Evaluation of proarrhythmic drug adverse effects using transgenic rabbit models of long QT syndrome
Hornyik Tibor, Husti Zoltán, Baczkó István
Szegedi Tudományegyetem, Szent-Györgyi Albert Orvostudományi Kar,
Farmakológiai és Farmakoterápiai Intézet, Szeged
Drug-induced proarrhythmia poses as a severe and potentially fatal adverse effect of various compounds. Proarrhythmic adverse effcts are often attributed to the drug’s capacity to inhibit repolarizing cardiac ion currents leading to a prolongation of the QT interval on the ECG. In spite of the sophisticated screening methods in drug development, the reliable prediction of proarrhythmia remains challenging. Although drug-induced long-QT-related proarrhythmia is often facilitated by pathological settings that reduce the patient’s repolarization reserve, most model systems used for drug safety screening focus on normal, healthy cells, tissues and animals. Recently, several transgenic long QT syndrome (LQTS) rabbit models with impaired repolarization reserve have been generated. In this review, we discuss the potential use of these models for drug-induced arrhythmia prediction, in relation to the different repolarizing cardiac ionic current impairment in the different models. In addition, we overview the electrophysiological characteristics of the available transgenic LQTS rabbit models, and the pharmacological proof-of-principle studies that have been carried out with these models, highlighting the advantages and disadvantages of transgenic rabbit LQTS models for proarrhythmia research.
ISSUE: CARDIOLOGIA HUNGARICA | 2023 | VOLUME 53, ISSUE 5
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