Role of L-type Calcium in Modulating Pro-Arrhythmic Effects of Dofetilide in Human

Abstract : Dofetilide is a class III drug whose use needs to be monitored due to the possible occurrence of Torsades de Pointes (TdP). The mechanisms are unclear but research suggests that both early-afterdepolarizations (EAD) and increased dispersion of action potential duration (APD) might be involved. Importantly, drug-induced TdP is more common in women, possibly due to higher L-type calcium current (ICaL) levels. Our goal is to use numerical simula- tion in order to investigate pro-arrhythmic mechanisms of dofetilide in human by characterizing its effects on APD, APD dispersion and EAD formation for varying doses and ICaL levels.