Electrophysiological Safety Profile of Antiestrogenic Therapies in the Isolated Rabbit Heart

Abstract

<b><i>Introduction:</i></b> Hormone-mediated therapies are on the rise and are key therapies in the treatment of some of the most common cancer entities. Proarrhythmic effects have been described in patients treated with SERMs while little to none is known about the electrophysiological effects of the potentially less arrhythmogenic selective estrogen receptor degraders. <b><i>Methods:</i></b> Twenty hearts of female New Zealand White rabbits were excised and retrogradely perfused employing a Langendorff setup. An electrophysiology study was performed to obtain CL-dependent action potential duration at 90% of repolarization (APD₉₀), QT interval, effective refractory period (ERP), and post-repolarization refractoriness (PRR = ERP-APD₉₀). After generating baseline data, the hearts were assigned to two groups and perfused with (<i>n</i> = 10) increasing doses of fulvestrant (1 µM and 5 µM; <i>n</i> = 10) or tamoxifen (2.5 µM and 7.5 µM; <i>n</i> = 10), and the protocol was repeated again. <b><i>Results:</i></b> Fulvestrant led to a decrease in APD₉₀ and QT interval and an increased PRR. The inducibility of ventricular tachycardia (VT) episodes was unaltered. Tamoxifen showed similar effects, resulting in a shortened APD₉₀ and QT interval and no increased VT incidence in the setting of a prolonged PRR. <b><i>Conclusion:</i></b> The present study shows no acute proarrhythmic effect of tamoxifen and fulvestrant in an established whole heart model when employing clinically relevant concentrations.