Background: Trimetazidine improves functional class and left ventricular function in patients with heart failure; however, its potential impact on QTc interval remains undefined. We analyzed the effects of trimetazidine on QTc interval in patients with ischemic heart failure. Methods: A prospective trial included 42 patients with ischemic heart failure (New York Heart Association [NYHA] 2 or 3) and reduced left ventricular ejection fraction (<55%), who were randomly allocated to conventional therapy plus trimetazidine in a modulated release formulation (35 mg twice daily; 22 patients) or conventional therapy alone (20 patients; controls). We measured QTc interval at baseline and after 1 month. Results: At baseline, QTc interval duration was similar in both groups (443 ± 41 milliseconds in trimetazidine group vs 446 ± 27 milliseconds in controls, P = .62). After 1 month, QTc interval decreased in the trimetazidine group (404 ± 36 milliseconds, P = .0002) but not in controls (452 ± 25 milliseconds, P = .74). QTc interval shortening with trimetazidine was more pronounced in patients with prolonged (>440 milliseconds) baseline QTc interval (—45 ± 38 milliseconds) than in patients with normal QTc interval (—19 ± 19 milliseconds P = .04). Significant QTc interval shortening (>20 milliseconds) was present in 14 of 22 patients (64%) in trimetazidine group compared to 3 of 20 (15%) patients in control group (P = .002). Conclusions: Trimetazidine therapy is associated with QTc interval shortening in patients with ischemic heart failure.
Kantor PF, Lucien A., Kozak R., Lopaschuk GDThe 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(5):580-588.
Timour Q., Harpney C., Francoise D., Faucon C.Is the antianginal action of trimetazidine independent of hemodynamic changes . Cardiovasc Drugs Ther. 1991;5(6):1043-1044.
4.
Fragasso G., Palloshi A., Puccetti P., et al. A randomized clinical trial of trimetazidine, a partial free fatty acid oxidation inhibitor, in patients with heart failure. J Am Coll Cardiol.2006;48(5):992-998.
5.
Metra M., Ponikowski P., Dickstein K., et al. Heart Failure Association of the European Society of Cardiology. Advanced chronic heart failure. A position statement from the Study Group on Advanced Heart Failure of the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail. 2007 ; 9(6-7):684-694.
6.
Bertomeu-Gonzalez V., Bouzas-Mosquera A., Kaski JCRole of trimetazidine in management of ischemic cardiomyopathy. Am J Cardiol.2006;98(5A):19J-24J.
7.
Boccalandro F., Velaso A., Thomas C., Richards B., Radovancevic B.Relations among heart failure severity, left ventricular loading conditions, repolarization length in advanced heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Am J Cardiol.2003;92(5):544-547.
8.
Vrtovec B., Delgado R., Zewail A., Thomas CD, Richartz BM, Radovancevic B.Prolonged QTc interval and high B-type natriuretic peptide levels together predict mortality in patients with advanced heart failure. Circulation. 2003;107(13): 1764-1769.
Elming H., Brendorp B., Kober L., Sahebzadah N., Torp-Petersen C.QTc interval in the assessment of cardiac risk. Card Electrophysiol Rev. 2002;6(3):289-294.
11.
Peters RW, Byington RP, Barker A., Yusuf S.Prognostic value of prolonged ventricular repolarization following myocardial infarction: the BHAT experience. The BHAT Study Group. J Clin Epidemiol. 1990;43(2):167-172.
12.
Rossing P., Breum L., Major-Pedersen A., et al. Prolonged QTc interval predicts mortality in patients with type 1 diabetes mellitus. Diabet Med. 2001;18(3):199-205.
13.
Straus SM, Kors JA, De Bruin ML, et al. Prolonged QTc interval and risk of sudden cardiac death in a population of older adults. J Am Coll Cardiol. 2006;47(2):362-367.
14.
Schouten EG, Dekker JM, Meppelink P., Kok FJ, Vandenbroucke JP, Pool J.QT interval prolongation predicts cardiovascular mortality in an apparently healthy population. Circulation. 1991;84(4):1516-1523.
15.
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(12):1301-1311.
