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

Abstract

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.