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 Ca2+-dependent open-state inactivation of IKv43; and 4) a sustained component of the inward Na+ current, I-NaL. The resulting simulations illustrate ways in which KChIP2- and Ca2+-dependent control of IKv43 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 IKv43 to INaL is capable of protecting epicardial myocytes from the early afterdepolarizations resulting from the SCN5A-I1768V mutation-induced increase in INaL. Experimentally observed transmural differences in Ca2+ handling, including greater sarcoplasmic reticulum Ca2+ content and faster Ca2+ 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.