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

Soh, M. S.; Kuanyshbek, A.; Mohamed Syazwan, E. S.; Lee, H. M.; McKenzie, C. E.; Phillips, A. M.; Hu, A.; Scheffer, I. E.; Semsarian, C.; Berkovic, S. F.; Reid, C. A.

doi:10.1101/2023.12.10.570964

bioRxiv · 10.1101/2023.12.10.570964

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

Soh, M. S.·Kuanyshbek, A.·Mohamed Syazwan, E. S.·Lee, H. M.·McKenzie, C. E.·Phillips, A. M.·Hu, A.·Scheffer, I. E.·Semsarian, C.·Berkovic, S. F.·Reid, C. A.

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Abstract

Sudden Unexpected Death in Epilepsy (SUDEP) is the leading cause of premature mortality in epilepsy. Genetic cardiac risk factors, including loss-of-function KCNH2 variants, have been linked to SUDEP. We hypothesised that seizures and LQTS interact to increase SUDEP risk. To investigate this, we crossed Kcnh2+/- and Gabrg2R43Q/+ mice that model LQTS and genetic epilepsy, respectively. Electrocorticography and electrocardiogram confirmed that Kcnh2+/- mice had a LQTS phenotype, while Gabrg2R43Q/+ 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 that Gabrg2R43Q/+/Kcnh2+/- mice experienced a disproportionate higher rate of seizure-related death. Long-term oral administration of atenolol, a cardiac-selective {beta}-blocker, significantly improved survival in the Gabrg2R43Q/+/Kcnh2+/- mice. An additional mouse model, Hcn1M294L/+/Kcnh2+/-, based on a HCN1 developmental 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-function KCNH2 variants as an important risk factor, and the potential repurposing of {beta}- blockers as a prevention strategy, for SUDEP in a subset of epilepsy patients.

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Soh, M. S., Kuanyshbek, A., Mohamed Syazwan, E. S., Lee, H. M., McKenzie, C. E., Phillips, A. M., Hu, A., Scheffer, I. E., Semsarian, C., Berkovic, S. F., Reid, C. A.. 2023-12-10. Atenolol reduces cardiac-mediated mortality in a genetic mouse model of sudden unexpected death in epilepsy. https://doi.org/10.1101/2023.12.10.570964

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