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.