Transgenic LQT2, LQT5 and LQT2-5 rabbit models with decreased repolarisation reserve for prediction of drug-induced ventricular arrhythmias.

BACKGROUND AND PURPOSE: The reliable prediction of pro-arrhythmic side-effects of novel drug candidates represents a major but unsolved challenge. Although drug-induced pro-arrhythmia occurs primarily in patients harbouring repolarisation disturbances, mostly healthy animal models are employed for pro-arrhythmia testing. To improve current safety screening, transgenic long-QT (LQTS) rabbit models with impaired repolarisation reserve were generated by overexpressing loss-of-function mutations of human HERG (HERG-G628S, loss of IKr ; LQT2), KCNE1 (KCNE1-G52R, decreased IKs ; LQT5), or both transgenes (LQT2-5) in the heart. EXPERIMENTAL APPROACH: The effects of K+ -channel-blockers on cardiac repolarisation and arrhythmia susceptibility were assessed in healthy wild-type (WT) and LQTS rabbits using in vivo ECG and ex vivo monophasic action potential and ECG recordings in Langendorff-perfused hearts. KEY RESULTS: LQTS models reflect patients with clinically 'silent' (LQT5) or 'manifest' (LQT2 and LQT2-5) impairment in cardiac repolarisation reserve: they were more sensitive in detecting IKr - (LQT5) or IK1 /IKs - (LQT2 and LQT2-5) blocking properties of drugs compared to healthy WT animals. Impaired QT-shortening capacity at fast heart rates was observed due to disturbed IKs function in LQT5 and LQT2-5. Importantly, LQTS models exhibited higher incidence, longer duration and more malignant type of ex vivo arrhythmias than WT. CONCLUSION AND IMPLICATIONS: LQTS models represent patients with reduced repolarisation reserve due to different patho-mechanisms. As they demonstrate increased sensitivity to different specific ion channel-blockers (IKr -blockade in LQT5, IK1 - and IKs -blockade in LQT2 and LQT2-5), their combined use could provide more reliable, and more thorough prediction of (multi-channel-based) pro-arrhythmic potential of novel drug candidates.