Cardiovascular Toxicology

, Volume 12, Issue 4, pp 312–317 | Cite as

Doxorubicin-induced Changes of Ventricular Repolarization Heterogeneity: Results of a Chronic Rat Study

  • Sergey N. Kharin
  • Valeria V. Krandycheva
  • Marina V. Strelkova
  • Aliona S. Tsvetkova
  • Dmitry N. Shmakov
Article

Abstract

Anthracycline chemotherapy produces cardiac repolarization abnormalities and arrhythmias because of cardiac toxicity of drugs. Ventricular arrhythmogenesis is attributable to increase in repolarization heterogeneity that is characterized by spatial dispersion of repolarization. The purpose of this work was to study the delayed effects of doxorubicin, the most frequently used anthracycline, on repolarization heterogeneity of the ventricular epicardium. Doxorubicin was administered to rats in a cumulative dose of 15 mg/kg (six equal intraperitoneal injections over a period of 2 weeks). Six weeks after the last injection, electrophysiological mapping of the ventricular epicardium was performed by sequential superimposition of a 64-electrode array on the left ventricular base, left ventricular apex, right ventricular base, and right ventricular apex. Activation–recovery intervals (ARIs) were measured. In doxorubicin-treated rats, ARIs were inhomogeneously prolonged, the overall ARI dispersion and local ARI dispersions were increased, and the interregional differences in ARI dispersion were decreased. These data demonstrate that doxorubicin-induced inhomogeneous prolongation of repolarization of the ventricular epicardium results in increasing heterogeneity of ventricular repolarization because of increasing intraregional heterogeneity while interregional differences are lost. Repolarization of the right ventricle is more sensitive to doxorubicin than that of the left one.

Keywords

Activation–recovery interval Anthracyclines Doxorubicin Heart ventricles Heterogeneity Rat model Repolarization 

