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 November 23, 2015
Citation Information: J Clin Invest. 2016;126(1):112-122. https://doi.org/10.1172/JCI84669.
View: Text | PDF
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

×

Figure 2

F1759A-NaV1.5 increases persistent Na+ current in atria and ventricles.

Options: View larger image (or click on image) Download as PowerPoint
F1759A-NaV1.5 increases persistent Na+ current in atria and ventricles. ...
(A and B) Exemplar whole cell Na+ current (INa) traces of ventricular (A) and atrial (B) cardiomyocytes isolated from control (CONT, single TG and NTG) and F1759A-dTG mice. Persistent INa was evaluated with a 190-ms depolarization from a holding potential of –110 to –30 mV in the absence (black) and presence (green) of 20 μM TTX; 5 mM Na+ was used in the intracellular solution, and 100 mM Na+ was used in the extracellular solution. Insets: For the assessment of peak INa and the fraction of lidocaine-resistant current, whole cell current traces were recorded with 5 mM Na+ in both extracellular and intracellular solutions, in the absence (black) and presence (red) of 3 mM lidocaine. (C) Bar graph of peak INa density recorded with 5 mM external Na+. Data are presented as mean ± SEM. (D) Graph of fraction of peak INa resistant to 3 mM lidocaine. ***P < 0.001, ****P < 0.0001; t test. (E) Graph of persistent INa. Red dashed line is maximal persistent INa in cardiomyocytes isolated from CONT mice. Data are presented as mean ± SEM. **P < 0.01, ***P < 0.001; t test. (F) Representative traces of Ca2+ transients. Bar graph of Ca2+ transients of littermate control (CONT) and F1759A-dTG mice. Data are presented as mean ± SEM. *P < 0.05; t test. n = 34, single TG and NTG ventricular cardiomyocytes; n = 107, F1759A-dTG cardiomyocytes.