Cardiovascular Drugs and Therapy

, Volume 22, Issue 1, pp 29–36 | Cite as

Trimetazidine Protective Effect Against Ischemia-Induced Susceptibility to Ventricular Fibrillation in Pigs

  • Fanny Vaillant
  • Panayota Tsibiribi
  • Giampiero Bricca
  • Bernard Bui-Xuan
  • Anne Bescond-JacquetEmail author
  • Alain Tabib
  • Jacques Descotes
  • Quadiri Timour



Ventricular fibrillation (VF) is a possible consequence of brief myocardial ischemia. Such a short ischemia does not provoke cell damage, but induces changes in intracellular cardiac metabolism due to diminished oxygen supply to the heart. Trimetazidine (TMZ) is a drug able to restore the metabolic balance between fatty acid and glucose oxidation in ischemic myocardial cells. The aim of this double-blind study was to investigate TMZ effect on VF in pigs during short-term ischemia.


Ischemia was induced after thoracotomy by complete, but brief (1 min) occlusion of the left anterior descending coronary artery under electrical stimulation. The ventricular fibrillation threshold (VFT), heart rate (HR), various hemodynamic parameters and malondialdehyde (MDA) blood levels were measured before and during ischemia in two groups of eight anesthetized pigs. The mass of ischemic myocardial tissue was also evaluated.


No effects on either the HR or the hemodynamic parameters were observed during myocardial ischemia, whereas TMZ increased the VFT and decreased both MDA blood levels (an index of lipid peroxidation) and the ischemic area.


TMZ limited ischemia-induced electrical dysfunction leading to cardiac susceptibility to VF by decreasing lipid peroxidation and maintaining ionic homeostasis. TMZ could therefore provide protection against ischemia-induced VF.

Key words

trimetazidine myocardial ischemia ventricular fibrillation pig 



This study was funded by the grant EA 1896 from Université Claude Bernard Lyon-I. The authors acknowledge the assistance of Brigitte Tourlière (librarian) for literature searches and Nicole Dizerens, Florence Arnal and Sylvianne Conti for technical assistance.


