Rational Pharmacotherapy in Cardiology

Advanced search


Full Text:


Data on the mechanisms of cardiomyocyte apoptosis in myocardial infarction are presented. It has been experimentally established that the ratio of the number of cardiomyocytes with signs of apoptosis and necrosis is 30:1 already 2 hours after acute artery occlusion. This fact points out the leading role of apoptosis in cardiomyocyte death in acute period of myocardial infarction. Cardiomyocyte apoptosis makes a significant contribution in myocardial remodeling and left ventricular dysfunction after myocardial infarction. The essential role of active forms of oxygen in the development of cell apoptosis after reperfusion was proved in experimental data. Carvedilol is a third-generation beta-blocker with additional pleiotropic and antioxidant effects. The multifactorial positive influence of carvedilol on apoptosis prevention gives the opportunity to adopt experimental results into real-life clinical practice. It was established in vivo that administration of carvedilol just after start of coronary reperfusion decreases by 77% the number of cells suffered from apoptosis. Carvedilol has antioxidant effects and prevents cell apoptosis due to reduction in calcium concentration in mitochondrial matrix. The experimental results and the data of large randomized clinical trials give an opportunity of using carvedilol in treatment of myocardial infarction to decrease necrotic zone and prevent cardiomyocyte apoptosis.

About the Authors

A. N. Zakirova
Bashkir State Medical University
Russian Federation

Alyara N. Zakirova – MD, PhD, Professor, Head of Chair of Clinical Cardiology 

Lenina ul. 3, Ufa, 450000

B. N. Garifullin
Bashkir State Medical University
Russian Federation

Bulat N. Garifullin – MD, PhD, Associate Professor, Chair of Clinical Cardiology 

Lenina ul. 3, Ufa, 450000

N. E. Zakirova
Bashkir State Medical University
Russian Federation

Nelly E. Zakirova – MD, PhD, Professor, Head of Chair of Clinical Functional Diagnostics 

Lenina ul. 3, Ufa, 450000


1. Lopez-Sendon J., Swedberg K., McMurray J., et al. Expert consensus document on beta-adrenergic receptor blockers. The Task force on beta-blockers of the European Society of Cardiology. Eur Heart J. 2004;25:1341-62. doi: 10.1016/j.ehj.2004.06.002.

2. O´Gara P.T., Kushner F.G., Ascheim D.D. et al. 2013 ACCF/AHA. Guidelines for Management of ST-Elevation Myocardial Infarction: A Report of the American College of Cardiology Foundation/American Heart Associate Task Force on Practice Guidelines. J Am Coll Cardiol. 2013;61(4):e78-e140. doi: 10.1016/j.jacc.2012.11.019.

3. ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. Rev Esp Cardiol. 2009;62(3):e1-47. doi: 10.1016/S1885-5857(09)71559-2

4. Basu S., Senior R., Raval U. et al. Benefitial effects of intravenous and oral carvedilol treatment in acute myocardial infarction. Circulation. 1997;96:183-91. doi: 10.1161/01.CIR.96.1.183.

5. Sackner-Bernstein J.D. New evidence from the CAPRICORN trial: the role of carvedilol in high-risk, post-myocardial infarction patients. Rev Cardiovasc Med. 2003;4:25-9.

6. Gottlieb R.A., Burleson K.O., Kloner R.A. et al. Reperfusion injury induces apoptosis in rabbit cardiomyocytes. J Clin Invest 1994; 94: 1621-1628. doi: 10.1172/JCI117504.

7. Umansky S.R., Cueno G.M., Khutzian S.S. et al. Post-ischemic apoptotic death of rat neonatal сardiomyocytes. Cell Death Differ. 1995;2:236-41.

8. Olivetti G., Quaini F., Sala R. et al. Acute myocardial infarction in humans is associated with activation of programmed myocyte cell death in the surviving portion of the heart. J Mol Cell Cardiol. 1994;28:2005-2016. doi: 10.1006/jmcc.1996.0193.

