Objective: Trimetazidine (TMZ) is a well-known anti-ischemic agent; however, its efficacy and mechanism of cardioprotection on coronary microembolization (CME) are largely unknown. The present study was undertaken to determine whether TMZ pretreatment could attenuate myocardial apoptosis and improve cardiac function in a swine model of CME. Methods: Fifteen swine were randomly and equally divided into a sham-operated (control) group, CME group and CME plus TMZ (TMZ) group. CME was induced by injecting inert plastic microspheres (42 μm in diameter) into the left anterior descending artery. For the control group, the same dose of normal saline was substituted for the microspheres, and the TMZ group was pretreated with TMZ 30 min before microsphere injection. Cardiac function was assessed by echocardiography, myocardial apoptosis was detected by TUNEL staining, and the expression levels of cleaved caspase-9/3 were measured by Western blot 12 h after operation. Results: Compared to the control group, cardiac function in the CME group was significantly decreased (p < 0.05); however, TMZ pretreatment showed significantly improved cardiac function as compared to the CME group (p < 0.05). The myocardial apoptotic rate and the expression levels of cleaved caspase-9/3 increased remarkably in CME group as compared with the control group (p < 0.001). Again, TMZ pretreatment significantly reduced the apoptotic rate and also the expression levels of cleaved caspase-9/3 (p < 0.001). Conclusion: The present study demonstrated that TMZ pretreatment could significantly inhibit CME-induced myocardial apoptosis and improve cardiac function, and that the cardioprotective effect appeared to be mediated by the blockade of the mitochondrial apoptotic pathway. These results emphasize the importance of TMZ pretreatment in the therapy of CME-induced myocardial injury.

Heusch G, Schulz R, Haude M, Erbel R: Coronary microembolization. J Mol Cell Cardiol 2004;37:23-31.
Topol EJ, Yadav JS: Recognition of the importance of embolization in atherosclerotic vascular disease. Circulation 2000;101:570-580.
Morishima I, Sone T, Okumura K, Tsuboi H, Kondo J, Mukawa H, Matsui H, Toki Y, Ito T, Hayakawa T: Angiographic no-reflow phenomenon as a predictor of adverse long-term outcome in patients treated with percutaneous transluminal coronary angioplasty for first acute myocardial infarction. J Am Coll Cardiol 2000;36:1202-1209.
Zhang QY, Ge JB, Chen JZ, Zhu JH, Zhang LH, Lau CP, Tse HF: Mast cell contributes to cardiomyocyte apoptosis after coronary microembolization. J Histochem Cytochem 2006;54:515-523.
Li L, Su Q, Wang Y, Su B, Dai RX, Lu YG, Wu XH, Liu TW: Cardiomyocyte apoptosis and death receptor pathway in a rat model of coronary microembolization (in Chinese). Zhonghua Xin Xue Guan Bing Za Zhi 2010;38:363-368.
Su Q, Li L, Liu YC, Zhou Y, Lu YG, Wen WM: Effect of metoprolol on myocardial apoptosis and caspase-9 activation after coronary microembolization in rats. Exp Clin Cardiol 2013;18:161-165.
Zhang FL, Chen LL, Li SM, Wang WW: Granulocyte colony stimulating factor attenuated myocardial apoptosis via Janus kinase 2/signal transducer and activator of transcription signal transduction pathway in rats with coronary microembolization (in Chinese). Zhonghua Xin Xue Guan Bing Za Zhi 2008;36:254-259.
Kim JS, Kim CH, Chun KJ, Kim JH, Park YH, Kim J, Choi JH, Lee SH, Kim EJ, Yu DG, Ahn EY, Jeong MH: Effects of trimetazidine in patients with acute myocardial infarction: data from the Korean Acute Myocardial Infarction Registry. Clin Res Cardiol 2013;102:915-922.
Danchin N, Marzilli M, Parkhomenko A, Ribeiro JP: Efficacy comparison of trimetazidine with therapeutic alternatives in stable angina pectoris: a network meta-analysis. Cardiology 2011;120:59-72.
Chen YD, Zhao LK, Tian F, Du ZM, Jiang H, Wei M: Evaluation of the myocardial protection of trimetazidine during percutaneous coronary intervention: a multi-center randomized and controlled clinical study (in Chinese). Zhonghua Nei Ke Za Zhi 2010;49:473-476.
Bonello L, Sbragia P, Amabile N, Com O, Pierre SV, Levy S, Paganelli F: Protective effect of an acute oral loading dose of trimetazidine on myocardial injury following percutaneous coronary intervention. Heart 2007;93:703-707.
Zhou X, Li C, Xu W, Chen J: Trimetazidine protects against smoking-induced left ventricular remodeling via attenuating oxidative stress, apoptosis, and inflammation. PLoS One 2012;7:e40424.
Khan M, Meduru S, Mostafa M, Khan S, Hideg K, Kuppusamy P: Trimetazidine, administered at the onset of reperfusion, ameliorates myocardial dysfunction and injury by activation of p38 mitogen-activated protein kinase and Akt signaling. J Pharmacol Exp Ther 2010;333:421-429.
Ruixing Y, Wenwu L, Al-Ghazali R: Trimetazidine inhibits cardiomyocyte apoptosis in a rabbit model of ischemia-reperfusion. Transl Res 2007;149:152-160.
