Prevention of Heart Failure in Rats by Trimetazidine Treatment: A Consequence of Accelerated Phospholipid Turnover?

Tabbi-Anneni, Imène; Héliès-Toussaint, Cécile; Morin, Didier; Bescond-Jacquet, Anne; Lucien, Arnaud; Grynberg, Alain

doi:10.1124/jpet.102.042143

Cited by 22 publications

(14 citation statements)

References 41 publications

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“…In patients with idiopathic dilated cardiomyopathy, PET studies, using palmitate and acetate tracers, show that trimetazidine decreases FAO and causes a compensatory increase in GO [25], consistent with our findings in RVH. Trimetazidine also prevents β-adrenergic receptor desensitization, elevation of brain natriuretic factor and cardiac hypertrophy in rats with left heart failure induced by aortic stenosis [26]. Guarnieri and Muscari reported the beneficial effect of trimetazidine in monocrotaline-induced RVH [13].…”

Section: Discussionmentioning

confidence: 99%

Therapeutic inhibition of fatty acid oxidation in right ventricular hypertrophy: exploiting Randle’s cycle

et al. 2011

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Right ventricular hypertrophy (RVH) and RV failure are major determinants of prognosis in pulmonary hypertension and congenital heart disease. In RVH, there is a metabolic shift from glucose oxidation (GO) to glycolysis. Directly increasing GO improves RV function, demonstrating the susceptibility of RVH to metabolic intervention. However, the effects of RVH on fatty acid oxidation (FAO), the main energy source in adult myocardium, are unknown. We hypothesized that partial inhibitors of FAO (pFOXi) would indirectly increase GO and improve RV function by exploiting the reciprocal relationship between FAO and GO (Randle’s cycle). RVH was induced in adult Sprague-Dawley rats by pulmonary artery banding (PAB). pFOXi were administered orally to prevent (trimetazidine, 0.7 g/L for 8 weeks) or regress (ranolazine 20 mg/day or trimetazidine for 1 week, beginning 3 weeks post-PAB) RVH. Metabolic, hemodynamic, molecular, electrophysiologic, and functional comparisons with sham rats were performed 4 or 8 weeks post-PAB. Metabolism was quantified in RV working hearts, using a dual-isotope technique, and in isolated RV myocytes, using a Seahorse Analyzer. PAB-induced RVH did not cause death but reduced cardiac output and treadmill walking distance and elevated plasma epinephrine levels. Increased RV FAO in PAB was accompanied by increased carnitine palmitoyl-transferase expression; conversely, GO and pyruvate dehydrogenase (PDH) activity were decreased. pFOXi decreased FAO and restored PDH activity and GO in PAB, thereby increasing ATP levels. pFOXi reduced the elevated RV glycogen levels in RVH. Trimetazidine and ranolazine increased cardiac output and exercise capacity and attenuated exertional lactic acidemia in PAB. RV monophasic action potential duration and QTc interval prolongation in RVH normalized with trimetazidine. pFOXi also decreased the mild RV fibrosis seen in PAB. Maladaptive increases in FAO reduce RV function in PAB-induced RVH. pFOXi inhibit FAO, which increases GO and enhances RV function. Trimetazidine and ranolazine have therapeutic potential in RVH.

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Section: Discussionmentioning

confidence: 99%

Therapeutic inhibition of fatty acid oxidation in right ventricular hypertrophy: exploiting Randle’s cycle

et al. 2011

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“…The reduction in triglyceride oxidation without a change in the cardiac lipid content suggests the diversion of FAs into a different cellular pool, in line with increased phospholipid synthesis in the myocardium [33]. Via this route, and other mechanisms mediated by the decline in FA oxidative metabolism, TMZ may consolidate mitochondrial stability and function [34,35]. The inhibition of FA oxidation induced by TMZ was accompanied by a compensatory enhancement in MGU, though this increment did not achieve statistical significance.…”

Section: Discussionmentioning

confidence: 99%

“…Taken together, our findings of a reduction in FAO and a small compensatory change in glucose utilization by the heart indicate a decrease in the global amount of substrate derivable energy, in accord with the evidence of creatine depletion. This energy sparing effect may result from the multiple TMZ effects on mitochondria [34,35].…”

Section: Discussionmentioning

confidence: 99%

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

Bucci

Borra

Någren

et al. 2011

Cardiovascular Therapeutics

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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.

