetazidine, NYHA class decreased from 3.04+/-0.26 to 2.45+/-0.52 (P = 0.005), whereas EF (34+/-10 vs. 39+/-10%, P = 0.03) and METS (from 7.44+/-1.84 to 8.78+/-2.72, P = 0.03) increased. The mean cardiac PCr/ATP ratio was 1.35+/-0.33 with placebo, but was increased by 33% to 1.80+/-0.50 (P = 0.03) with trimetazidine. CONCLUSION: Trimetazidine improves functional class and LV function in patients with heart failure. These effects are associated to the observed trimetazidine-induced increase in the PCr/ATP ratio, indicating preservation of the myocardial high-energy phosphate levels.
Eur Heart J. 2006 Apr;27(8):942-8
Modulation of fatty acids oxidation in heart failure by selective pharmacological inhibition of 3-ketoacyl coenzyme-A thiolase.
A direct approach to manipulate cardiac energy metabolism consists in modifying substrate utilization by the heart. Pharmacological agents that directly inhibit fatty acid oxidation include inhibitors of 3-ketoacyl coenzyme A thiolase (3-KAT), the last enzyme involved in ss-oxidation. The most extensively investigated agents of this group of drugs are trimetazidine and ranolazine. Clinical studies have shown that these agents can substantially increase the ischemic threshold in patients with effort angina. However, the results of current research is also supporting the concept that shifting the energy substrate preference away from fatty acid metabolism and toward glucose metabolism by 3-KAT inhibitors could be an effective adjunctive treatment in patients with heart failure, in terms of left ventricular function and glucose metabolism improvement. In fact, these agents have also been shown to improve overall glucose metabolism in diabetic patients with left ventricular dysfunction. In this paper, the recent literature on the beneficial effects of this new class of drugs on left ventricular dysfunction and glucose metabolism is reviewed and discussed.
Curr Clin Pharmacol. 2007 Sep;2(3):190-6
The effects of chronic trimetazidine treatment on mechanical function and fatty acid oxidation in diabetic rat hearts.
Clinical and experimental evidence suggest that increased rates of fatty acid oxidation in the myocardium result in impaired contractile function in both normal and diabetic hearts. Glucose utilization is decreased in type 1 diabetes, and fatty acid oxidation dominates for energy production at the expense of an increase in oxygen requirement. The objective of this study was to examine the effect of chronic treatment with trimetazidine (TMZ) on cardiac mechanical function and fatty acid oxidation in streptozocin (STZ)-diabetic rats. Spontaneously beating hearts from male Sprague-Dawley rats were subjected to a 60-minute aerobic perfusion period with a recirculating Krebs-Henseleit solution containing 11 mmol/L glucose, 100 muU/mL insulin, and 0.8 mmol/L palmitate prebound to 3% bovine serum albumin (BSA). Mechanical function of the hearts, as cardiac output x heart rate (in (mL/min).(beats/min).10-2), was deteriorated in diabetic (73 +/- 4) and TMZ-treated diabetic (61 +/- 7) groups compared with control (119 +/- 3) and TMZ-treated controls (131 +/- 6). TMZ treatment increased coronary flow in TMZ-treated control (23 +/- 1 mL/min) hearts compared with untreated controls (18 +/- 1 mL/min). The mRNA expression of 3-ketoacyl-CoA thiolase (3-KAT) was increased in diabetic hearts. The inhibitory effect of TMZ on fatty acid oxidation was not detected at 0.8 mmol/L palmitate in the perfusate. Addition of 1 mumol/L TMZ 30 min into the perfusion did not affect fatty acid oxidation rates, cardiac work, or coronary flow. Our results suggest that higher expression of 3-KAT in diabetic rats might require increased concentrations of TMZ for the inhibitory effect on fatty acid oxidation. A detailed kinetic analysis of 3-KAT using different concentrations of fatty acid will determine the fatty acid inhibitory concentration of TMZ in diabetic state where plasma fatty acid levels are increased.
Can J Physiol Pharmacol. 2007 May;85(5):527-35
Trimetazidine revisited: a comprehensive review of the pharmacological effects and analytical techniques for the determination of trimetazidine.
Trimetazidine (TMZ) is an effective and well-tolerated antianginal drug that possesses protective properties against ischemia-induced heart injury. Growing interest in metabolic modulation in recent years urged an up-to-date review of the literature on TMZ. This review consists of two major sections: (1) comprehensive and critical information about the pharmacological effects, mechanism of action, pharmacokinetics, side effects, and current usage of TMZ, and (2) developments in analytical techniques for the determination of the drug in raw material, pharmaceutical dosage forms, and biological samples.
Cardiovasc Ther. 2008 Summer;26(2):147-65
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.
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.
Circ Res. 2000 Mar 17;86(5):580-8
Trimetazidine-induced enhancement of myocardial glucose utilization in normal and ischemic myocardial tissue: an evaluation by positron emission tomography.
