Potentiation of dofetilide LQT-related effects by late sodium current enhancement: A simulation study

Torsades de pointes (TdP) is a life-threatening ventricular tachycardia associated to reduction of the rapid delayed rectifier potassium current (I_Kr) and prolongation of ventricular action potential duration (APD) and long QT (LQT) syndrome. An abnormal increase of the late sodium current (I_NaL) is also associated to susceptibility to TdP. In this work, a mathematical model of I_NaL has been proposed and incorporated to the Shannon model of the rabbit ventricular AP. We analyzed the effects of I_NaL enhancement alone and in combination with dofetilide, a blocker of I_Kr, on the AP. This study demonstrates that an increase of I_NaL prolongs APD in a rate dependent manner. Also, triangulation is increased by I_NaL, especially at higher BCLs. Finally, the effect of dofetilide was included in order to assess the mixed action of the drug and I_NaL enhancement. Under these conditions, EADs arose only when I_NaL was increased 10-fold.