Beta-blocker Atenolol Reduces Cardiac-mediated Mortality in Preclinical Mouse Model of Sudden Unexpected Death in Epilepsy
Abstract number :
3.103
Submission category :
2. Translational Research / 2D. Models
Year :
2023
Submission ID :
117
Source :
www.aesnet.org
Presentation date :
12/4/2023 12:00:00 AM
Published date :
Authors :
Presenting Author: Ming Soh, PhD – The Florey Institute of Neuroscience and Mental Health
Erlina Mohamed Syazwan, BSci (Hons) – The Florey Institute of Neuroscience and Mental Health; Alibek Kuanyshbek, MD – The Florey Institute of Neuroscience and Mental Health; Hian Lee, MD – The Florey Institute of Neuroscience and Mental Health; Chaseley McKenzie, BSci (Hons) – The Florey Institute of Neuroscience and Mental Health; Marie Phillips, PhD – The Florey Institute of Neuroscience and Mental Health; Lauren Bleakley, PhD – The Florey Institute of Neuroscience and Mental Health; Ingrid Scheffer, MD PhD – The Florey Institute of Neuroscience and Mental Health; Samuel Berkovic, MD – Epilepsy Research Centre, University of Melbourne; Christopher Semsarian, MD PhD – Centenary Institute, The University of Sydney; Christopher Reid, PhD – The Florey Institute of Neuroscience and Mental Health
Rationale:
Sudden Unexpected Death in Epilepsy (SUDEP) is a common cause of premature mortality for individuals with epilepsy. An increasing body of evidence supports the role of cardiac dysfunction in SUDEP, particularly arrhythmias. Recent genetic studies have found pathogenic variants in cardiac arrhythmia genes, including the voltage-gated potassium channel gene KCNH2, in humans who died of SUDEP. Loss-of-function KCNH2 is an established cause of the inherited arrhythmia long-QT syndrome (LQTS). Our functional study revealed a three fold enrichment in loss-of-function KCNH2 variants in SUDEP patients compared to control epilepsy cohort. This study sought to elucidate the interaction between epileptic seizures, KCNH2-mediated cardiac arrhythmia and SUDEP risk. We hypothesize that loss-of-function KCNH2 that causes LQTS will increase the risk of sudden death during an epileptic seizure, and that this risk can be reduced by repurposing a LQTS treatment.
Methods:
We engineered a novel SUDEP mouse model that has both genetic epilepsy and cardiac arrhythmia by crossing a mouse model of LQTS (Kcnh2+/-) with a mouse model of genetic epilepsy with febrile seizures plus (Gabrg2R43Q). We compared the survival between the littermates which were video-recorded 24/7 until P100. Electrocardiogram (ECG) and electrocorticography (ECoG) recordings were made in a subset of mice to measure cardiac and brain function respectively. A cohort of double mutant mice were randomly assigned either untreated (normal drinking water) or 0.6 g/L atenolol-treated group (a cardiac-selective beta-blocker dissolved in drinking water). Survival analysis was done using a Mantel-Cox log-rank test. Student’s t-test was used for comparison between two groups. Statistical significance was set at P< 0.05.
Translational Research