Arrhythmogenic consequences of Na⁺ channel mutations in the transmurally heterogeneous mammalian left ventricle: Analysis of the I1768V SCN5A mutation

Background

Congenital mutations in the cardiac Na⁺ channel (encoded by SCN5A) underlie long QT syndrome type 3. The sea anemone peptide toxin ATX-II mimics the slowed inactivation kinetics characteristic of many long QT type 3 (LQT3) mutations. However, the I1768V SCN5A mutation is associated with faster recovery kinetics, for which there exists no known pharmacologic equivalent.

Objective

The purpose of this study was to investigate the proarrhythmic consequences of the I1768V SCN5A mutation in a transmurally heterogeneous canine left ventricular wedge. We hypothesized that amplification of intrinsic electrical heterogeneities may contribute to abnormal repolarization patterns.

Methods

We developed a multiscale computational model of the canine ventricular wedge preparation that accounts for a comprehensive set of ionic currents (including transmural heterogeneities of the voltage-dependent transient outward current I_Kv43, the late sodium current I_NaL, the slowly activating delayed rectifier current I_Ks, and the sarco[endo]plasmic reticulum Ca²⁺-ATPase pump SERCA) and includes mechanistic descriptions of intracellular Ca²⁺ cycling, the effects of ATX-II, and the I1768V mutation.

Results

Experimentally observed QT intervals and rate-dependent transmural gradients in action potential duration were recapitulated in our simulations, both with and without ATX-II. With the I1768V SCN5A mutation, the model predicted endocardial early afterdepolarizations that triggered epicardial beats and R-on-T extrasystoles. Brief episodes of polymorphic, followed by sustained monomorphic, ventricular tachycardia were observed at slow pacing rates. Importantly, these arrhythmias are driven by recurring reactivation of Na⁺ channels localized to the endocardium.

Conclusion

Our findings suggest that an increase in sustained inward Na⁺ current arising from the I1768V SCN5A mutation leads to clinically relevant arrhythmias in the transmurally heterogeneous canine left ventricular myocardium. This novel approach for simulating transmural heterogeneity provides new insight into the development of rhythm disturbances in the mammalian left ventricle.

Keywords: Transmural heterogeneity, Long QT syndrome, Arrhythmia mechanisms, Multiscale model, I1768V mutation, Late sodium current