Aberrant sodium influx causes cardiomyopathy and atrial fibrillation in mice
Elaine Wan, … , Hasan Garan, Steven O. Marx
Elaine Wan, … , Hasan Garan, Steven O. Marx
Published January 4, 2016; First published November 23, 2015
Citation Information: J Clin Invest. 2016;126(1):112-122. https://doi.org/10.1172/JCI84669.
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Technical Advance Cardiology

Aberrant sodium influx causes cardiomyopathy and atrial fibrillation in mice

Abstract

Increased sodium influx via incomplete inactivation of the major cardiac sodium channel NaV1.5 is correlated with an increased incidence of atrial fibrillation (AF) in humans. Here, we sought to determine whether increased sodium entry is sufficient to cause the structural and electrophysiological perturbations that are required to initiate and sustain AF. We used mice expressing a human NaV1.5 variant with a mutation in the anesthetic-binding site (F1759A-NaV1.5) and demonstrated that incomplete Na+ channel inactivation is sufficient to drive structural alterations, including atrial and ventricular enlargement, myofibril disarray, fibrosis and mitochondrial injury, and electrophysiological dysfunctions that together lead to spontaneous and prolonged episodes of AF in these mice. Using this model, we determined that the increase in a persistent sodium current causes heterogeneously prolonged action potential duration and rotors, as well as wave and wavelets in the atria, and thereby mimics mechanistic theories that have been proposed for AF in humans. Acute inhibition of the sodium-calcium exchanger, which targets the downstream effects of enhanced sodium entry, markedly reduced the burden of AF and ventricular arrhythmias in this model, suggesting a potential therapeutic approach for AF. Together, our results indicate that these mice will be important for assessing the cellular mechanisms and potential effectiveness of antiarrhythmic therapies.

Authors

Elaine Wan, Jeffrey Abrams, Richard L. Weinberg, Alexander N. Katchman, Joseph Bayne, Sergey I. Zakharov, Lin Yang, John P. Morrow, Hasan Garan, Steven O. Marx

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Figure 3

Increased persistent Na+ current is sufficient to initiate structural changes in the atria and ventricles.

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Increased persistent Na+ current is sufficient to initiate structural ch...
(A) Photographs of littermate control (CONT) and F1759A-dTG hearts at 4 weeks and 3.5 months after birth. (B) H&E-stained cross section of ventricle. Scale bars: 1 mm. (C and D) Graphs of ejection fraction and LAD (in mm) of littermate control and F1759A-dTG mice, assessed by echocardiography at ages shown. Data are presented as mean ± SEM. n ≥ 5 mice per age group per genotype. *P < 0.05, **P < 0.01, ***P < 0.001, ***P < 0.0001. (E) H&E stain of right and left atria showing bi-atrial enlargement in F1759A-dTG mice. Scale bars: 1 mm. Bar graph of left atrial and right atrial area of littermate control and F1759A-dTG mice at 3–4 months of age. Data are presented as mean ± SEM. *P < 0.05; t test. n = 5 for each group. (F) Masson’s trichrome stain of atria of littermate control and F1759A-dTG mice. Scale bars: 50 μm. Bar graph quantifying atrial fibrosis. Data are presented as mean ± SEM. *P < 0.05; t test. n ≥ 5 for each group. (G) Representative 2-dimensional TEM images (n = 2 for dTG and littermate control) showing left to right, gross morphology of atrial and ventricular samples at 6 weeks (first row) and 12 weeks (second and third rows) in littermate control mice compared with dTG mice. At 6 weeks, dTG mice show signs of myofibril disarray with loss of congruous parallel myofibrils in the atrium. By 12 weeks of age, atrial and ventricular cardiomyocytes from the F1759A-dTG mice demonstrated mitochondrial injury, with circular and swollen mitochondria and ruptured outer membranes. In the ventricle, the red arrows point to T-tubule cross sections, which are larger in the dTG mice compared with littermate control. Scale bars: 500 nm.