56 Role of ZFHX3 in atrial fibrillation

Background Atrial fibrillation (AF) is the most common clinical arrhythmia, although the pathophysiology remains poorly understood. Population-based genetic studies have identified a susceptibility locus for AF at the gene ZFHX3 . Hypothesis We hypothesized that a cardiac-restricted knockout of the transcription factor ZFHX3 in a mammalian model organism would perturb normal cardiac development and function, and illuminate the role of ZFHX3 in AF. Methods and results We generated a murine cardiac-restricted knockdown of ZFHX3 using cre-lox recombination. Knockdown was confirmed by organ specific genotyping. Among knockdown mice, increased inducibility of atrial arrhythmias was observed at in vivo electrophysiology testing at 3 months of age (% arrhythmia induction maneuvers 10 vs 0, p ZFHX3 , with a marked atrial predominance. Optical mapping of Langendorff-perfused hearts demonstrated increased conduction velocity in knockdown atria (p -11 ) and upregulated in the knockdown right atria (FDR=1.1 × 10 -12 ). Functional analysis further implicated differential control of the hedgehog signaling pathway as the most significantly enriched pathway for differentially expressed genes common to both atria (BH value=7.9 × 10 -6 ), with global upregulation in the left atrium and downregulation in the right atrium. Functional analysis of differentially expressed genes by atrium also revealed abnormalities in calcium ion binding and ion transmembrane transporter activity. Conclusion We have uncovered a role for ZFHX3 in the left-right patterning of cardiac atria. Disruption of this developmental process predisposes to atrial cardiomyopathy, affects atrial electrophysiology properties, changes which may increase the susceptibility to AF.