NFATC1 modulation of atrial excitability in zebrafish.

Abstract

Atrial fibrillation (AF) is a common cardiac arrhythmia with a strong component of heritability. We recently identified the cardiac transcription factor NFATC1 as a novel AF susceptibility gene in a family with autosomal dominant young-onset AF. To further explore the role for NFATC1 in cardiac excitability, we generated a nfatc1 null (KO) zebrafish using CRISPR/Cas9. The absence of nfatc1 resulted in increased event of ∼80% of sudden death (log rank test p=0.0001) in nfatc1 null fish in the juvenile stage (5‑7 weeks) with a grossly indistinguishable morphology in the fish or explanted heart. Furthermore, nfatc1 juvenile null fish showed significantly faster heart rates (95±3 bpm in KO (n=18) vs 70±4 bpm in WT (n=15), p=0.0001) and an increased incidence of arrhythmogenesis and spontaneous delayed afterdepolarizations (DADs) in explanted juvenile hearts (29 /40 atrial records in KO fish showed some form of irregular rhythm, versus 11/28 atrial records in WT (Chi-Squared, p=0.0013)). Optical action potentials (AP) with a voltage‑sensitive dye revealed an abbreviated AP in KO atrium (80±1 ms in KO (n=607) vs 91±1 ms in WT (n=441), p=0.0001), but not ventricle (186±3 ms in KO (n=109) vs 191±2 ms in WT (n=160), p=0.0001). Our data suggest NFATC1 modulates atrial excitability but not ventricular, which reinforces our initial assessment as an AF susceptibility gene. Experiments are ongoing to further define the mechanism behind the DADs we observed in the nfact1 null fish.