Knock-in Kcnh2 Rabbit Model of Long QT Syndrome Type-2, Epilepsy, and Sudden Death

Area of Science:

• Cardiovascular Genetics
• Neuroscience
• Translational Medicine

Background:

• Long QT Syndrome Type-2 (LQT2) is a genetic disorder caused by loss-of-function variants in the KCNH2 gene, which encodes the K_v11.1 potassium channel.
• LQT2 is associated with severe clinical manifestations including cardiac arrhythmias, seizures, sudden cardiac death, and sudden unexpected death in epilepsy (SUDEP).
• Existing models do not fully recapitulate the complex neuro-cardiac electrical abnormalities and risk of sudden death seen in LQT2 patients.

Purpose of the Study:

• To develop a translational rabbit model that accurately reproduces the neuro-cardiac electrical abnormalities and sudden death phenotypes observed in Long QT Syndrome Type-2 (LQT2).
• To investigate the underlying mechanisms of LQT2-associated sudden death and epilepsy.

Main Methods:

• Generation of the first knock-in rabbit model of LQT2, designated Kcnh2^(+/7bp-del), by introducing a 7 base-pair deletion in the pore domain of the endogenous rabbit Kcnh2 gene.
• Characterization of mutant Kcnh2 expression levels in the heart and brain of the rabbit model.
• Assessment of cardiac repolarization parameters (QTc, JT_ec, JT_pc) and electrophysiological activity, including seizure prevalence and sudden death events.

Main Results:

• The Kcnh2^(+/7bp-del) rabbits exhibited reduced expression of both total and wild-type (WT) K_v11.1 channels in the heart and brain.
• Significant prolongation of cardiac ventricular repolarization was observed in Kcnh2^(+/7bp-del) rabbits compared to WT controls.
• A marked increase in spontaneous epileptiform activity, clinical seizures (7/37 vs 1/68 rabbits), and sudden spontaneous death (18.9% vs 1.5% of rabbits) was recorded in the LQT2 rabbit model, including both sudden cardiac death and seizure-mediated sudden death.

Conclusions:

• The Kcnh2^(+/7bp-del) rabbit represents the first genetic model of LQT2 that successfully replicates the associated cardiac and epileptic phenotypes.
• This novel rabbit model serves as a valuable preclinical tool for investigating LQT2 pathogenesis, developing novel neurotherapeutics, and conducting cardiac safety assessments.
• The model facilitates further mechanistic studies into the complex interplay between cardiac and neurological dysfunction in LQT2.