Changes in action potentials and intracellular ionic homeostasis in a ventricular cell model related to a persistent sodium current in SCN5A mutations underlying LQT3

In LQT3 patients, SCN5A mutations induce ultraslow inactivation of a small fraction of the hNav1.5 current, i.e. persistent Na + current ( I pNa). We explored the time course of effects of such a change on the intracellular ionic homeostasis in a model of guinea-pig cardiac ventricular cell [Pasek, M., Simurda, J., Orchard, C.H., Christé, G., 2007b. A model of the guinea-pig ventricular cardiomyocyte incorporating a transverse–axial tubular system. Prog. Biophys. Mol. Biol., this issue]. Sudden addition of I pNa prevented action potential (AP) repolarization when its conductance ( g pNa) exceeded 0.12% of the maximal conductance of fast I Na ( g Na). With g pNa at 0.1% g Na, the AP duration at 90% repolarization (APD 90) was initially lengthened to 2.6-fold that in control. Under regular stimulation at 1 Hz it shortened progressively to 1.37-fold control APD 90, and intracellular [Na +] i increased by 6% with a time constant of 106 s. Further increasing g pNa to 0.2% g Na caused an immediate increase in APD 90 to 5.7-fold that in control, which decreased to 2.2-fold that in control in 30 s stimulation at 1 Hz. At this time diastolic [Na +] i and [Ca 2+] i were, respectively, 34% and 52% higher than in control and spontaneous erratic SR Ca release occurred. In the presence of I pNa causing 46% lengthening of APD 90, the model cell displayed arrhythmogenic behaviour when external [K +] was lowered to 5 mM from an initial value at 5.4 mM. By contrast, when K + currents I Kr and I Ks were lowered in the model cell to produce the same lengthening of APD 90, no proarrhythmic behaviour was observed, even when external [K +] was lowered to 2.5 mM.