Figure 2. Abnormal atrial cardiomyocyte electrical activity caused by Tbx5 haploinsufficiency is rescued by Gata4 haploinsufficiency.

(A–D) Representative AP recordings from atrial myocytes isolated from R26^CreERT2, Tbx5^fl/+;R26^CreERT2, Gata4^fl/+;R26^CreERT2, and Gata4^fl/+;Tbx5^fl/+;R26^CreERT2 mice 2 weeks after receiving TM. Prolongation of phase 2 and 3 of the AP was observed exclusively in Tbx5^fl/+;R26^CreERT2 mice (B) but not in Gata4^fl/+;Tbx5^fl/+;R26^CreERT2 littermates (D), suggesting rescue of AP abnormalities. (E) Corresponding properties of AP from mice in A–D. Tbx5 heterozygotes showed significant prolongation of APD90 in comparison with R26^CreERT2 controls. These defects were completely rescued in Gata4/Tbx5 compound heterozygote mice (APD90, P = 0.006). APD50, APD at 50% repolarization; APD90, APD at 90% repolarization. Data represent mean ± SEM (n = 3–5 animals per genotype; n = 9 cardiomyocytes R26^CreERT2, n = 14 Tbx5^fl/+;R26^CreERT2, n = 10 Gata4^fl/+;R26^CreERT2, and n = 13 Gata4^fl/+;Tbx5^fl/+;R26^CreERT2). P values of APD50 and APD90 were determined by 1-way ANOVA followed by Tukey post-hoc test. (F and G) Representative tracings of EADs and DADs in Tbx5^fl/+;R26^CreERT2 atrial myocytes. (H) Representative abnormal depolarization events (EADs and DADs) observed in atrial myocytes. Reduced Gata4 gene dosage rescued abnormal triggers observed in Tbx5- haploinsufficient atrial myocytes. Total number of ectopic depolarization events were recorded in R26^CreERT2 (n = 9), Tbx5^fl/+;R26^CreERT2 (n = 14), Gata4^fl/+;R26^CreERT2 (n = 10), and Gata4^fl/+;Tbx5^fl/+;R26^CreERT2 (n = 13) atrial myocytes from n > 4 for each genotype. P values of triggers were determined by Fisher’s exact test. (I) The cellular conduction deficits caused by Tbx5 haploinsufficiency, including AP prolongation and triggered activity and normalization by reduced Gata4 dose.