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Computational Analyses in Ion Channelopathies

Contributions of sustained I_Na and I_Kv43 to transmural heterogeneity of early repolarization and arrhythmogenesis in canine left ventricular myocytes

Department of Bioengineering, University of California, San Diego, La Jolla, California

Submitted 31 March 2006 ; accepted in final form 29 June 2006

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 I_Kv43; 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 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 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.

sustained sodium ion current; Kv4 channel regulation

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