Contributions of sustained INa and IKv43 to transmural heterogeneity of early repolarization and arrhythmogenesis in canine left ventricular myocytes

The roles of sustained components of I(Na) and I(Kv43) in shaping the action potentials (AP) of myocytes isolated from the canine left ventricle (LV) have not been studied in detail. Here we investigate the hypothesis that these two currents can contribute substantially to heterogeneity of early repolarization and arrhythmic risk. Quantitative data from voltage-clamp and expression profiling experiments were used to complete meaningful modifications to an existing "local control" model of canine midmyocardial myocyte excitation-contraction coupling for epicardial and endocardial cells. We include 1) heterogeneous I(Kv43), I(Ks), and I(SERCA) density; 2) modulation of I(Kv43) by Kv channel interacting protein type 2 (KChIP2) channel subunits; 3) a possible Ca(2+)-dependent open-state inactivation of I(Kv43); and 4) a sustained component of the inward Na(+) current, I(NaL). The resulting simulations illustrate ways in which KChIP2- and Ca(2+)-dependent control of I(Kv43) can result in a sustained outward current that can neutralize I(NaL) in a rate- and myocyte subtype-dependent manner. Both these currents appear to play significant roles in modulating AP duration and rate dependence in midmyocardial myocytes. Furthermore, an increased ratio of I(Kv43) to I(NaL) is capable of protecting epicardial myocytes from the early afterdepolarizations resulting from the SCN5A-I1768V mutation-induced increase in I(NaL). Experimentally observed transmural differences in Ca(2+) handling, including greater sarcoplasmic reticulum Ca(2+) content and faster Ca(2+) transient decay rates on the epicardium, were recapitulated in our simulations. By design, these models allow upward integration into organ models or may be used as a basis for further investigations into cellular heterogeneities.