References

  1. 1.
    Singal, P. K., Li, T., Kumar, D., Danelisen, I., & Iliskovic, N. (2000). Adriamycin-induced heart failure: Mechanism and modulation. Molecular and Cellular Biochemistry, 207, 77–85.PubMedCrossRefGoogle Scholar
  2. 2.
    Chen, B., Peng, X., Pentassuglia, L., Lim, C. C., & Sawyer, D. B. (2007). Molecular and cellular mechanisms of anthracycline cardiotoxicity. Cardiovascular Toxicology, 7, 114–121.PubMedCrossRefGoogle Scholar
  3. 3.
    Monsuez, J. J., Charniot, J. C., Vignat, N., & Artigou, J. Y. (2010). Cardiac side-effects of cancer chemotherapy. International Journal of Cardiology, 144, 3–15.PubMedCrossRefGoogle Scholar
  4. 4.
    Senkus, E., & Jassem, J. (2011). Cardiovascular effects of systemic cancer treatment. Cancer Treatment Reviews, 37, 300–311.PubMedCrossRefGoogle Scholar
  5. 5.
    Horacek, J. M., Jakl, M., Horackova, J., Pudil, R., Jebavy, L., & Maly, J. (2009). Assessment of anthracycline-induced cardiotoxicity with electrocardiography. Experimental Oncology, 31, 115–117.PubMedGoogle Scholar
  6. 6.
    Guglin, M., Aljayeh, M., Saiyad, S., Ali, R., & Curtis, A. B. (2009). Introducing a new entity: Chemotherapy-induced arrhythmia. Europace, 11, 1579–1586.PubMedCrossRefGoogle Scholar
  7. 7.
    Jensen, R. A., Acton, E. M., & Peters, J. H. (1984). Doxorubicin cardiotoxicity in the rat: Comparison of electrocardiogram, transmembrane potential, and structural effects. Journal of Cardiovascular Pharmacology, 6, 186–200.PubMedCrossRefGoogle Scholar
  8. 8.
    Agen, C., Bernardini, N., Danesi, R., Della Torre, P., Costa, M., & Del Tacca, M. (1992). Reducing doxorubicin cardiotoxicity in the rat using deferred treatment with ADR-529. Cancer Chemotherapy and Pharmacology, 30, 95–99.PubMedCrossRefGoogle Scholar
  9. 9.
    Cirillo, R., Sacco, G., Venturella, S., Brightwell, J., Giachetti, A., & Manzini, S. (2000). Comparison of doxorubicin- and MEN 10755-induced long-term progressive cardiotoxicity in the rat. Journal of Cardiovascular Pharmacology, 35, 100–108.PubMedCrossRefGoogle Scholar
  10. 10.
    Xu, M., Sheng, L., Zhu, X., Zeng, S., Chi, D., & Zhang, G. J. (2010). Protective effect of tetrandrine on doxorubicin-induced cardiotoxicity in rats. Tumori, 96, 460–464.PubMedGoogle Scholar
  11. 11.
    Hazari, M. S., Haykal-Coates, N., Winsett, D. W., Costa, D. L., & Farraj, A. K. (2009). Continuous electrocardiogram reveals differences in the short-term cardiotoxic response of Wistar-Kyoto and spontaneously hypertensive rats to doxorubicin. Toxicological Sciences, 110, 224–234.PubMedCrossRefGoogle Scholar
  12. 12.
    Antzelevitch, C. (2007). Role of spatial dispersion of repolarization in inherited and acquired sudden cardiac death syndromes. American Journal of Physiology Heart and Circulatory Physiology, 293, H2024–H2038.PubMedCrossRefGoogle Scholar
  13. 13.
    Killeen, M. J., Sabir, I. N., Grace, A. A., & Huang, C. L. (2008). Dispersions of repolarization and ventricular arrhythmogenesis: Lessons from animal models. Progress in Biophysics and Molecular Biology, 98, 219–229.PubMedCrossRefGoogle Scholar
  14. 14.
    Earm, Y. E., Ho, W. K., & So, I. (1994). Effects of adriamycin on ionic currents in single cardiac myocytes of the rabbit. Journal of Molecular and Cellular Cardiology, 26, 163–172.PubMedCrossRefGoogle Scholar
  15. 15.
    Wang, Y. X., & Korth, M. (1995). Effects of doxorubicin on excitation-contraction coupling in guinea pig ventricular myocardium. Circulation Research, 76, 645–653.PubMedCrossRefGoogle Scholar
  16. 16.
    Ducroq, J., Moha ou Maati, H., Guilbot, S., Dilly, S., Laemmel, E., Pons-Himbert, C., et al. (2010). Dexrazoxane protects the heart from acute doxorubicin-induced QT prolongation: A key role for I(Ks). British Journal of Pharmacology, 159, 93–101.PubMedCrossRefGoogle Scholar
  17. 17.
    Lazarus, M. L., Rossner, K. L., & Anderson, K. M. (1980). Adriamycin-induced alterations of the action potential in rat papillary muscle. Cardiovascular Research, 14, 446–450.PubMedCrossRefGoogle Scholar
  18. 18.
    Doherty, J. D., & Cobbe, S. M. (1990). Electrophysiological changes in animal model of chronic cardiac failure. Cardiovascular Research, 24, 309–316.PubMedCrossRefGoogle Scholar
  19. 19.
    Shenasa, H., Calderone, A., Vermeulen, M., Paradis, P., Stephens, H., Cardinal, R., et al. (1990). Chronic doxorubicin induced cardiomyopathy in rabbits: Mechanical, intracellular action potential, and beta adrenergic characteristics of the failing myocardium. Cardiovascular Research, 24, 591–604.PubMedCrossRefGoogle Scholar
  20. 20.
    Venditti, P., Balestrieri, M., De Leo, T., & Di Meo, S. (1998). Free radical involvement in doxorubicin-induced electrophysiological alterations in rat papillary muscle fibres. Cardiovascular Research, 38, 695–702.PubMedCrossRefGoogle Scholar
  21. 21.
    Dhein, S., Garbade, J., Rouabah, D., Abraham, G., Ungemach, F. R., Schneider, K., et al. (2006). Effects of autologous bone marrow stem cell transplantation on beta-adrenoceptor density and electrical activation pattern in a rabbit model of non-ischemic heart failure. Journal of Cardiothoracic Surgery, 1, 17.PubMedCrossRefGoogle Scholar
