Transgenic short-QT syndrome 1 rabbits mimic the human disease phenotype with QT/action potential duration shortening in the atria and ventricles and increased ventricular tachycardia/ventricular fibrillation inducibility.

AIMS: Short-QT syndrome 1 (SQT1) is an inherited channelopathy with accelerated repolarization due to gain-of-function in HERG/IKr. Patients develop atrial fibrillation, ventricular tachycardia (VT), and sudden cardiac death with pronounced inter-individual variability in phenotype. We generated and characterized transgenic SQT1 rabbits and investigated electrical remodelling. METHODS AND RESULTS: Transgenic rabbits were generated by oocyte-microinjection of ß-myosin-heavy-chain-promoter-KCNH2/HERG-N588K constructs. Short-QT syndrome 1 and wild type (WT) littermates were subjected to in vivo ECG, electrophysiological studies, magnetic resonance imaging, and ex vivo action potential (AP) measurements. Electrical remodelling was assessed using patch clamp, real-time PCR, and western blot. We generated three SQT1 founders. QT interval was shorter and QT/RR slope was shallower in SQT1 than in WT (QT, 147.8 ± 2 ms vs. 166.4 ± 3, P < 0.0001). Atrial and ventricular refractoriness and AP duration were shortened in SQT1 (vAPD90, 118.6 ± 5 ms vs. 154.4 ± 2, P < 0.0001). Ventricular tachycardia/fibrillation (VT/VF) inducibility was increased in SQT1. Systolic function was unaltered but diastolic relaxation was enhanced in SQT1. IKr-steady was increased with impaired inactivation in SQT1, while IKr-tail was reduced. Quinidine prolonged/normalized QT and action potential duration (APD) in SQT1 rabbits by reducing IKr. Diverse electrical remodelling was observed: in SQT1, IK1 was decreased-partially reversing the phenotype-while a small increase in IKs may partly contribute to an accentuation of the phenotype. CONCLUSION: Short-QT syndrome 1 rabbits mimic the human disease phenotype on all levels with shortened QT/APD and increased VT/VF-inducibility and show similar beneficial responses to quinidine, indicating their value for elucidation of arrhythmogenic mechanisms and identification of novel anti-arrhythmic strategies.

Differential effects of the ß-adrenoceptor blockers carvedilol and metoprolol on SQT1- and SQT2-mutant channels.

BACKGROUND: N588K-KCNH2 and V307L-KCNQ1 mutations lead to a gain-of-function of IKr and IKs thus causing short-QT syndromes (SQT1, SQT2). Combined pharmacotherapies using K(+) -channel-blockers and ß-blockers are effective in SQTS. Since ß-blockers can block IKr and IKs , we aimed at determining carvedilol's and metoprolol's electrophysiological effects on N588K-KCNH2 and V307L-KCNQ1 channels. METHODS: Wild-type (WT)-KCNH2, WT-KCNQ1 and mutant N588K-KCNH2 and V307L-KCNQ1 channels were expressed in CHO-K1 or HEK-293T cells and IKs and IKr were recorded at baseline and during ß-blocker exposure. RESULTS: Carvedilol (10 µM) reduced IKs tail in WT- and V307L-KCNQ1 by 36.5 ± 5% and 18.6 ± 9% (P < 0.05). IC50 values were 16.3 µM (WT) and 46.1 µM (V307L), indicating a 2.8-fold decrease in carvedilol's IKs -blocking potency in V307L-KCNQ1. Carvedilol's (1 µM) inhibition of the IKr tail was attenuated in N588K-KCNH2 (4.5 ± 3% vs 50.3 ± 4%, WT, P < 0.001) with IC50 values of 2.8 µM (WT) and 25.4 µM (N588K). Carvedilol's IKr end-pulse inhibition, however, was increased in N588K-KCNH2 (10 µM, 60.7 ± 6% vs 36.5 ± 5%, WT, P < 0.01). Metoprolol (100 µM) reduced IKr end-pulse by 0.23 ± 3% (WT) and 74.1 ± 7% (N588K, P < 0.05), IKr tail by 32.9 ± 10% (WT) and 68.8 ± 7% (N588K, P < 0.05), and reduced IKs end-pulse by 18.3 ± 5% (WT) and 57.1 ± 11% (V307L, P < 0.05) and IKs tail by 3.3 ± 1% (WT) and 45.1 ± 13 % (V307L, P < 0.05), indicating an increased sensitivity to metoprolol in SQT mutated channels. CONCLUSIONS: N588K-KCNH2 and V307L-KCNQ1 mutations decrease carvedilol's inhibition of the IKs or IKr tail but increase carvedilol's IKr end-pulse inhibition and metoprolol's inhibition of tail and end-pulse currents. These different effects on SQT1 and SQT2 mutated channels should be considered when using ß-blocker therapy in SQTS patients.