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 (I
_Nap
) with g
_Nap
0.02 ms/cm
²
led to a prolongation of the action potential from 153 ms (control) to 223 ms and an increase of [Na
⁺
]i, diastolic and systolic [Ca
²⁺
]
_i
and [Ca
²⁺
]
_SRup
by 10%, 30%, 40% and 43%, respectively. These changes were larger at 3 Hz. Such intracellular Na
⁺
and Ca
²⁺
overload was not found when the action potential prolongation (to 222 ms at 1 Hz) was due to decreased I
_Kr
and I
_Ks
currents. The model with I
_Nap
became arrhythmo genie 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