Arrhythmogenic mechanism of an LQT-3 mutation of the human heart Na+ channel alpha-subunit - A computational analysis

Background-D1790G, a mutation of SCN5A, the gene that encodes the human Na channel alpha-subunit, is linked to 1 form of the congenital long-QT syndr ome (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 or 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 N a+ channel according to our patch-clamp analysis of D1790G channels, Our re sults 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 balanc e of net plateau currents by modulation of calcium-sensitive exchange and i on channel currents. Conclusions-We conclude that the D1790G mutation of the Na+ channel alpha-s ubunit can prolong the cardiac ventricular AP despite the absence of mutati on-induced sustained Na+ channel current, This prolongation is calcium-depe ndent, is enhanced at slow heart rates, and at sufficiently slow heart rate triggers arrhythmogenic early after depolarizations.