Dofetilide unmasks occult congenital long QT syndrome type 2: A simulation study

摘要

Accurate diagnosis of long QT syndrome is a key factor for reducing the risk of cardiac arrhythmias. Our goal is to investigate the potential use of dofetilide to unmask latent IKr mutation carriers. A modified version of the O'Hara et al. model was used to simulate the electrical activity of isolated cardiac cells. The original IKr formulation was replaced by the Fink et al. Markov model of the human IKr channels and our dynamic model of dofetilide was used to simulate drug administration. A sensitivity analysis was performed to study the effect of IKr transition rate alterations on AP duration (APD) prolongation in the absence and in the presence of dofetilide. Our results show that acceleration of the rate transition from open to the last closed state (ββ) produced the shortest prolongation of the APD in the absence of the drug. However, ββ acceleration provoked the highest additional APD prolongation under dofetilide exposure related to the APD prolongation observed before the drug application. In addition, this IKr alteration was the transition rate modification that most increased the rate of deactivation. In conclusion, our observations indicate that dofetilide could potentially be used to unmask IKr mutations accelerating the deactivation process.