Effects of a Persistent Sodium Current Through Mutated hNav1.5 Sodium Channels on Intracellular Ionic Homeostasis in a Ventricular Cell Model

In LQT3 patients, SCN5A mutations were found that lead to a small fraction of persistent hNav1.5 current. We explored the effects of such a change on the intracellular ionic homeostasis in a model of guinea-pig cardiac ventricular cell. At steady-state under 1 Hz stimulation, the presence of a persistent Na+ current (INap) with gNap 0.02 ms/cm2 led to a prolongation of the action potential from 153 ms (control) to 223 ms and an increase of [Na+]i, diastolic and systolic [Ca2+]i and [Ca2+]SRup by 10 %, 30 %, 40 % and 43 %, respectively. These changes were larger at 3 Hz. Such intracellular Na+ and Ca2+ overload was not found when the action potential prolongation (to 222 ms at 1 Hz) was due to decreased IKr and IKs currents. The model with INap became arrhythmogenic when [K+]e was lowered from 5.4 to 5.0 mM, whereas control and low K+ current models did not produce arrhythmias even when [K+]e was 2.5 mM. 1