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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

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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 5

Normalization of SERCA2 function eliminates AF susceptibility in Tbx5fl/+;R26CreERT2.

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Normalization of SERCA2 function eliminates AF susceptibility in Tbx5fl/...
(A–D) Representative SERCA2 traces of R26CreERT2 (A), Tbx5fl/+;R26CreERT2 (B), Pln+/–;R26CreERT2 (C), and Tbx5fl/+;Pln+/–;R26CreERT2 (D) atrial myocytes. (E and F) Representative SR load and SERCA2 measurements from A–D. SR load (E) and SERCA2 function (F) was low in Tbx5fl/+;R26CreERT2 and normalized in Tbx5/Pln compound heterozygous mice (n = 43 R26CreERT2, n = 40 Tbx5fl/+;R26CreERT2, n = 30 Pln+/–;R26CreERT2, and n = 18 Tbx5fl/+;Pln+/–;R26CreERT2) For SR load and SERCA2 measurements, 3–4 mice per genotype were analyzed. (G–J) Intracardiac atrial electrogram recordings and corresponding surface ECG of R26CreERT2 (n = 9), Tbx5fl/+;R26CreERT2 (n = 6), Pln+/–;R26CreERT2 (n = 8), and Pln+/–;Tbx5fl/+;R26CreERT2 (n = 7) mice. Tbx5 heterozygotes displayed irregular atrial electrogram, representative of AF (H). A, atrial electrical signal; V, far-field ventricular electrical signal. (K) Pacing induction by intra-atrial pacing of mice in G–J. AF was reproducibly induced in 4 of 6 Tbx5 heterozygotes (60%) in contrast to 0 of 7 Pln/Tbx5 compound heterozygotes, indicating complete rescue of atrial arrhythmias. P values were determined by Fisher’s exact test; *P < 0.05. (L) Calcium homeostasis in control atrial myocytes is disrupted by Tbx5 haploinsufficiency and rescued by decreasing Pln gene dosage.
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