title: Trimetazidine-induced enhancement of myocardial glucose utilization in normal and ischemic myocardial tissue: an evaluation by positron emission tomography.
abstract: 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.
authors.affiliation: West Los Angeles Veterans Administration Medical Center, Division of Cardiology W111E, California 90073, USA.
authors.forename: F V
authors.initials: FV
authors.lastname: Mody
authors.forename: B N
authors.initials: BN
authors.lastname: Singh
authors.forename: I H
authors.initials: IH
authors.lastname: Mohiuddin
authors.forename: K B
authors.initials: KB
authors.lastname: Coyle
authors.forename: D B
authors.initials: DB
authors.lastname: Buxton
authors.forename: H W
authors.initials: HW
authors.lastname: Hansen
authors.forename: R
authors.initials: R
authors.lastname: Sumida
authors.forename: H R
authors.initials: HR
authors.lastname: Schelbert
mesh_terms: D000818:Animals; D001783:Blood Flow Velocity / Q000187:drug effects; D003326:Coronary Circulation / Q000187:drug effects; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D006321:Heart / Q000000981:diagnostic imaging / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D019344:Lactic Acid / Q000378:metabolism; D017202:Myocardial Ischemia / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D010084:Oxidation-Reduction / Q000187:drug effects; D014055:Tomography, Emission-Computed; D014292:Trimetazidine / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D005230:Fatty Acids, Nonesterified; D014665:Vasodilator Agents; D019344:Lactic Acid; D005947:Glucose; D014292:Trimetazidine