Effects of late sodium current enhancement during LQT-related arrhythmias. A simulation study

Long QT syndrome is a repolarization disorder characterized by marked prolongation of QT interval. A clear consequence of long QT syndrome is the occurrence of a polymorphic ventricular tachycardia called Torsade de Pointes, which has been related to early after depolarizations (EADs) formation. This repolarizing disorder has been observed under pathological situations, such as heart failure, oxidative stress, ventricular hypertrophy and/or in the presence of pure class III antiarrhythmics. Under such pathologies electrophysiological changes affect the electrical activity of the cell. Lately, the enhancement of late sodium current (I_NaL) and its role has become a source of interest. In this work, a mathematical model of I_NaL has been proposed and incorporated to the ten Tussher model of the human ventricular action potential (AP), specifically in M cells. We simulated and analyzed the effects of I_NaL enhancement in combination with LQT-related pathologies and administration of I_Kr blockers, on the AP. This study demonstrates that I_NaL prolongs AP duration (APD) in a rate-dependent manner. Indeed, a 10-fold increase of I_NaL prolongs APD in 80% for a stimulation rate of 1 Hz and 100% for 0.25 Hz. Also, intracellular sodium concentration [Na⁺]_i significantly increases in the presence of enhanced I_NaL, increasing the probability of EADs formation through calcium overload in cells prone to develop EADs.