Atrial fibrillation risk loci interact to modulate Ca2+-dependent atrial rhythm homeostasis
Brigitte Laforest, … , Christopher R. Weber, Ivan P. Moskowitz
Brigitte Laforest, … , Christopher R. Weber, Ivan P. Moskowitz
Published October 14, 2019
Citation Information: J Clin Invest. 2019;129(11):4937-4950. https://doi.org/10.1172/JCI124231.
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Research Article Cardiology Genetics

Atrial fibrillation risk loci interact to modulate Ca2+-dependent atrial rhythm homeostasis

Abstract

Atrial fibrillation (AF), defined by disorganized atrial cardiac rhythm, is the most prevalent cardiac arrhythmia worldwide. Recent genetic studies have highlighted a major heritable component and identified numerous loci associated with AF risk, including the cardiogenic transcription factor genes TBX5, GATA4, and NKX2-5. We report that Tbx5 and Gata4 interact with opposite signs for atrial rhythm controls compared with cardiac development. Using mouse genetics, we found that AF pathophysiology caused by Tbx5 haploinsufficiency, including atrial arrhythmia susceptibility, prolonged action potential duration, and ectopic cardiomyocyte depolarizations, were all rescued by Gata4 haploinsufficiency. In contrast, Nkx2-5 haploinsufficiency showed no combinatorial effect. The molecular basis of the TBX5/GATA4 interaction included normalization of intra-cardiomyocyte calcium flux and expression of calcium channel genes Atp2a2 and Ryr2. Furthermore, GATA4 and TBX5 showed antagonistic interactions on an Ryr2 enhancer. Atrial rhythm instability caused by Tbx5 haploinsufficiency was rescued by a decreased dose of phospholamban, a sarco/endoplasmic reticulum Ca2+-ATPase inhibitor, consistent with a role for decreased sarcoplasmic reticulum calcium flux in Tbx5-dependent AF susceptibility. This work defines a link between Tbx5 dose, sarcoplasmic reticulum calcium flux, and AF propensity. The unexpected interactions between Tbx5 and Gata4 in atrial rhythm control suggest that evaluating specific interactions between genetic risk loci will be necessary for ascertaining personalized risk from genetic association data.

Authors

Brigitte Laforest, Wenli Dai, Leonid Tyan, Sonja Lazarevic, Kaitlyn M. Shen, Margaret Gadek, Michael T. Broman, Christopher R. Weber, Ivan P. Moskowitz

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Figure 1

Gata4 haploinsufficiency rescues atrial arrhythmias caused by Tbx5 haploinsufficiency.

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Gata4 haploinsufficiency rescues atrial arrhythmias caused by Tbx5 hapl...
(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 Tbx5fl/+;R26CreERT2, Gata4fl/+;R26CreERT2, and Gata4/Tbx5 compound heterozygotes 2 weeks after TM treatment. Data are represented as means ± SEM normalized to GAPDH and relative to R26CreERT2 mice (set as 1) (n = 7–8 R26CreERT2, n = 6–7 Tbx5fl/+;R26CreERT2, n = 9–10 Gata4fl/+;R26CreERT2, n = 12 Gata4fl/+;Tbx5fl/+;R26CreERT2). 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 R26CreERT2 (n = 6), Tbx5fl/+;R26CreERT2 (n = 8–9), Gata4fl/+;R26CreERT2 (n = 6), and Gata4fl/+;Tbx5fl/+;R26CreERT2 (n = 10) mice. Tbx5fl/+;R26CreERT2 adult mice displayed significant increase in P-wave duration (C) and prolongation of the PR interval compared with R26CreERT2 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 R26CreERT2 (n = 8), Tbx5fl/+;R26CreERT2 (n = 18), Gata4fl/+;R26CreERT2 (n = 12), and Gata4fl/+;Tbx5fl/+;R26CreERT2 (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.