Beneficial normalization of cardiac repolarization by carnitine in transgenic SQT1 rabbit models.

Abstract

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. 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. 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.