Wang J, Li L, Su Q, Zhou Y, Chen H, Ma G, Liu T, Tang Z, Liu Y: The involvement of phosphatase and tensin homolog deleted on chromosome ten (PTEN) in the regulation of inflammation following coronary microembolization. Cell Physiol Biochem 2014;33:1963-1974.
Castedo E, Segovia J, Escudero C, Olmedilla B, Granado F, Blas C, Guardiola JM, Millan I, Pulpon LA, Ugarte J: Ischemia-reperfusion injury during experimental heart transplantation: evaluation of trimetazidine's cytoprotective effect. Rev Esp Cardiol 2005;58:941-950.
Thielmann M, Dorge H, Martin C, Belosjorow S, Schwanke U, van de Sand A, Konietzka I, Buchert A, Kruger A, Schulz R, Heusch G: Myocardial dysfunction with coronary microembolization: signal transduction through a sequence of nitric oxide, tumor necrosis factor-alpha, and sphingosine. Circ Res 2002;90:807-813.
Erbel R, Heusch G: Coronary microembolization. J Am Coll Cardiol 2000;36:22-24.
Skyschally A, Schulz R, Erbel R, Heusch G: Reduced coronary and inotropic reserves with coronary microembolization. Am J Physiol Heart Circ Physiol 2002;282:H611-H614.
Dorge H, Neumann T, Behrends M, Skyschally A, Schulz R, Kasper C, Erbel R, Heusch G: Perfusion-contraction mismatch with coronary microvascular obstruction: role of inflammation. Am J Physiol Heart Circ Physiol 2000;279:H2587-H2592.
Li L, Su Q, Wang Y, Dai R, Lu Y, Su B, Zhao Y: Effect of atorvastatin (Lipitor) on myocardial apoptosis and caspase-8 activation following coronary microembolization. Cell Biochem Biophys 2011;61:399-406.
Bucci M, Borra R, Nagren K, Parkka JP, Del Ry S, Maggio R, Tuunanen H, Viljanen T, Cabiati M, Rigazio S, Taittonen M, Pagotto U, Parkkola R, Opie LH, Nuutila P, Knuuti J, Iozzo P: Trimetazidine reduces endogenous free fatty acid oxidation and improves myocardial efficiency in obese humans. Cardiovasc Ther 2012;30:333-341.
Kantor PF, Lucien A, Kozak R, Lopaschuk GD: 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;86:580-588.
Shehata M: Impact of trimetazidine on incidence of myocardial injury and contrast-induced nephropathy in diabetic patients with renal dysfunction undergoing elective percutaneous coronary intervention. Am J Cardiol 2014;114:389-394.
Demirelli S, Karakelleoglu S, Gundogdu F, Tas MH, Kaya A, Duman H, Degirmenci H, Hamur H, Simsek Z: The impact of trimetazidine treatment on left ventricular functions and plasma brain natriuretic peptide levels in patients with non-ST segment elevation myocardial infarction undergoing percutaneous coronary intervention. Korean Circ J 2013;43:462-467.
Gambert S, Vergely C, Filomenko R, Moreau D, Bettaieb A, Opie LH, Rochette L: Adverse effects of free fatty acid associated with increased oxidative stress in postischemic isolated rat hearts. Mol Cell Biochem 2006;283:147-152.
Argaud L, Gomez L, Gateau-Roesch O, Couture-Lepetit E, Loufouat J, Robert D, Ovize M: Trimetazidine inhibits mitochondrial permeability transition pore opening and prevents lethal ischemia-reperfusion injury. J Mol Cell Cardiol 2005;39:893-899.
Holleyman CR, Larson DF: Apoptosis in the ischemic reperfused myocardium. Perfusion 2001;16:491-502.
Kuida K: Caspase-9. Int J Biochem Cell Biol 2000;32:121-124.
Acehan D, Jiang X, Morgan DG, Heuser JE, Wang X, Akey CW: Three-dimensional structure of the apoptosome: implications for assembly, procaspase-9 binding, and activation. Mol Cell 2002;9:423-432.
Bratton SB, Salvesen GS: Regulation of the Apaf-1-caspase-9 apoptosome. J Cell Sci 2010;123:3209-3214.
Maheshwari A, Misro MM, Aggarwal A, Sharma RK, Nandan D: Pathways involved in testicular germ cell apoptosis induced by H2O2 in vitro. FEBS J 2009;276:870-881.
Takatani T, Takahashi K, Uozumi Y, Shikata E, Yamamoto Y, Ito T, Matsuda T, Schaffer SW, Fujio Y, Azuma J: Taurine inhibits apoptosis by preventing formation of the Apaf-1/caspase-9 apoptosome. Am J Physiol Cell Physiol 2004;287:C949-C953.
Balsam LB, Kofidis T, Robbins RC: Caspase-3 inhibition preserves myocardial geometry and long-term function after infarction. J Surg Res 2005;124:194-200.
Sodhi RK, Singh M, Singh N, Jaggi AS: Protective effects of caspase-9 and poly(ADP-ribose) polymerase inhibitors on ischemia-reperfusion-induced myocardial injury. Arch Pharm Res 2009;32:1037-1043.
Liu Q: Lentivirus mediated interference of caspase-3 expression ameliorates the heart function on rats with acute myocardial infarction. Eur Rev Med Pharmacol Sci 2014;18:1852-1858.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.