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

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 K_V11.1 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 K_V11.1 channel function on mortality.

Methods: Both the Gabrg2^R43Q/+ and Hcn1^M294L/+ genetic mouse models of monogenic epilepsy were crossed with Kcnh2^+/- mice. All genotypes were video-recorded post-weaning and time to death was measured. Additional mice underwent surgery to enable simultaneous electrocorticography and electrocardiography recordings. Atenolol was delivered in drinking water to a subset of mice.

Results: Both single mutant Gabrg2^R43Q/+ and Hcn1^M294L/+ mice displayed spontaneous seizures recapitulating the human phenotypes. Single mutant Kcnh2^+/- mice exhibited an LQTS phenotype. Double mutant mice (Gabrg2^R43Q/+/Kcnh2^+/- and Hcn1^M294L/+/Kcnh2^+/-) had both seizure and prolonged QT interval phenotypes that were similar to their respective single mutant mice. Survival analysis revealed that Gabrg2^R43Q/+/Kcnh2^+/- and Hcn1^M294L/+/Kcnh2^+/- mice experienced a disproportionately higher rate of seizure-related death when compared to wild-type and their respective single mutant littermates. Oral administration of the cardiac-selective β-blocker atenolol significantly improved survival in Gabrg2^R43Q/+/Kcnh2^+/-, Hcn1^M294L/+, and Hcn1^M294L/+/Kcnh2^+/- mice. Atenolol attenuated the sympathetic cardiac response to non-terminal seizures.

Significance: The data support the premise that LOF KCNH2 variants can contribute to SUDEP risk in a subset of epilepsy patients. Our findings also highlight the potential use of β-blockers as a prevention strategy in SUDEP.