Abstract Body: Introduction: KCNJ2 mutations are associated with Andersen-Tawil Syndrome (ATS1), however the arrhythmia mechanisms are relatively unexplored. We previously reported KCNJ2 mutation G300D results in loss of I_K1 in a heterologous expression system. We generated a cardiac-specific G300D-KCNJ2 knock-in mouse that recapitulates the patient phenotype.
Objective: To elucidate the arrhythmia mechanism of KCNJ2 mutation G300D in an in vivo model.
Methods: Ambulatory continuous telemetry to capture arrhythmic activity at rest and following administration of epinephrine (2mg/kg) and caffeine (120mg/kg) in WT-Kir2.1 and G300D-Kir2.1 mice.
Results: G300D^+/- mice display pauses, ectopy and ventricular tachycardia at rest, whereas WT mice did not. Following adrenergic challenge, G300D^+/- mice had increased pauses, AV node dissociation, ventricular tachycardia and bi-directional ventricular tachycardia, whereas WT mice had sinus tachycardia. RR interval and QRS intervals were not significantly different between control and G300D^+/- mice either at rest (RR: Control 116.58 ± 13.67ms vs G300D^+/- 97.96 ± 9.65ms; QRS: Control 13.34 ± 0.93ms vs G300D^+/- 13.31 ± 0.27ms) or following adrenergic stimulation (RR: Control 92.15 ± 0.69ms vs G300D^+/- 109.25 ± 9.89ms; QRS: Control 14.09 ± 0.82ms vs G300D^+/- 13.78 ± 0.38ms).
Conclusions: In a novel in vivo model of ATS, our data indicate that G300D-Kir2.1 mutation results in arrhythmia at rest and following adrenergic stimulation. This suggests that loss of IK1 leads to heart rate variability, lowering the threshold for arrhythmogenesis.