Atenolol reduces cardiac-mediated mortality in genetic mouse model of sudden unexpected death in epilepsy

Abstract

AbstractSudden Unexpected Death in Epilepsy (SUDEP) is the leading cause of premature mortality in epilepsy. Genetic cardiac risk factors, including loss-of-functionKCNH2variants, have been linked to SUDEP. We hypothesised that seizures and LQTS interact to increase SUDEP risk. To investigate this, we crossedKcnh2+/-andGabrg2R43Q/+mice that model LQTS and genetic epilepsy, respectively. Electrocorticography and electrocardiogram confirmed thatKcnh2+/-mice had a LQTS phenotype, whileGabrg2R43Q/+mice displayed spontaneous seizures. Double mutant mice (Gabrg2R43Q/+/Kcnh2+/-) had both seizure and LQTS phenotypes that were indistinguishable from the respective single mutant mice. Survival analysis revealed thatGabrg2R43Q/+/Kcnh2+/-mice experienced a disproportionate higher rate of seizure-related death. Long-term oral administration of atenolol, a cardiac-selective β-blocker, significantly improved survival in theGabrg2R43Q/+/Kcnh2+/-mice. An additional mouse model,Hcn1M294L/+/Kcnh2+/-, based on aHCN1developmental epileptic encephalopathy variant, also experienced a disproportionately higher rate of premature death that was rescued by atenolol.Kcnh2+/-mice also spent more time in ventricular arrhythmia during proconvulsant-induced seizures. Overall, the data implicates cardiac and loss-of-functionKCNH2variants as an important risk factor, and the potential repurposing of β- blockers as a prevention strategy, for SUDEP in a subset of epilepsy patients.