9. Saraste A., Pulkki K., Kallajoki M. et al. Apoptosis in human acute myocardial infarction. Circulation 1997;95:320-3. doi: 10.1161/01.CIR.95.2.320.

10. Anversa P, Cheng W, Liu Y. et al. Apoptosis and myocardial infarction. Basic Res Cardiol. 1998;93(Suppl 3):8-12. doi: 10.1007/s003950050195.

11. Bennett M.R. Apoptosis in the cardiovascular system. Heart. 2002;87:480-7. doi: 10.1136/heart.87.5.480.

12. Zhang R., Khoo M.S, Wu Y. et al. Calmodulin kinase II inhibition protects against structural heart disease. Nat Med. 2005;11:409-17. doi: 10.1038/nm1215.

13. Romeo F., Li D., Shi M., Mehta J.L. Carvedilol prevents epinephrine-induced apoptosis in human coronary artery endothelial cells: Modulation of Fas/Fas ligand and caspase-3 pathway. Cardiovasc Res 2000; 45:788-794. doi: 10.1016/S0008-6363(99)00369-7.

14. Ahmet I., Krawczyk M., Heller P. et al. Beneficial effects of chronic pharmacological manipulation of β-adrenoreceptor subtype signaling in rodent dilated ischemic cardiomyopathy. Circulation. 2004;110:1083-90. doi: 10.1161/01.CIR.0000139844.15045.F9.

15. Chesley A., Lundberg M.S., Asai T. et al. The β(2)-adrenergic receptor delivers an antiapoptotic signal to cardiomyocytes through G(i)-dependent coupling to phosphatidylinositol 3´-kinase. Circ Xydas S Res. 2000;87:1172-9.

16. Xydas S., Kherani A.R., Chang J.S. et al. β2-Adrenergic stimulation attenuates left ventricular remodeling, decreases apoptosis, and improves calcium homeostasis in a rodent model of ischemic cardiomyopathy. J Pharm Exp Ther. 2006;317(2):553-61. doi: 10.1124/jpet.105.099432.

17. Buttke T.M., Sandstrom P.A. Oxidative stress as a mediator of apoptosis. Immunol Today. 1994;15:710. doi: 10.1016/0167-5699(94)90018-3.

18. Giordano F.J. Oxygen, oxidative stress, hypoxia and heart failure. J Clin Investig. 2005; 115:500-8. doi: 10.1172/JCI200524408.

19. Sabri A., Hughie H.H., Lucchesi P.A. Regulation of hypertrophic and apoptotic signaling pathways by reactive oxygen species in cardiac myocytes. Antioxid. Redox Signal. 2003;5:731-40. doi: 10.1089/152308603770380034.

20. Ide T, Tsutsui H, Hayashidani S. et al. Mitochondrial DNA damage and dysfunction associated with oxidative stress in failing hearts after myocardial infarction. Circ Res. 2001;88:529-35. doi: 10.1161/01.RES.88.5.529.

21. Koitabashi N., Arai M., Tomaru K. et al. Carvedilol effectively blocks oxidative stress-mediated downregulation of sarcoplasmic reticulum Ca2+-ATPase 2 gene transcription through modification of Sp1 binding. Biochem Biophys Res Commun. 2005;328:116-24. doi: 10.1016/j.bbrc.2004.12.139.

22. Spallarossa P., Garibaldi S., Altieri P. et al. Carvedilol prevents doxorubicin-induced free radical release and apoptosis in cardiomyocytes in vitro. J Mol Cell Cardiol. 2004;37:837-46. doi: 10.1016/j.yjmcc.2004.05.024.

23. Wang R., Miura T., Harada N. et al. Pleiotropic effects of the β-adrenoreceptor blocker carvedilol on calcium regulation during oxidative stress-induced apoptosis in cardiomyocytes. J Pharm Exp Ther. 2006;1:42-52.

24. Kastratovic D.A., Vasiljevic Z.M., Spasic M.B. et al. Carvedilol increases copperzinc superoxide dismutase activity in patients with acute myocardial infarction. Basic Clin Pharmacol Toxicol. 2007;101(2):138-42. doi: 10.1111/j.1742-7843.2007.00094.x.

