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SHR Neuro Cancer Cardio Lipid Metab Microb

Bodi, I; Mettke, L; Michaelides, K; Hornyik, T; Meier, S; Nimani, S; Perez-Feliz, S; El-Battrawy, I; Bugger, H; Zehender, M; Brunner, M; Heijman, J; Odening, KE.
Beneficial normalization of cardiac repolarization by carnitine in transgenic short QT syndrome type 1 rabbit models.
Cardiovasc Res. 2024; 120(13):1550-1561 Doi: 10.1093/cvr/cvae149 [OPEN ACCESS]
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Co-authors Med Uni Graz: Bugger Heiko Matthias; Heijman Jordi
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Abstract:: AIMS: Short QT syndrome type 1 (SQT1) is a genetic channelopathy caused by gain-of-function variants in human-ether-a-go-go (HERG) underlying the rapid delayed-rectifier K+ current (IKr), leading to QT-shortening, ventricular arrhythmias, and sudden cardiac death. Data on efficient pharmacotherapy for SQT1 are scarce. In patients with primary carnitine-deficiency, acquired-short QT syndrome (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 electrocardiograms (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. Two-dimensional computer simulations were performed to assess re-entry-based ventricular tachycardia-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 the main factor for L-Carnitine/C16-Carnitine-induced APD-prolongation. 2D simulations revealed increased sustained re-entry-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 a potential future QT-normalizing, anti-arrhythmic therapy in SQT1.
Find related publications in this database (using NLM MeSH Indexing): Animals - administration & dosage; Rabbits - administration & dosage; Carnitine - pharmacology, metabolism; Action Potentials - drug effects; Disease Models, Animal - administration & dosage; Heart Rate - drug effects; Animals, Genetically Modified - administration & dosage; Arrhythmias, Cardiac - physiopathology, metabolism, genetics, drug therapy; Isolated Heart Preparation - administration & dosage; ERG1 Potassium Channel - metabolism, genetics; Models, Cardiovascular - administration & dosage; Computer Simulation - administration & dosage; Myocytes, Cardiac - metabolism, drug effects, pathology; Time Factors - administration & dosage; Phenotype - administration & dosage; Electrocardiography - administration & dosage; Genetic Predisposition to Disease - administration & dosage; Humans - administration & dosage; Male - administration & dosage; Tachycardia, Ventricular - physiopathology, metabolism, genetics, drug therapy; Muscular Diseases - genetics, physiopathology, metabolism, drug therapy; Heart Conduction System - abnormalities; Heart Defects, Congenital - administration & dosage
Find related publications in this database (Keywords): Carnitine; Short QT syndrome; Cardiac repolarization; Animal model; Arrhythmia