Arrhythmogenic mechanism of an LQT-3 mutation of the human heart Na+ channel α-subunit: A comptutational analysis

Abstract

Background - D1790G, a mutation of SCN5A, the gene that encodes the human Na+ channel α-subunit, is linked to 1 form of the congenital long-QT syndrome (LQT-3). In contrast to other LQT-3-linked SCN5A mutations, D1790G does not promote sustained Na+ channel activity but instead alters the kinetics and voltage-dependence of the inactivated state. Methods and Results - We modeled the cardiac ventricular action potential (AP) using parameters and techniques described by Luo and Rudy as our control. On this background, we modified only the properties of the voltage-gated Na+ channel according to our patch-clamp analysis of D1790G channels. Our results indicate that D1790G-induced changes in Na+ channel activity prolong APs in a steeply heart rate-dependent manner not directly due to changes in Na+ entry through mutant channels but instead to alterations in the balance of net plateau currents by modulation of calcium-sensitive exchange and ion channel currents. Conclusions - We conclude that the D1790G mutation of the Na+ channel α-subunit can prolong the cardiac ventricular AP despite the absence of mutation-induced sustained Na+ channel current. This prolongation is calcium-dependent, is enhanced at slow heart rates, and at sufficiently slow heart rate triggers arrhythmogenic early afterdepolarizations.