Arrhythmogenic Mechanism of an LQT-3 Mutation of the Human Heart Na + Channel α-Subunit

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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.