  22. 22.
    Tong, J., Ganguly, P. K., & Singal, P. K. (1991). Myocardial adrenergic changes at two stages of heart failure due to adriamycin treatment in rats. American Journal of Physiology, 260, H909–H916.PubMedGoogle Scholar
  23. 23.
    Siveski-Iliskovic, N., Kaul, N., & Singal, P. K. (1994). Probucol promotes endogenous antioxidants and provides protection against adriamycin-induced cardiomyopathy in rats. Circulation, 89, 2829–2835.PubMedCrossRefGoogle Scholar
  24. 24.
    Kazachenko, A. A., Okovityĭ, S. V., Kulikov, A. N., Gustaĭnis, K. R., Nagornyĭ, M. B., Shulenin, S. N., et al. (2008). Comparative characteristics of some pharmacological models of chronic heart failure. Eksperimental’naia i Klinicheskaia Farmakologiia, 71, 16–19.PubMedGoogle Scholar
  25. 25.
    Millar, C. K., Kralios, F. A., & Lux, R. L. (1985). Correlation between refractory periods and activation-recovery intervals from electrograms: Effects of rate and adrenergic interventions. Circulation, 72, 1372–1379.PubMedCrossRefGoogle Scholar
  26. 26.
    Coronel, R., de Bakker, J. M., Wilms-Schopman, F. J., Opthof, T., Linnenbank, A. C., Belterman, C. N., et al. (2006). Monophasic action potentials and activation recovery intervals as measures of ventricular action potential duration: Experimental evidence to resolve some controversies. Heart Rhythm, 3, 1043–1050.PubMedCrossRefGoogle Scholar
  27. 27.
    Binah, O., Cohen, I. S., & Rosen, M. R. (1983). The effects of adriamycin on normal and ouabain-toxic canine Purkinje and ventricular muscle fibers. Circulation Research, 53, 655–662.PubMedCrossRefGoogle Scholar
  28. 28.
    Casis, O., Iriarte, M., Gallego, M., & Sánchez-Chapula, J. A. (1998). Differences in regional distribution of K + current densities in rat ventricle. Life Sciences, 63, 391–400.PubMedCrossRefGoogle Scholar
  29. 29.
    Aimond, F., Alvarez, J. L., Rauzier, J. M., Lorente, P., & Vassort, G. (1999). Ionic basis of ventricular arrhythmias in remodeled rat heart during long-term myocardial infarction. Cardiovascular Research, 42, 402–415.PubMedCrossRefGoogle Scholar
  30. 30.
    Varró, A., & Baczkó, I. (2011). Cardiac ventricular repolarization reserve: A principle for understanding drug-related proarrhythmic risk. British Journal of Pharmacology, 164, 14–36.PubMedCrossRefGoogle Scholar
  31. 31.
    Kilickap, S., Barista, I., Akgul, E., Aytemir, K., Aksoy, S., & Tekuzman, G. (2007). Early and late arrhythmogenic effects of doxorubicin. Southern Medical Journal, 100, 262–265.PubMedCrossRefGoogle Scholar
  32. 32.
    Arbel, Y., Swartzon, M., & Justo, D. (2007). QT prolongation and Torsades de Pointes in patients previously treated with anthracyclines. Anti-Cancer Drugs, 18, 493–498.PubMedCrossRefGoogle Scholar
  33. 33.
    Dragojevic-Simic, V. M., Dobric, S. L., Bokonjic, D. R., Vucinic, Z. M., Sinovec, S. M., Jacevic, V. M., et al. (2004). Amifostine protection against doxorubicin cardiotoxicity in rats. Anti-Cancer Drugs, 15, 169–178.PubMedCrossRefGoogle Scholar
  34. 34.
    Ammar, El-S. M., Said, S. A., Suddek, G. M., & El-Damarawy, S. L. (2011). Amelioration of doxorubicin-induced cardiotoxicity by deferiprone in rats. Canadian Journal of Physiology and Pharmacology, 89, 269–276.CrossRefGoogle Scholar
  35. 35.
    Ewer, M. S., & Ewer, S. M. (2010). Cardiotoxicity of anticancer treatments: What the cardiologist needs to know. Nature Reviews Cardiology, 7, 564–575.PubMedCrossRefGoogle Scholar
  36. 36.
    Chauhan, V. S., Downar, E., Nanthakumar, K., Parker, J. D., Ross, H. J., Chan, W., et al. (2006). Increased ventricular repolarization heterogeneity in patients with ventricular arrhythmia vulnerability and cardiomyopathy: A human in vivo study. American Journal of Physiology Heart and Circulatory Physiology, 290, H79–H86.PubMedCrossRefGoogle Scholar
  37. 37.
    Akar, F. G. (2010). Left ventricular repolarization heterogeneity as an arrhythmic substrate in heart failure. Minerva Cardioangiologica, 58, 205–212.PubMedGoogle Scholar
  38. 38.
    Ajijola, O. A., Nandigam, K. V., Chabner, B. A., Orencole, M., Dec, G. W., Ruskin, J. N., et al. (2008). Usefulness of cardiac resynchronization therapy in the management of Doxorubicin-induced cardiomyopathy. The American Journal of Cardiology, 101, 1371–1372.PubMedCrossRefGoogle Scholar
  39. 39.
    Tsvetkova, A. S., Kibler, N. A., Nuzhny, V. P., Shmakov, D. N., & Azarov, J. E. (2011). Acute effects of pacing site on repolarization and haemodynamics of the canine ventricles. Europace, 13, 889–896.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Sergey N. Kharin
    • 1
  • Valeria V. Krandycheva
    • 1
  • Marina V. Strelkova
    • 1
  • Aliona S. Tsvetkova
    • 1
  • Dmitry N. Shmakov
    • 1
  1. 1.Laboratory of Cardiac PhysiologyInstitute of Physiology, Komi Science Centre, Ural Branch, Russian Academy of SciencesSyktyvkar, Komi RepublicRussian Federation

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