Analysis of QT Interval Prolongation With Heart Failure by Simulation of Repolarization Process.
It has been postulated that action potential duration (APD) is prolonged and I<inf>Ks</inf>, a slow component of delayed rectifier potassium current, decreases in heart failure. We have reported that QT interval is prolonged and expression weight of KCNE1, coding I<inf>Ks</inf>channel, increases in patients with heart failure. Since it is known that increase in KCNE1 increases the maximum conductance of I<inf>Ks</inf>channel, the mechanism of APD prolongation is not explained by over expression of KCNE1. In this study, we construct a cardiac membrane action potential simulation model based on the experimental data from Xenopus oocytes expressed KCNQ1 and KCNE1 to investigate the relationship between increase in KCNE1 and APD. In addition, we investigated effect of reduction in Ca2+-independent transient outward potassium current (I<inf>to</inf>) on APD in heart failure. In simulation, APD at 5ng KCNE1 was 180.96ms, which was 4.63% longer than that at 1ng KCNE1 (APD=172.96ms) and 55.9% longer than that at 0.2ng KCNE1 (APD=110.96ms. In the cases of KCNQ1 alone and 0.2ng KCNE1 coinjected, APD shortened as density of I<inf>to</inf>decreased, and APD prolonged as density of I<inf>to</inf>decreased in other cases. This study shows that increase in KCNE1 expression level makes maximum conductance of I<inf>Ks</inf>channel increase and I<inf>Ks</inf>channel open slowly and conductance of I<inf>Ks</inf>channel decrease according to the APD time scale. Therefore increasing the KCNE1 expression level may prolong APD with this mechanism. This method of constructing a simulation model based on experiments helps to explain the relationship between potassium currents and QT interval prolongation.
Yamaguchi
T
T
Graduate School of Frontier Sciences, the University of Tokyo, Tokyo 113-8656 JAPAN (phone: +81-3-5841-7480; fax: +81-3-5841-7480; e-mail: takahiro@miki.pe.u-tokyo.ac.jp).
Arafune
T
T
Sakuma
I
I
Watanabe
E
E
Shibata
N
N
Honjo
H
H
Kodama
I
I
Kamiya
K
K