Aberrant sodium influx causes cardiomyopathy and atrial fibrillation in mice
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
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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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 6

Inhibition of NCX attenuates atrial and ventricular arrhythmogenesis in F1759A-dTG mice.

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Inhibition of NCX attenuates atrial and ventricular arrhythmogenesis in ...
(A) Schematic depicting proposed mechanisms of arrhythmogenesis in F1759A-dTG mice. (B) Diary plot of fraction of AF/hour during a 20-hour period for 5 male F1759A-dTG mice. Burden of AF was determined by manually reviewing the entire 20-hour period. (C) Diary plot of fraction of AF/hour for same 5 male F1759A-dTG mice during a 20-hour period after i.p. injection of SEA-0400. (D) Graph (left) summarizing fraction of AF during 20-hour period before (white bars) and after (blue bars) single i.p. injection of SEA-0400 for each mouse. Percent change is shown above each data pair. Graph (right) showing fraction AF/hour before and after SEA injection for the 5 F1759A-dTG mice. Data are presented as mean ± SEM. *P < 0.05; t test. (E) Quantification of number of PVC normalized to pre-SEA. Data are presented as mean ± SEM. *P < 0.05; t test. (F) Bar graph showing QT interval before and after SEA-0400.