Investigating the role of genetic cardiac arrhythmia in sudden unexpected death in epilepsy

We are aiming to develop and measure the electrophysiology of stem cell-derived cardiomyocytes, including 3D ‘mini heart’ cardiac organoids, that express the cardiac arrhythmia variant identified in SUDEP patients. These models provide an opportunity to test cardio-protective strategies on SUDEP risk. Successful applicants will have the opportunity to learn to operate multi-electrode array system, optogenetics, patch-clamp electrophysiology, perform EEG-ECG surgery/monitoring/analysis, mouse handling/injections, stem cell culture, molecular biology, and be involved in manuscript preparation.

Epilepsy patients have an increased risk of sudden unexpected death (SUDEP). Our recent publications showed that genetic dysfunction in cardiac ion channels, which leads to cardiac arrhythmia, can increase SUDEP risk, further highlighting the role of cardiac arrhythmia in SUDEP pathophysiology. This gives us a unique opportunity to develop novel preclinical models based on the human genetic biomarker.

Using our recently engineered SUDEP mouse models that have human-equivalent genetic heart dysfunction, we will perform EEG-ECG surgery and recording to monitor changes in brain and heart function during seizure and death events. We will also use this model to trial known treatments for cardiac arrhythmia to see if these reduce the risk of SUDEP.

The mouse models will allow us to:

• understand the cardiac role in SUDEP pathomechanisms
• test and repurpose therapies for cardiac arrhythmia to reduce SUDEP risk
• translate our findings to the clinic, where our biomarkers and treatment strategies can be used to identify epilepsy patients at risk and help determine the appropriate intervention.

Successful applicants will have the opportunity to learn to perform EEG-ECG surgery/monitoring/analysis, mouse handling/injections, molecular biology, and be involved in manuscript preparation.