Abstracts

Long QT Syndrome Type-2 (LQT2) is due to an ion channelopathy caused by KCNH2 gene variants. LQT2 patients are at an increased risk of arrhythmias, seizures, and sudden death. Our lab developed a clinically relevant genetic rabbit model of LQT2 with epileptic seizures and cardiac ECG abnormalities (QT_c prolongation). The objective of the study is to investigate the incidence and prevalence of epileptiform discharges in WT and LQT2-mutant rabbits, particularly in those that died of sudden death.

Using CRISPR-Cas9 technology, we generated three mutant rabbit lines. We introduced a frameshift 7BP (Kcnh2^(+/7BP)) and 43BP(Kcnh2^(+/43BP)) deletion in the pore domain of one allele of the endogenous rabbit Kcnh2 gene. The third mutant line has a point mutation (A561V) and a 127BP insertion in the pore domain of one allele of the endogenous rabbit Kcnh2 gene (Kcnh2^(+/A561V+)). We acquired video, EEG, and ECG recordings from conscious restrained rabbits.

Epileptiform activity is documented in 6:10 Kcnh2^(+/7BP), 3:6 Kcnh2^(+/43BP), and 2:2 Kcnh2^(+/A561V+) rabbits. In contrast, none of the WT rabbits exhibited epileptiform activity (n=16). Additionally, clinical seizures were noted in 1 Kcnh2^(+/43BP) and 5 Kcnh2^(+/7BP) rabbits.

Seven of 27 Kcnh2^(+/7BP) rabbits died suddenly and spontaneously. There was a rapid onset of rigor, and no cause of death was found during necropsy. After rigorous analysis of the baseline EEG recordings of five out seven sudden death cases, spontaneous epileptiform discharges and clinical seizures were documented in 4 Kcnh2^(+/7BP) rabbits. For the other two cases of sudden death, video/EEG/ECG recordings indicated electrographic and clinical seizures, post-ictal generalized EEG suppression, and ECG abnormalities leading up to sudden death. Detailed analysis in one case of sudden death indicates a high incidence of epileptiform activity (45 EEG discharges per 30 seconds) leading up to sudden death. While none of the WT littermates exhibited any epileptiform activity, 2 of 3 Kcnh2^(+/7bp) littermates also exhibited intermittent epileptiform activity (10 EEG discharges per 30 seconds).

Kcnh2^(+/mut) rabbits exhibit EEG and ECG abnormalities, clinical seizures, and seizure-related sudden death. We developed a genetic rabbit model of LQT2 that reproduces the neuro-cardiac pathologies seen in people with LQT2.