title: Effects of late sodium current enhancement during LQT-related arrhythmias. A simulation study.
abstract: 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.
authors.affiliation: Universidad Politecnica de Valencia (I3BH), 46022 Spain.
authors.forename: K
authors.initials: K
authors.lastname: Cardona
authors.forename: B
authors.initials: B
authors.lastname: Trenor
authors.forename: S
authors.initials: S
authors.lastname: Rajamani
authors.forename: L
authors.initials: L
authors.lastname: Romero
authors.forename: J M
authors.initials: JM
authors.lastname: Ferrero
authors.forename: J
authors.initials: J
authors.lastname: Saiz
mesh_terms: D000818:Animals; D003198:Computer Simulation; D006329:Heart Conduction System / Q000187:drug effects / Q000503:physiopathology*; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects; D008133:Long QT Syndrome / Q000188:drug therapy* / Q000503:physiopathology*; D008955:Models, Cardiovascular; D012964:Sodium / Q000378:metabolism*; D026941:Sodium Channel Blockers / Q000008:administration & dosage*; D015222:Sodium Channels / Q000187:drug effects*
chemical_list: D026941:Sodium Channel Blockers; D015222:Sodium Channels; D012964:Sodium