Trimetazidine has an anti-ischemic effect in angina pectoris. This agent has no hemodynamic effects, and its benefit is presumed to be based on a metabolic mechanism of action. A group of 33 dogs undergoing openchest left anterior descending coronary artery (LAD) ligation causing prolonged ischemia were imaged with quantitative positron emission tomography (PET) using 2-[18F]fluoro-2-deoxy-D-glucose (18FDG) to measure regional glucose metabolic utilization (rGMU) and [11C]acetate to measure regional monoexponential washout rate constant (Kmono) for oxidative metabolism in nonrisk and ischemic-risk myocardium. A total of 20 dogs were pretreated with trimetazidine at low dose (n = 10, 1 mg/kg) and high dose (n = 10, 5 mg/kg) and compared with 13 control dogs. Microsphere-measured myocardial blood flow (mL/min/g) was measured preocclusion and repeated hourly after occlusion and expressed as a ratio of preocclusion myocardial blood flow to verify a stable level of ischemia during PET. No differences were seen in postocclusion ischemic risk/nonrisk myocardial blood flow between treatment groups (p = not significant [NS]). Preocclusion and hourly measurements of heart rate and blood pressure corrected for baseline revealed no difference in control dogs versus trimetazidine (low-dose and high-dose) groups (p = NS). 18FDG-derived rGMU (micromol/min/g) was increased in high-dose trimetazidine versus control dogs in nonrisk and ischemic risk groups, respectively (1.16+/-0.57 vs 0.51+/-0.38 and 0.43+/-0.29 vs 0.20+/-0.14; p <0.05). rGMU was increased proportionately in nonrisk and ischemic risk in all groups without significant differences when corrected for nonrisk rGMU (ischemic risk/nonrisk was 0.92+/-1.3 vs 0.64+/-0.66 vs 0.40+/-0.22 for control dogs, all trimetazidine and high-dose trimetazidine groups). Kmono (min(-1) was not altered in any group (nonrisk = 0.13+/-0.03 vs 0.13+/-0.03 vs 0.14+/-0.02 and ischemic risk = 0.18+/-0.05 vs 0.17+/-0.06 vs 0.16+/-0.06 for control dogs, all trimetazidine and high-dose trimetazidine groups, respectively; p = NS for nonrisk vs ischemic risk, between and within groups). Our data verify that trimetazidine does not alter hemodynamic porameters. It increases total glucose utilization (oxidative and glycolytic) in myocardium without preferential increase in ischemic tissue. Absence of change in total oxidative metabolism suggests increased glucose metabolism is predominantly glycolysis or an increase in glucose oxidation with similar decrease in fatty acid oxidation.
Am J Cardiol. 1998 Sep 3;82(5A):42K-49K
Improvement of long-term preservation of the isolated arrested rat heart by trimetazidine: effects on the energy state and mitochondrial function.
Rat hearts, arrested in situ after intracaval injection of a cardioplegic solution, were preserved for 15 hours at 4 degrees C either by simple immersion or by low-flow (0.3 mL/min) perfusion. After preservation under both conditions, the left ventricular pressure developed by the reperfused hearts reached 8% and 43% of the control value (80 mm Hg), respectively. The addition of trimetazidine (TMZ; 10(-6) M) to the cardioplegic solution induced an improvement in functional recovery (by 2.4 and 1.5, respectively). This effect of TMZ was accompanied by a better energy profile illustrated by a 2-fold increase in the adenosine triphosphate to inorganic phosphate ratio and a reduction of intracellular acidosis as determined by 31P nuclear magnetic resonance spectroscopy. The function of the mitochondria (state 3, reduced nicotinamide-adenine dinucleotide [NADH] formation) isolated from the preserved hearts was significantly depressed in the stored hearts. The addition of TMZ to the cardioplegic solution partially protected oxoglutarate (and succinate) mitochondrial respiration and induced an increase in Ca2+ triggered NADH formation. These results show that the bioenergy status of the myocardial cell in isolated arrested stored rat heart is improved by the presence of TMZ in the preservation solution. Moreover, the experiments demonstrate that this effect includes protection of mitochondrial function and suggest that the drug could exert some control in the Ca2+ regulation of mitochondria.
Am J Cardiol. 1995 Aug 24;76(6):45B-49B
Effects of trimetazidine on metabolic and functional recovery of postischemic rat hearts.
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.
Cardiovasc Drugs Ther. 1998 Dec;12(6):543-9
Effects of trimetazidine on ischemic contracture in isolated perfused rat hearts.
Trimetazidine (1-[2,3,4-trime-thoxibenzyl)]-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.
J Cardiovasc Pharmacol. 1994 Jul;24(1):45-9
Effects of trimetazidine administration before thrombolysis in patients with anterior myocardial infarction: short-term and long-term results.
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.
Cardiovasc Drugs Ther. 1999 Sep;13(5):423-8
Effects of chronic trimetazidine treatment on myocardial preconditioning in anesthetized rats.
