Arrhythmogenesis in a Novel Murine Model with KCNJ2 Mutation of Familial Atrial Fibrillation

Abstract

Background A family with inherited atrial fibrillation (AF) has been discovered expressing a gain of function mutation (V93I) in the KCNJ2 gene coding the strong inward rectifier potassium channel expressing the current IK1. Our objective is to determine the biophysical alterations in Ik1 caused by this mutation and its consequential arrhythmogenesis. Methods Whole cell patch clamp techniques were used to characterize control and mutant KCNJ2V93I IK1 in HEK cells. A mouse line with the targeted knock-in mutation KCNJ2V93I was generated. ECGs of anesthetized animals (N=4) were used to determine the incidence of arrhythmias and RR intervals in the presence of 6µL/g mL isoproterenol (ISO). Results Whole cell patch clamp analysis of V93I mutation expressed in HEK cells demonstrated an increase in IK1 density (A) and unitary channel events that exhibited a higher incidence of channel substates (B2) compared to controls (B1). Control animals challenged with ISO demonstrated a transient rise in heart rate but otherwise unremarkable ECGs (C1). In contrast, KCNJ2V93I/WT (heterozygote) animals given ISO exhibited irregular atrial activity and brief episodes of AF characterized by the lack of p-waves and variable RR intervals (C2). KCNJ2V93I/WT animals also displayed instances of ectopic activity and complete A-V dissociation (C3, C4).. Conclusions A clinically relevant mutation in KCNJ2 resulting in gain of function in IK1 and altered single channel conductance recapitulated the clinical phenotype seen in patients displaying both atrial and ventricular arrhythmias.