COMPARISON OF ACUTE EFFECTS OF ANTHRACYCLINES ON CARDIAC ELECTROPHYSIOLOGICAL PARAMETERS OF ISOLATED GUINEA-PIG HEARTS

This study was performed to evaluate the acute effects of two anthracycline derivatives, doxorubicin and 4′O-tetrahydropyranyl-doxorubicin [(THP)-doxorubicin], on the conduction intervals, heart rate and refractoriness of isolated spontaneously beating guinea-pig hearts using a high-resolution ECG recording technique (SST-ECG). Doxorubicin as well as (THP)-doxorubicin were added to the perfusate in increasing concentrations of 0.1, 1 and 10 μm. Doxorubicin did not significantly alter the heart rate or conduction intervals. Only the rate-dependent QT interval was significantly shortened under the influence of 10 μm doxorubicin. In contrast, 10 μm (THP)-doxorubicin led to a significant reduction in the heart rate (-13% ± 3%;P <0.01, n = 7) and to a prolongation of atrioventricular conduction time (24% ± 10%;P <0.05, n = 7). The rate-dependent repolarization period (QT interval) was only insignificantly shortened in the presence of 10 μm (THP)-doxorubicin. The maximal following frequencies of each part of the conduction system were not changed by 10 μm doxorubicin. In the presence of (THP)-doxorubicin, the maximal following frequency of the ventricular myocardium was increased by as much as 36% ± 8% (P <0.01, n = 7), indicating a shortening of the effective refractory period of the ventricular myocardium (V-ERP). These results show that the activation of (THP)-doxorubicin resembles the effects of Ca-antagonistic compounds on the heart (i.e. decrease in the spontaneous sinus rate and prolongation of the AV-nodal conduction interval). Changes in the QT interval exerted by doxorubicin and the shortening of the ventricular effective refractory period by (THP)-doxorubicin may indicate an alteration of the K+-conductance of the membrane. As the acute electrophysiological effects of doxorubicin and (THP)-doxorubicin are modest and occur only at excessive concentrations (10 μm), a direct influence on the generation of arrhythmias in healthy hearts is unlikely. © 1990 Springer-Verlag.