  1. 1.
    Janse MJ, Wit AL. Electrophysiological mechanisms of ventricular arrhythmias resulting from myocardial ischemia and infarction. Physiol Rev. 1989;69:1049–169.PubMedGoogle Scholar
  2. 2.
    Roelandt J, Klootwijk P, Lubsen J, Janse MJ. Sudden death during long-term ambulatory monitoring. Eur Heart J. 1984;5:7–20.PubMedGoogle Scholar
  3. 3.
    Cardiac Arrhythmia Suppression Trial (CAST) Investigators. Mortality and morbidity in patients receiving encainide, flecainide or placebo. N Engl J Med. 1991;324:781–8.CrossRefGoogle Scholar
  4. 4.
    Aupetit JF, Loufoua-Moundanga J, Faucon G, Timour Q. Ischaemia-induced loss or reversal of the effects of the class I antiarrhythmic drugs on vulnerability to fibrillation. Br J Pharmacol. 1997;120:523–9.PubMedCrossRefGoogle Scholar
  5. 5.
    Timour Q, Bui-Xuan B, Aupetit JF, Freysz M, Evreux JC, Faucon G. Calcium antagonists and prevention of ventricular fibrillation induced by transient or persistent ischemia. Jpn Heart J. 1997;38:237–51.PubMedGoogle Scholar
  6. 6.
    Pantos C, Bescond-Jacquet A, Tzeis S, Paizis I, Mourouzis I, Moraïtis P, et al. Trimetazidine protects isolated rat hearts against ischemia-reperfusion in an experimental timing-dependant manner. Basic Res Cardiol. 2005;100:154–60.PubMedCrossRefGoogle Scholar
  7. 7.
    Szwed H, Sadowski Z, Elikowski W, Koronkiewicz A, Mamcarz A, Orszulak W, et al. Combination treatment in stable effort angina using trimetazidine and metoprolol. Results of a randomised, double-blind, multicentre study (TRIMPOL II). Eur Heart J. 2001;22:2267–74.PubMedCrossRefGoogle Scholar
  8. 8.
    Sellier P, Broustet JP. Assessment of anti-ischemic and antianginal effect at trough plasma concentration and safety of trimetazidine MR 35 mg in patients with stable angina pectoris: a multicenter, double-blind, placebo-controlled study. Am J Cardiovasc Drugs. 2003;3:361–9.PubMedCrossRefGoogle Scholar
  9. 9.
    Marzilli M, Klein WW. Efficacy and tolerability of trimetazidine in stable angina: a meta-analysis of randomized, double-blind, controlled trials. Coron Artery Dis. 2003;14:171–9.PubMedCrossRefGoogle Scholar
  10. 10.
    Kantor PF, Lucien A, Kozak R, et al. 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;86:487–9.Google Scholar
  11. 11.
    Sentex E, Sergiel JP, Lucien A, Grynberg A. Trimetazidine increased phospholipid turnover in ventricular myocytes. Mol Cell Biochem. 1997;175:153–62.PubMedCrossRefGoogle Scholar
  12. 12.
    Lopaschuk GD, Barr R, Thomas PD, Dyck JR. Beneficial effects of trimetazidine in ex vivo working ischemic hearts are due to a stimulation of glucose oxidation secondary to inhibition of long-chain 3-ketoacyl coenzyme a thiolase. Circ Res. 2003;93:33–7.CrossRefGoogle Scholar
  13. 13.
    Guarnieri C, Muscari C. Effect of trimetazidine on mitochondrial function and oxidative damage during reperfusion of ischaemic hypertrophied rat myocardium. Pharmacology 1993;46:324–31.PubMedGoogle Scholar
  14. 14.
    Kara AF, Demiryurek S, Celik A, Tarakcioglu M, Demiryurek AT. Effects of trimetazidine on myocardial preconditioning in anesthetized rats. Eur J Pharmacol. 2004;503:135–45.PubMedCrossRefGoogle Scholar
  15. 15.
    Yagi K. A simple fluorimetric assay for lipoperoxides in blood plasma. Biochem Res. 1976;15:212–6.Google Scholar
  16. 16.
    Nachlas MM, Shnitka TK. Macroscopic identification of early myocardial infarcts by alteration in dehydrogenase activity. Am J Pathol. 1963;42:379–83.PubMedGoogle Scholar
  17. 17.
    Feola M, Biggi A, Francini A, et al. Trimetazidine improves myocardial perfusion and left ventricular function in ischemic left ventricular dysfunction. Clin Nucl Med. 2004;29:117–8.PubMedCrossRefGoogle Scholar
  18. 18.
    Dalla-Volta S, Maraglino G, Della-Valentina P, Viena P, Desideri A. Comparison of trimetazidine with nifedipine in effort angina. A double-blind, crossover study. Cardiovasc Drugs Ther. 1990;4:853–60.PubMedCrossRefGoogle Scholar
  19. 19.
