Figure 1. Gata4 haploinsufficiency rescues atrial arrhythmias caused by Tbx5 haploinsufficiency.

(A) Common and rare gene variants in the transcription factors TBX5, GATA4, and NKX2-5 have been linked to increased AF susceptibility. (B) Relative transcript expression by qPCR in the left atrium of Tbx5^fl/+;R26^CreERT2, Gata4^fl/+;R26^CreERT2, and Gata4/Tbx5 compound heterozygotes 2 weeks after TM treatment. Data are represented as means ± SEM normalized to GAPDH and relative to R26^CreERT2 mice (set as 1) (n = 7–8 R26^CreERT2, n = 6–7 Tbx5^fl/+;R26^CreERT2, n = 9–10 Gata4^fl/+;R26^CreERT2, n = 12 Gata4^fl/+;Tbx5^fl/+;R26^CreERT2). Experiments were performed in technical duplicates. P values were determined by 1-way ANOVA followed by Tukey post-hoc test. **P = 0.01; ***P = 0.001; ****P = 0.0001. (C and D) P-wave duration and PR interval calculated from ambulatory telemetry ECG recordings from R26^CreERT2 (n = 6), Tbx5^fl/+;R26^CreERT2 (n = 8–9), Gata4^fl/+;R26^CreERT2 (n = 6), and Gata4^fl/+;Tbx5^fl/+;R26^CreERT2 (n = 10) mice. Tbx5^fl/+;R26^CreERT2 adult mice displayed significant increase in P-wave duration (C) and prolongation of the PR interval compared with R26^CreERT2 littermate controls (D). P values were determined by 1-way ANOVA followed by post-hoc Tukey test. (E–H) Intracardiac atrial electrogram recordings and corresponding surface ECG of R26^CreERT2 (n = 8), Tbx5^fl/+;R26^CreERT2 (n = 18), Gata4^fl/+;R26^CreERT2 (n = 12), and Gata4^fl/+;Tbx5^fl/+;R26^CreERT2 (n = 12) mice. Tbx5 heterozygotes displayed an irregular atrial electrogram, consistent with lack of P wave on surface ECG, which is representative of AF (F). A, atrial electrical signal; V, far-field ventricular electrical signal. (I) Pacing induction by intra-atrial pacing of mice in D–G. AF was reproducibly induced in 11 of 18 Tbx5 heterozygotes (60%) in contrast to 1 of 12 Gata4/Tbx5 compound heterozygotes, indicating rescue of atrial arrhythmias. P values were determined by Fisher’s exact test.