25. Cheng J., Kamiya K., Kodama I. Carvedilol: molecular and cellular basis for its multifaceted therapeutic potential. Cardiovasc Drugs Rev. 2001;19:152-71. doi: 10.1111/j.15273466.2001.tb00061.x.

26. Yue T.L., Ma X.L., Wang X. et al. Possible involvement of stress-activated protein kinase signaling pathway and Fas receptor expression in prevention of ischemia/reperfusion-induced cardiomyocyte apoptosis by carvedilol. Circ Res. 1998;82:166-74.

27. Schwarz E.R., Kersting P.H., Reffelmann T. Cardioprotection by carvedilol: antiapoptosis is independent of beta-adrenoceptor blockade in the rat heart. J Cardiovasc Pharmacol Ther. 2003; 8(3):207215. doi: 10.1177/107424840300800306.

28. Dun Y., Zhi J.M., Sun H.Y. et al. Activated polymorphonuclear leukocytes induce cardiomyocyte apoptosis and the protective effects of carvedilol. Methods Find Exp Clin Pharmacol. 2002;24(7):403-6. doi: 10.1358/mf.2002.24.7.696541.

29. Zakirova N.E., Zakirova A.N. The Role of Immune Inflammatory Reactions and Endothelial Dysfunction in Myocardial Remodeling and Progression of Ischemic Heart Disease. Rational Pharmacotherapy in Cardiology. 2014;10(5):488-494. (In Russ.) [Закирова Н.Э., Закирова А.Н. Роль иммуновоспалительных реакций и дисфункции эндотелия в ремоделировании миокарда и прогрессировании ишемической болезни сердца. Рациональная Фармакотерапия в Кардиологии. 2014;10(5):488-93]. doi: 10.20996/1819-6446-2014-10-5-488-494.

30. Zakirova A.N., Mukhamedrakhimova A.R., Zakirova N.E. Remodeling of the left ventricle and the level of proinflammatory cytokines in acute myocardial infarction. Cardiovascular Therapy and Prevention. 2004;3(4):170-2. (In Russ.) [Закирова А.Н., Мухамедрахимова А.Р., Закирова Н.Э. Ремоделирование левого желудочка и уровень провоспалительных цитокинов при остром инфаркте миокарда. Кардиоваскулярная Терапия и Профилактика. 2004; 3(4):170-2].

31. Zakirova A.N., Gabidullin R.R., Zakirova N.E. Clinico-hemodynamic effects of carvedilol, the effect on lipid peroxidation and markers of inflammation in patients with coronary heart disease with chronic heart failure. Serdechnaja Nedostatochnost '. 2006;2:24-8. (In Russ.) [Закирова А.Н., Габидуллин Р.Р., Закирова Н.Э. Клинико-гемодинамические эффекты карведилола, влияние на перекисное окисление липидов и маркеры воспаления у больных ишемической болезнью сердца с хронической сердечной недостаточностью. Сердечная Недостаточность. 2006;2:24-8].

32. Garifullin B.N., Zakirova A.N., Zarudij F.S. Metoprolol and carvedilol in therapy of acute myocardial infarction: when and which drug to prefer. Rational Pharmacotherapy in Cardiology. 2009;5(4):51-7. (In Russ.) [Гарифуллин Б.Н., Закирова А.Н., Зарудий Ф.С. Метопролол и карведилол в терапии острого периода инфаркта миокарда: когда и какой препарат предпочесть. Рациональная Фармакотерапия в Кардиологии. 2009;5(4):51-7]. doi: 10.20996/1819-6446-2009-5-4-51-57.

For citation:

Zakirova A.N., Garifullin B.N., Zakirova N.E. THE ROLE OF CARVEDILOL IN THE PREVENTION OF CARDIOMYOCYTE APOPTOSIS CAUSED BY ACUTE MYOCARDIAL INFARCTION. Rational Pharmacotherapy in Cardiology. 2017;13(6):880-884. (In Russ.)

Views: 245

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.

ISSN 1819-6446 (Print)
ISSN 2225-3653 (Online)