    Detry JM, Sellier P, Pennaforte S, Cokkinos D, Dargie H, Mathes P. Trimetazidine: a new concept in the treatment of angina. Comparison with propranolol in patients with stable angina. Br J Clin Pharmacol. 1994;37:279–88.PubMedGoogle Scholar
  20. 20.
    Szwed H. Clinical benefits of trimetazidine in patients with recurrent angina. Coron Artery Dis. 15 2004;Suppl 1:S17–21.Google Scholar
  21. 21.
    Emre M, Karayaylali I, San M, Demirkazik A, Kavak S. The acute effect of trimetazidine on the high frequency fatigue in the isolated rat diaphragm muscle. Arch Pharm Res. 2004;27:646–52.PubMedGoogle Scholar
  22. 22.
    Lazzarino G, Tavazzi B, Di Pierro D, Vagnozzi R, Penco M, Giardina B. The relevance of malondialdehyde as a biochemical index of lipid peroxidation of postischemic tissues in the rat and human beings. Biol Trace Elem Res. 1995;47:165–70.PubMedCrossRefGoogle Scholar
  23. 23.
    Mateos R, Lecumberri E, Ramos S, Goya L, Bravo L. Determination of malondialdehyde (MDA) by high-performance liquid chromatography in serum and liver as a biomarker for oxidative stress. Application to a rat model for hypercholesterolemia and evaluation of the effect of diets rich in phenolic antioxidants from fruits. J Chromatogr B Analyt Technol Biomed Life Sci. 2005;827:76–82.PubMedCrossRefGoogle Scholar
  24. 24.
    Monteiro P, Duarte AI, Goncalves LM, Moreno A, Providencia LA. Protective effect of trimetazidine on myocardial mitochondrial function in an ex-vivo model of global myocardial ischemia. Eur J Pharmacol. 2004;503:123–8.PubMedCrossRefGoogle Scholar
  25. 25.
    Koning MMG, Krams R, Xiao CS, van Meegen JR, Bezstarosti K, Lamers JMJ, Verdouw PD. Intracoronary trimetazidine does not improve recovery of regional function in a porcine model of repeated ischemia. Cardiovasc Drugs Ther. 1993;7:801–7.PubMedCrossRefGoogle Scholar
  26. 26.
    Roberts MJ, Young IS, Trouton TG, Trimble ER, Khan MM, Webb SW, Wilson CM, Patterson GC, Adgey AA. Transient release of lipid peroxides after coronary artery balloon angioplasty. Lancet. 1990;336:143–5.PubMedCrossRefGoogle Scholar
  27. 27.
    Kioueh I, Mosnier M, Bui-Xuan B, Frassati D, Descotes J, Timour Q. [Deleterious cardiac effects of serotonin in myocardial ischemia: role of naftidrofuryl]. Ann Cardiol Angeiol (Paris). 2001;50:229–38.CrossRefGoogle Scholar
  28. 28.
    Tani M. Mechanisms of Ca2+ overload in reperfused ischemic myocardium. Annu Rev Physiol. 1990;52:543–59.PubMedGoogle Scholar
  29. 29.
    Gettes LS, Cascio WE, Johnson T, Fleet WF. Local myocardial biochemical and ionic alterations during myocardial ischaemia and reperfusion. Drugs. 1991;42:7–13.PubMedCrossRefGoogle Scholar
  30. 30.
    Clusin WT, Bristow MR, Karagueuzian HS, Katzung BG, Schroeder JS. Do calcium-dependent ionic currents mediate ischemic ventricular fibrillation? Am J Cardiol. 1982;49:606–12.PubMedCrossRefGoogle Scholar
  31. 31.
    Coetzee WA, Enous R, Opie LH. Trimetazidine: effects on delayed afterdepolarizations (DADs) and upstroke velocity of the action potential. Cardiovasc Drugs Ther. 1990;4:806–7.PubMedCrossRefGoogle Scholar
  32. 32.
    Kiyosue T, Nakamura S, Arita M. Effects of trimetazidine on action potentials and membrane currents of guinea-pig ventricular myocytes. J Mol Cell Cardiol. 1986;18:1301–11.PubMedCrossRefGoogle Scholar
  33. 33.
    Timour Q, Bui-Xuan B, Faucon G, Aupetit JF. Delay by a calcium antagonist, amlodipine, of the onset of primary ventricular fibrillation in myocardial ischemia. Cardiovasc Drugs Ther. 1996;10:447–54.PubMedCrossRefGoogle Scholar
  34. 34.
    Timour Q, Aupetit JF, Freysz M, Frassati D, Faucon G. Possible prevention by amlodipine of ventricular fibrillation related to brief ischemia episodes. Can J Physiol Pharmacol. 1996a;74:1308–14.PubMedCrossRefGoogle Scholar
  35. 35.
    Timour Q, Larbre JP, Kioueh I, Aupetit JF, Loufoua-Moundanga J, Vialle A, Faucon G. Calcium channel modulators and susceptibility to ischaemic ventricular fibrillation: modification of cellular calcium overload. Arch Int Pharmacodyn Ther. 1992;315:30–46.PubMedGoogle Scholar
