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

• Published in: Basic research in cardiology Vol. 102; no. 1; pp. 42 - 51
• Main Authors: Milberg, Peter, Fleischer, Dirk, Stypmann, Jörg, Osada, Nani, Mönnig, Gerold, Engelen, Markus A, Bruch, Christian, Breithardt, Günter, Haverkamp, Wilhelm, Eckardt, Lars
• Format: Journal Article
• Language: English
• Published: Germany Springer Nature B.V 01.01.2007
• Subjects: Action Potentials - drug effects; Animals; Antibiotics, Antineoplastic - adverse effects; Delayed Rectifier Potassium Channels - antagonists & inhibitors; Dose-Response Relationship, Drug; Doxorubicin - adverse effects; Electrocardiography; Erythromycin - adverse effects; Heart Conduction System - drug effects; In Vitro Techniques; Male; Rabbits; Stroke Volume - drug effects; Torsades de Pointes - chemically induced
• ISSN: 0300-8428; 1435-1803
• DOI: 10.1007/s00395-006-0609-0

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. 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 I(Kr)-blocker erythromycin (150-300 microM) 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, I(Kr)-block led to a more marked increase of dispersion of MAP(90) 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). 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 I(Kr)-blocking drugs. Thus, anthracycline therapy reduces repolarization reserve and thereby represents a novel contributing factor for the development of life-threatening proarrhythmia.