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Reduced repolarization reserve due to anthracycline therapy facilitates torsade de pointes induced by IKr blockers

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Abstract

Background

Cytostatic agents such as anthracyclines may cause changes in the electrophysiologic properties of the heart. We hypothesized that anthracyclines facilitate life-threatening proarrhythmic side effects of cardiovascular and non-cardiovascular repolarization prolonging drugs.

Methods and results

The electrophysiologic effects of chronic administration of doxorubicin (Dox) were studied in ten rabbits, which were treated with Dox twice a week (1.5 mg/kg i. v.). A control group (11 rabbits) was given NaCl solution. Two of ten Dox rabbits died suddenly, the remaining animals showed mild clinical signs of heart failure after a period of six weeks. Echocardiography demonstrated a decrease in ejection fraction (pre treatment: 74 ± 23% to post treatment: 63 ± 16% (p <0.05)). In isolated hearts, action potential duration measured by eight simultaneously recorded monophasic action potentials (MAP) was similar in Dox and control hearts. However, in Dox rabbits, administration of the IKr–blocker erythromycin (150–300 μM) led to a significant greater prolongation of the mean MAP duration (63 ± 21ms vs 29 ± 12 ms, p <0.05) and the QT interval (100 ± 32ms vs 58 ± 17 ms, p <0.05) as compared to control. Moreover, IKr–block led to a more marked increase of dispersion of MAP90 in the Dox group as compared to control hearts (23 ± 7ms vs. 9 ± 4 ms). In the presence of hypokalemia more episodes of early afterdepolarizations and torsade de pointes occurred (p <0.05).

Conclusion

Even during the early phase of chemotherapeutic treatment,before significant QT-prolongation is present,anthracyclines lead to an increased sensitivity to the proarrhythmic potency of IKr-blocking drugs. Thus, anthracycline therapy reduces repolarization reserve and thereby represents a novel contributing factor for the development of lifethreatening proarrhythmia.

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Author information

Author notes

  1. M. A. Engelen MD

    Present address: Dept. of Medical Physiology, University Medical Center Utrecht, Utrecht, The Netherlands

Authors and Affiliations

  1. Hospital of the Westfälische Wilhelms-University, Dept. of Cardiology and Angiology, Münster, Germany

    P. Milberg MD, D. Fleischer MS, J. Stypmann MD, G. Mönnig MD, M. A. Engelen MD, C. Bruch MD, G. Breithardt MD, FESC, FACC & L. Eckardt MD

  2. Medizinische Klinik und Poliklinik C, Kardiologie und Angiologie, Universitätsklinikum Münster, Albert-Schweitzer Str. 33, 48149, Münster, Germany

    P. Milberg MD

  3. Interdisciplinary Center for Clinical Research (IZKF), Central Project Group 4a (ZPG4a), Münster, Germany

    J. Stypmann MD

  4. Dept. of Medical Informatics and Biomathematics, University of Münster, Münster, Germany

    N. Osada PhD

  5. Dept. of Cardiology, Campus Virchow Clinic, Charité – University Medicine, Berlin, Germany

    W. Haverkamp MD, FESC

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  1. P. Milberg MD
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  2. D. Fleischer MS
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  5. G. Mönnig MD
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Correspondence to P. Milberg MD.

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Milberg, P., Fleischer, D., Stypmann, J. et al. Reduced repolarization reserve due to anthracycline therapy facilitates torsade de pointes induced by IKr blockers. Basic Res Cardiol 102, 42–51 (2007). https://doi.org/10.1007/s00395-006-0609-0

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  • DOI: https://doi.org/10.1007/s00395-006-0609-0

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