Presentation description

Atrial fibrillation (AF) is the most common form of cardiac arrhythmia. The condition causes erratic, rapid atrial depolarization and leads to a substantially increased risk of stroke, heart failure, and other life-threatening complications. We identified a Utahn family with a young-onset AF phenotype segregating. Sequencing revealed a damaging genetic variant (M527L) in the nuclear factor of activated T-cells 1 (NFATC1) gene that segregated with the AF phenotype. NFATC1 encodes a calcium-dependent transcription factor. To determine how the NFATC1 mutation affects cardiac function, we used a CRISPR-Cas9 approach to create a humanized line of nfatc1 mutated zebrafish that contains the equivalent mutation (M468L). Using light microscopy, we recorded the zebrafish's heart rates and gross morphology at 72 hours post-fertilization (hpf). The video recordings revealed increased base heart rate (measured in beats per minute (bpm)) in the homozygous mutant strains (128±2bpm WT (n=44) vs. 149±3bpm MUT (n=30), p <0.0001), with no observable change in gross morphology, including length (3.06±0.02mm WT (n=38) vs. 2.98±0.03mm MUT (n=30), p = 1). These results imply that NFATC1 influences atrial activity. Future steps include obtaining data on the heterozygote nfatc1 embryos, completing data acquisition on other developmental stages, and testing response to stress by using adrenergic agonist drugs. Determination of the relationship between nfatc1 and atrial activity in embryonic zebrafish will support the development of new therapeutics and risk stratification for atrial arrhythmias.