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

Background and Purpose: Reliable prediction of pro-arrhythmic side effects of novel drug candidates is still a major challenge. Although drug-induced pro-arrhythmia occurs primarily in patients with pre-existing repolarisation disturbances, healthy animals 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 I_Kr; LQT2), KCNE1 (KCNE1-G52R, decreased I_Ks; LQT5), or both transgenes (LQT2-5) in the heart. Experimental Approach: 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 I_Kr-blocking (LQT5) or I_K1/I_Ks-blocking (LQT2 and LQT2-5) properties of drugs compared to healthy WT animals. Impaired QT-shortening capacity at fast heart rates was observed due to disturbed I_Ks function in LQT5 and LQT2-5. Importantly, LQTS models exhibited higher incidence, longer duration, and more malignant types of ex vivo arrhythmias than WT. Conclusion and Implications: LQTS models represent patients with reduced repolarisation reserve due to different pathomechanisms. As they demonstrate increased sensitivity to different specific ion channel blockers (I_Kr blockade in LQT5 and I_K1 and I_Ks blockade in LQT2 and LQT2-5), their combined use could provide more reliable and more thorough prediction of (multichannel-based) pro-arrhythmic potential of novel drug candidates.