ABSTRACT
AIMS: Short-QT-syndrome type 1 (SQT1) is a genetic channelopathy caused by gain-of-function variants in HERG underlying the rapid delayed-rectifier K+ current (IKr), leading to QT-shortening, ventricular arrhythmias, and sudden cardiac death. Data on efficient pharmaco-therapy for SQT1 are scarce. In patients with primary carnitine-deficiency, acquired-SQTS has been observed and rescued by carnitine-supplementation. Here, we assessed whether carnitine exerts direct beneficial (prolonging) effects on cardiac repolarization in genetic SQTS. METHODS AND RESULTS: Adult wild-type (WT) and transgenic SQT1 rabbits (HERG-N588K, gain of IKr) were used. In vivo ECGs, ex vivo monophasic action potentials (APs) in Langendorff-perfused hearts, and cellular ventricular APs and ion currents were assessed at baseline and during L-Carnitine/C16-Carnitine-perfusion. 2D computer simulations were performed to assess reentry-based VT-inducibility.L-Carnitine/C16-Carnitine prolonged QT intervals in WT and SQT1, leading to QT-normalization in SQT1. Similarly, monophasic and cellular AP duration (APD) was prolonged by L-Carnitine/C16-Carnitine in WT and SQT1. As underlying mechanisms, we identified acute effects on the main repolarizing ion currents: IKr-steady, which is pathologically increased in SQT1, was reduced by L-Carnitine/C16-Carnitine and deactivation kinetics were accelerated. Moreover, L-Carnitine/C16-Carnitine decreased IKs-steady and IK1. In silico modelling identified IKr-changes as main factor for L-Carnitine/C16-Carnitine-induced APD-prolongation. 2D-simulations revealed increased sustained reentry-based arrhythmia formation in SQT1 compared to WT, which was decreased to the WT-level when adding carnitine-induced ion current changes. CONCLUSION: L-Carnitine/C16-Carnitine prolong/normalize QT and whole heart/cellular APD in SQT1 rabbits. These beneficial effects are mediated by acute effects on IKr. L-Carnitine may serve as potential future QT-normalizing, anti-arrhythmic therapy in SQT1.
ABSTRACT
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.