16.
Hunt SA, Abraham WT, Chin MH, et al. ACC/AHA 2005 guideline update for the diagnosis and management of chronic heart failure in the adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure). J Am Coll Cardiol.2005 ;46(6):1-82. Erratum in: J Am Coll Cardiol.2006;47(7):1503-1505.
17.
Swedberg K. , Cleland J., Dargie H., et al. Guidelines for the diagnosis and treatment of chronic heart failure: executive summary (update 2005): The Task Force for the Diagnosis and Treatment of Chronic Heart Failure of the European Society of Cardiology. Eur Heart J. 2005;26(11):1115-1140.
18.
Yan GX, Antzelevitch C.Cellular basis for the normal T wave and the electrocardiographic manifestations of the long-QT syndrome. Circulation. 1998 ;98(18):1928-1936.
19.
Antzelevitch C., Shimizu W.Cellular mechanisms underlying the long QT syndrome. Curr Opin Cardiol. 2002;17(1):43-51.
20.
Kjaer A., Hesse B.Heart failure and neuroendocrine activation: diagnostic, prognostic and therapeutic perspectives. Clin Physiol. 2001;21(6):661-672.
21.
Berton G., Cordiano R., Palmieri R., Pianca S., Pagliara V., Palatini P.C-reactive protein in acute myocardial infarction: association with heart failure. Am Heart J. 2003;145(6):1094-1101.
22.
Alonso-Martinez JL, Llorente-Diez B., Echegaray-Agara M., Olaz-Preciado F., Urbieta-Echezarreta M., González-Arencibia C.C-reactive protein as a predictor of improvement and readmission in heart failure. Eur J Heart Fail.2002;4(3):331-336.
23.
Liuzzo G., Biasucci LM, Gallimore JR, et al. The prognostic value of C-reactive protein and serum amyloid a protein in severe unstable angina. N Engl J Med. 1994;331(7):417-424.
24.
Libby P., Ridker PM, Maseri A.Inflammation and atherosclerosis. Circulation. 2002;105(9):1135-1143.
25.
Maseri A.Inflammation, atherosclerosis, and ischemic events: exploring the hidden side of the moon. N Engl J Med. 1997; 336(14):1014-1016.
26.
Avanzas P., Arroyo-Espliguero R., Cosin-Sales J., Quiles J., Zouridakis E., Kaski JCMultiple complex stenoses, high neutrophil count and C-reactive protein levels in patients with chronic stable angina. Atherosclerosis. 2004;175(1):151-157.
27.
Arroyo-Espliguero R., Avanzas P., Cosin-Sales J., Aldama G., Pizzi C., Kaski JCC-reactive protein elevation and disease activity in patients with coronary artery disease. Eur Heart J.2004;25(5):401-408.
28.
Zouridakis E., Avanzas P., Arroyo-Espliguero R., Fredericks S., Kaski JCMarkers of inflammation and rapid coronary artery disease progression in patients with stable angina pectoris. Circulation. 2004;110(13):1747-1753.
29.
Ihling C., Szombathy T., Bohrmann B., Brockhaus M., Schaefer HE, Loeffler BMCoexpression of endothelin-converting enzyme-1 and endothelin-1 in different stages of human atherosclerosis. Circulation. 2001;104(8):864-869.
30.
Ihling C., Bohrmann B., Schaefer HE, Technau-Ihling K., Loeffler BMEndothelin-1 and endothelin converting enzyme-1 in human atherosclerosis-novel targets for pharmacotherapy in atherosclerosis. Curr Vasc Pharmacol. 2004;2(3):249-258.
31.
Suresh DP, Lamba S., Abraham WTNew developments in heart failure: role of endothelin and the use of endothelin receptor antagonists. J Card Fail. 2000;6(4):359-368.
32.
Konstam MA, DeNofrio D.Endothelin expression and the progression of heart failure: exemplifying the vagaries of therapeutic development. Circulation. 2004;109(2):143-145.
33.
Ertl G., Bauersachs J.Endothelin receptor antagonists in heart failure: current status and future directions. Drugs. 2004;64(10): 1029-1040.