Trimetazidine is a widely used anti-ischemic agent, but effects of its chronic treatment on myocardial preconditioning in anesthetized animals have not been investigated. The aim of this study was to examine the effects of 15-day treatment of trimetazidine on ischemic preconditioning and carbachol-induced preconditioning in anesthetized rats. Ischemic preconditioning, induced by 5 min of coronary artery occlusion and 5 min of reperfusion, significantly decreased the total number of ventricular ectopic beats, the incidence of ventricular tachycardia and abolished the occurrence of ventricular fibrillation (VF) during 30 min of ischemia. Trimetazidine (10 mg/kg/day, i.p. for 15 days and 10 mg/kg, i.v.) itself attenuated these arrhythmia parameters with no marked effect on hemodynamic effects. In the presence of trimetazidine, anti-arrhythmic effects of ischemic preconditioning were present. Carbachol infusion induced preconditioning with a marked depression of mean arterial blood pressure, heart rate and the total number of ventricular ectopic beats. No VF was observed in carbachol-induced preconditioning. The marked reductions in arrhythmia parameters that induced carbachol-induced preconditioning were also preserved in the presence of trimetazidine. Arrhythmia scores and myocardial infarct size were reduced significantly with ischemic preconditioning or carbachol-induced preconditioning and were not modified by trimetazidine. Lactate and malondialdehyde levels were suppressed significantly with preconditioning or trimetazidine + preconditioning groups. These results show that chronic treatment of trimetazidine protects the heart against ischemia-induced arrhythmias, reduces myocardial infarct size, plasma lactate and malondialdehyde levels, and preserves the effects of ischemic and pharmacological preconditioning in anesthetized rats.
Fundam Clin Pharmacol. 2006 Oct;20(5):449-59
Effects of trimetazidine on myocardial preconditioning in anesthetized rats.
Trimetazidine is a widely used anti-ischemic agent, but its effect on myocardial preconditioning in anesthetized animals has not been investigated. The aim of this study was to examine the effects of trimetazidine on ischemic preconditioning and carbachol preconditioning in anesthetized rats. Ischemic preconditioning, induced by 5-min coronary artery occlusion and 5-min reperfusion, decreased the incidence of ventricular tachycardia and abolished the occurrence of ventricular fibrillation during 30-min ischemia. Trimetazidine (10 mg/kg, i.v.) alone attenuated these parameters of arrhythmia. Carbachol infusion induced preconditioning with a marked depression of mean arterial blood pressure, heart rate and ventricular tachycardia. The marked reductions in parameters of arrhythmia induced by ischemic preconditioning and carbachol preconditioning were preserved in the presence of trimetazidine. Arrhythmia scores and myocardial infarct size were significantly reduced with ischemic preconditioning or carbachol preconditioning and were not inhibited by trimetazidine. These results show that trimetazidine protects the heart against ischemia-induced arrhythmias, reduces myocardial infarct size, preserves the effects of ischemic preconditioning and pharmacological preconditioning, and is able to mimic ischemic preconditioning in anesthetized rats.
Eur J Pharmacol. 2004 Oct 25;503(1-3):135-45
Effects of trimetazidine on in vivo coronary arterial platelet thrombosis.
We used Folts’ model of critical coronary artery stenosis with endothelial damage, which measures platelet-rich thrombus accumulation from cyclic flow reductions (CFRs). This paper reports results applied to trimetazidine, a member of the piperazine group. Trimetazidine at a dose of 1 mg/kg completely abolished CFRs caused by accumulating thrombus in the circumflex coronary artery in 4 of 8 open-chest anesthetized beagles. More trimetazidine (up to 5 mg/kg) abolished CFRs in two more and attenuated them in the remaining two dogs. There were no systemic hemodynamic effects observed. Adrenaline was then infused to stimulate platelet activation. At a rate of 0.4 microgram/kg/min, CFRs were restored in one dog only. Adrenaline given at 1.6 micrograms/kg/min resulted in restoration or increase in the slope of CFRs in all animals. A further six nonoperated dogs were anesthetized and given trimetazidine 3 mg/kg. Routine coagulation studies were not altered. However, aspirin 5 mg/kg significantly increased bleeding time, whereas trimetazidine alone did not. These findings suggest that trimetazidine is effective in preventing intracoronary platelet aggregation in this model. Because of its demonstrated sparing of coagulation factors and its lack of effect on bleeding time, the cause is unlikely to be inhibition of the fibrinogen or thrombin receptors, or interference with arachidonic acid metabolism.
Cardiovasc Drugs Ther. 1993 Feb;7(1):149-57
Chronic treatment with trimetazidine reduces the upregulation of atrial natriuretic peptide in heart failure.
Trimetazidine (TMZ) is effective for the treatment of ischemic cardiomyopathy; however, little is known about the effect of TMZ in established injury-induced heart failure. When rats with established infarct-induced heart failure were treated for 12 weeks with TMZ there was no effect on left ventricular function or dilation, or on mRNA expression of fatty acid oxidation enzymes. On the other hand, TMZ significantly reduced atrial natriuretic peptide mRNA levels compared with untreated rats.
Fundam Clin Pharmacol. 2006 Oct;20(5):503-5