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“…Rats were fed, ad libitum , a semipurified jellied diet in accordance with the American Institute of Nutrition (AIN) recommendations, 18 prepared to form a jellied mass cut into cubes, stored at −20°C and fed daily to maintain moisture content and food intake. For the insulin‐deficiency model, we prepared two diets, which differed in the presence or not of TMZ (310 mg/kg, to allow a 7.8 mg intake/rat per day) 19 . The standard diet was composed of starch (526.2 g/kg), sucrose (100 g/kg), cellulose (50 g/kg), soy protein isolate (140 g/kg; ICN 905456), l ‐cystine (1.8 g/kg), salt mixture (40 g/kg; ICN 960401), vitamin mixture (10 g/kg; ICN 960402), choline bitartrate (2 g/kg) and gelatin (50 g/kg).…”

Section: Methodsmentioning

confidence: 99%

Cardiac mitochondrial alterations induced by insulin deficiency and hyperinsulinaemia in rats: Targeting membrane homeostasis with trimetazidine

Ovide-Bordeaux

Bescond-Jacquet

Grynberg

2005

Clin Exp Pharma Physio

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The present study investigated the ability of trimetazidine (TMZ) to maintain cardiac mitochondrial function during the development of insulin deficiency and hyperinsulinaemia. The anti-ischaemic drug TMZ is known to increase phospholipid synthesis in cardiac membranes and to have a cardioprotective effect. Insulin deficiency was obtained by streptozotocin injection and hyperinsulinaemia was achieved via a fructose diet. Trimetazidine was incorporated into the diet (7.8 mg/day) and mitochondrial function was evaluated in skinned cardiac fibres. Insulin deficiency decreased mitochondrial affinity for ADP and the index of creatine kinase functional activity. This last alteration was partially prevented by TMZ treatment. Insulin deficiency strongly decreased n-3 polyunsaturated fatty acids, especially the docosahexaenoic acid (DHA) content, in cardiac and mitochondrial membranes, inducing a strong increase in the n-6/n-3 ratio. Trimetazidine treatment limited the increase in the n-6/n-3 ratio and prevented the decrease in DHA content in mitochondrial membranes. Insulin deficiency decreased glutamate- and palmitoylcarnitine-supported respiration. Hyperinsulinaemia affected neither mitochondrial affinity for ADP nor the index of creatine kinase functional activity. Hyperinsulinaemia slightly and significantly affected mitochondrial fatty acid composition, by a small increase the n-6/n-3 ratio. Trimetazidine did not modify membrane-bound mitochondrial function but increased the n-6/n-3 ratio. Moreover, hyperinsulinaemia decreased glutamate-supported respiration. In conclusion, modification of membrane homeostasis with TMZ partially prevented the alterations in fatty acid composition and function in cardiac mitochondria induced by insulin deficiency. Three months of hyperinsulinaemia did not modify membrane-bound mitochondrial function and had only slight effects on fatty acid composition.

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Prevention of Heart Failure in Rats by Trimetazidine Treatment: A Consequence of Accelerated Phospholipid Turnover?

Cited by 22 publications

References 41 publications

Therapeutic inhibition of fatty acid oxidation in right ventricular hypertrophy: exploiting Randle’s cycle

Therapeutic inhibition of fatty acid oxidation in right ventricular hypertrophy: exploiting Randle’s cycle

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

Cardiac mitochondrial alterations induced by insulin deficiency and hyperinsulinaemia in rats: Targeting membrane homeostasis with trimetazidine

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