34.
Posa I., Horkay F., Seres L., et al. Effects of Experimental Diabetes on Endothelin-induced Ventricular Arrhythmias in Dogs. J Cardiovasc Pharmacol. 2004;44(suppl 1):S380-S382.
35.
Toth M., Solti F., Merkely B., et al. Bradycardia increases the arrhythmogenic effect of endothelin . J Cardiovasc Pharmacol. 1998;31(suppl 1):S431-S433.
36.
Raghunandan DS, Desai N., Mallavarapu M., Berger RD, Yeragani VKIncreased beat-to-beat QT variability in patients with congestive cardiac failure. Indian Heart J. 2005;57(2): 138-142.
37.
Kay L., Finelli C., Aussedat J., Guarnieri C., Rossi A.Improvement of long-term preservation of the isolated arrested rat heart by trimetazidine: effects on the energy state and mitochondrial function. Am J Cardiol.1995;76(6):45B-49B.
38.
Fantini E., Demaison L., Sentex E., Grynberg A., Athias P.Some biochemical aspects of the protective effect of trimetazidine on rat cardiomyocytes during hypoxia and reoxygenation. J Mol Cell Cardiol. 1994;26(8):949-958.
39.
Lavanchy N. , Martin J., Rossi A.Anti-ischemia effects of trimetazidine: 31P-NMR spectroscopy in the isolated rat heart. Arch Int Pharmacodyn Ther. 1987;286(1):97-110.
40.
Fragasso G. , Perseghin G., De Cobelli F., et al. Effects of metabolic modulation by trimetazidine on left ventricular function and phosphocreatine/adenosine triphosphate ratio in patients with heart failure. Eur Heart J. 2006;27(8): 942-948.
41.
Lagadic-Gossmann D., Le Prigent K., Feuvray D.Effects of trimetazidine on phi in the rat isolated ventricular myocyte. Br J Pharmacol. 1996;117(5):831-838.
42.
Renaud JFInternal pH, Na, and Ca regulation by trimetazidine during cardiac cell acidosis . Cardiovasc Drugs Ther. 1988;1(6): 677-686.
43.
Maridonneau-Parini I., Harpey C.Effects of trimetazidine on membrane damage induced by oxygen free radicals in human red cells. Br J Clin Pharmacol.1985;20(2):148-151.
44.
Birand A., Kudaiberdieva GZ, Batyraliev TA, Akgul F., Usal A.Effects of trimetazidine on heart rate variability and left ventricular systolic performance in patients with coronary artery disease after percutaneous transluminal angioplasty. Angiology. 1997;48(5):413-422.
45.
Ulgen MS, Akdemir O., Toprak N.The effects of trimetazidine on heart rate variability and signal-averaged electrocardiography in early period of acute myocardial infarction. Int J Cardiol. 2001; 77(2-3):255-262.
46.
Di Napoli P., Taccardi AA, Barsotti A.Long term cardioprotective action of trimetazidine and potential effect on the inflammatory process in patients with ischaemic dilated cardiomyopathy . Heart. 2005;91(2):161-165.
47.
Williams FM , Tanda K., Kus M., Williams TJTrimetazidine inhibits neutrophil accumulation after myocardial ischemia and reperfusion in rabbits. J Cardiovasc Pharmacol. 1993;22(6): 828-833.
48.
Tritto I., Wang P., Kuppusamy P., Giraldez R., Zweier JL, Ambrosio G.The anti-anginal drug trimetazidine reduces neutrophil-mediated cardiac reperfusion injury. J Cardiovasc Pharmacol.2005;46(1):89-98.
49.
Fragasso G. , Piatti PM, Monti L., et al. Short- and long-term beneficial effects of trimetazidine in patients with diabetes and ischemic cardiomyopathy. Am Heart J. 2003;146(5): E18-E25.
50.
Monti LD, Setola E., Fragasso G., et al. Metabolic and endothelial effects of trimetazidine on forearm skeletal muscle in patients with type 2 diabetes and ischemic cardiomyopathy . Am J Physiol Endocrinol Metab.2006;290(1):E54-E59.