  36. 36.
    El Banani H, Bernard M, Baetz D, et al. Changes in intracellular sodium and pH during ischaemia-reperfusion are attenuated by trimetazidine. Comparison between low- and zero-flow ischaemia. Cardiovasc Res. 2000;47:688–96.PubMedCrossRefGoogle Scholar
  37. 37.
    Van Emous JG, Nederhoff MG, Ruigrok TJ, Van Echteld CJ. The role of the Na+ channel in the accumulation of intracellular Na+ during myocardial ischemia: consequences for post-ischemic recovery. J Mol Cell Cardiol. 1997;29:85–96.PubMedCrossRefGoogle Scholar
  38. 38.
    Van Emous JG, Schreur JHM, Ruigrok TJ, Van Echteld CJ. Both Na+-K+ ATPase and Na+-H+ exchange are immediately active upon post-ischaemic reperfusion in isolated rat hearts. J Mol Cell Cardiol. 1998;30:337–48.PubMedCrossRefGoogle Scholar
  39. 39.
    Renaud JF. Internal pH, Na+, and Ca2+ regulation by trimetazidine during cardiac cell acidosis. Cardiovasc Drugs Ther. 1988;1:677–86.PubMedCrossRefGoogle Scholar
  40. 40.
    Lee L, Horowitz J, Frenneaux M. Metabolic manipulation in ischaemic heart disease, a novel approach to treatment. Eur Heart J. 2004;25:634–41.PubMedCrossRefGoogle Scholar
  41. 41.
    Belardinelli L, Antzelevitch C, Fraser H. Inhibition of late (sustained/persistent) sodium current: a potential target to reduce intracellular sodium-dependent calcium overload and its detrimental effects on cardiomyocyte function. Eur Heart J. 2004;6:3–7.CrossRefGoogle Scholar
  42. 42.
    Stanley WC. Myocardial energy metabolism during ischemia and the mechanisms of metabolic therapies. J Cardiovasc Pharmacol Ther. 2004;9:S31–45.PubMedCrossRefGoogle Scholar
  43. 43.
    Kudo N, Barr AJ, Barr RL, Desai S, Lopaschuk GD. High rates of fatty acid oxidation during reperfusion of ischemic hearts are associated with a decrease in malonyl-CoA levels due to an increase in 5′-AMP-activated protein kinase inhibition of acetyl-CoA carboxylase. J Biol Chem. 1995;270:17513–20.PubMedCrossRefGoogle Scholar
  44. 44.
    Wolff AA, Rotmensch HH, Stanley WC, et al. Metabolic approaches to the treatment of ischemic heart disease: the clinicians′ perspective. Heart Fail Rev. 2002;7:187–203.PubMedCrossRefGoogle Scholar
  45. 45.
    Argaud L, Ovize M. Myocardial metabolism abnormalities during ischemia and reperfusion. Arch Mal Coeur Vaiss. 2000;93:87–90.PubMedGoogle Scholar
  46. 46.
    MacInnes A, Fairman DA, Binding P, Rhodes J, Wyatt MJ, Phelan A, Haddock PS, Karran EH. The antianginal agent trimetazidine does not exert its functional benefit via inhibition of mitochondrial long-chain 3-ketoacyl coenzyme A thiolase. Circ Res. 2003;93:26–32.CrossRefGoogle Scholar
  47. 47.
    Lopaschuk GD, Belke DD, Gamble J, Itoi I, Schönekess BO. Regulation of fatty acid oxidation in the mammalian heart in health and disease. Biochim Biophys Acta. 1994;1213:263–76.PubMedGoogle Scholar
  48. 48.
    Stanley WC, Lopaschuk GD, Hall JL, McCormack JG. Regulation of myocardial carbohydrate metabolism under normal and ischemic conditions: potential for pharmacological interventions. Cardiovasc Res. 1997;33:243–57.PubMedCrossRefGoogle Scholar
  49. 49.
    Liu B, Clanachan AS, Schulz R, Lopaschuk GD. Cardiac efficiency is improved after ischemia by altering both the source and fate of protons. Circ Res. 1996;79:940–8.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Fanny Vaillant
    • 1
  • Panayota Tsibiribi
    • 1
  • Giampiero Bricca
    • 1
  • Bernard Bui-Xuan
    • 1
  • Anne Bescond-Jacquet
    • 2
    Email author
  • Alain Tabib
    • 3
  • Jacques Descotes
    • 4
  • Quadiri Timour
    • 1
    • 4
  1. 1.Laboratoire de Pharmacologie Médicale, Faculté de Médecine Grange-BlancheINSERM ERI 22, Université Claude Bernard Lyon-ILyon cedex 08France
  2. 2.Institut de Recherches Internationales ServierCourbevoie cedexFrance
  3. 3.Hôpital Cardiologique, Service d’Anatomie et de Cytologie pathologiquesBronFrance
  4. 4.Centre Antipoison-Centre de PharmacovigilanceLyon cedex 03France

Personalised recommendations