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 V 11.1 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 V 11.1 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.