Trimetazidine Reduces Endogenous Free Fatty Acid Oxidation and Improves Myocardial Efficiency in Obese Humans

Abstract

SUMMARY Introduction:The metabolic modulator trimetazidine (TMZ) has been suggested to induce a metabolic shift from myocardial fatty acid oxidation (FAO) to glucose utilization, but this mechanism remains unproven in humans. The oxidation of plasma derived FA is commonly measured in humans, whereas the contribution of FA from triglycerides stored in the myocardium has been poorly characterized. Aims: To verify the hypothesis that TMZ induces a metabolic shift, we combined positron emission tomography (PET) and magnetic resonance spectroscopy ( 1 H-MRS) to measure myocardial FAO from plasma and intracellular lipids, and myocardial glucose metabolism. Nine obese subjects were studied before and after 1 month of TMZ treatment. Myocardial glucose and FA metabolism were assessed by PET with 18 F-fluorodeoxyglucose and 11 C-palmitate. 1 H-MRS was used to measure myocardial lipids, the latter being integrated into the PET data analysis to quantify myocardial triglyceride turnover. Results: Myocardial FAO derived from intracellular lipids was at least equal to that of plasma FAs (P = NS). BMI and cardiac work were positively associated with the oxidation of plasma derived FA (P ≤ 0.01). TMZ halved total and triglyceride-derived myocardial FAO (32.7 ± 8.0 to 19.6 ± 4.0 μmol/min and 23.7 ± 7.5 to 10.3 ± 2.7 μmol/min, respectively; P ≤ 0.05). These changes were accompanied by increased cardiac efficiency since unchanged LV work (1.6 ± 0.2 to 1.6 ± 0.1 Watt/g × 10 2 , NS) was associated with decreased work energy from the intramyocardial triglyceride oxidation (1.6 ± 0.5 to 0.4 ± 0.1 Watt/g × 10 2 , P = 0.036). Conclusions: In obese subjects, we demonstrate that myocardial intracellular triglyceride oxidation significantly provides FA-derived energy for mechanical work. TMZ reduced the oxidation of triglyceride-derived myocardial FAs improving myocardial efficiency.

Treatment with the 3-Ketoacyl-CoA Thiolase Inhibitor Trimetazidine Does Not Exacerbate Whole-Body Insulin Resistance in Obese Mice

“…These results are consistent with findings from Tuunanen et al (2008), whereby treatment of idiopathic dilated cardiomyopathy patients with trimetazidine caused a modest 10% decrease in myocardial fatty acid oxidation rates but a significant improvement in LV function. These authors also showed that trimetazidine inhibits endogenous TAG-derived fatty acid oxidation, consistent with the trend to increased gastrocnemius TAG content that we observed in HFD-induced obese mice treated with trimetazidine (Bucci et al, 2011). Therefore, it appears that the antianginal agent trimetazidine elicits cardioprotection in the setting of obesity without adversely affecting muscle insulin sensitivity, though a more prolonged treatment may yield different results.…”

Effects of trimetazidine on the Akt/eNOS signaling pathway and oxidative stress in anin vivorat model of renal ischemia-reperfusion

“…12,13,25 It is recognized that TMZ has antioxidant effects and its role in lipid peroxidation inhibition has been well established in different organs. [26][27][28] Hauet et al 11 demonstrated, in isolated perfused pig kidneys, that addition of TMZ to the EuroCollins (EC) storage solution reduces lipid peroxidation and improves renal tubular function compared to EC solution alone. Sulikowski et al 12 demonstrated that the pretreatment of animals with TMZ markedly attenuated renal dysfunction, morphological alterations and restored the depleted renal antioxidant enzymes.…”

Trimetazidine Pretreatment Inhibits Myocardial Apoptosis and Improves Cardiac Function in a Swine Model of Coronary Microembolization

“…TMZ is a clinically effective anti-ischemic agent that shifts myocardial metabolism from fatty acid oxidation to more oxygen-efficient glucose oxidation pathways, thus reducing ischemia without any hemodynamic effects [22,23]. The beneficial effects of TMZ on mortality, hospitalization and left ventricular function in ischemic heart disease have been confirmed by clinical [24,25] and animal studies [13,14]; however, the underlying molecular mechanisms of cardioprotective effects of TMZ remain to be elucidated.…”