Atenolol rescues premature mortality in genetic mouse models of sudden unexpected death in epilepsy

Abstract

Objective: Sudden unexpected death in epilepsy (SUDEP) is the leading cause of premature mortality in epilepsy. Genetic studies have identified that loss-of-function (LOF) KCNH2 variants are enriched in SUDEP patients, suggesting that they may act as a risk factor. KCNH2 encodes the KV11.1 channel, with LOF pathogenic variants a cause of long-QT syndrome (LQTS), increasing the risk of arrhythmia and sudden cardiac death. Here, we engineered preclinical rodent models that combine epilepsy-causing pathogenic variants with heterozygous Kcnh2 knockout mice to explore the impact of reduced KV11.1 channel function on mortality. Methods: Both the Gabrg2R43Q/+ and Hcn1M294L/+ genetic mouse models of..