TY - GEN
T1 - Synergistic anti-arrhythmic effects of combined blockade of sodium and ultra-rapid delayed rectifier potassium channels in human atria
AU - Ni, Haibo
AU - Whittaker, Dominic G.
AU - Wang, Wei
AU - Zhang, Henggui
N1 - Publisher Copyright:
© 2016 CCAL.
PY - 2016/3/1
Y1 - 2016/3/1
N2 - Atrial fibrillation (AF) is the commonest cardiac arrhythmia. Developing effective and safe anti-AF drugs remains unmet. Atrial-selective blocking the ultra-rapid delayed rectifier potassium current (IKur) and sodium channel (INa) was recently reported to be potentially effective in the treatment of AF. We used computational models of human atria to assess the antiarrhythmic effects of IKur and INa blocks on human atria. A mathematical model of IKur channel block was developed to describe the blocking effects of acacetin, an IKur-selective blocker. INa blockade was simulated using the guarded-receptor model. The effects of these channel blocks were simulated using mathematical models of human atrial myocytes and tissue. Applying acacetin rendered significant APD prolongation (by 29.3 ms at 1 Hz). The INa blocker significantly reduced peak INa at fast pacing rates, but produced no effect at 1 Hz in both atria and ventricles. Combined actions of the two drugs further decreased peak INa and prolonged APD at a fast pacing rate. These effects were also demonstrated in two-dimensional simulations, where combined blockers showed reduced the life span of re-entrant excitation waves, exerting synergistic antiarrhythmic effects in the human atria, indicating that combined blocks of IKur and INa may be a valuable strategy for the treatment of AF.
AB - Atrial fibrillation (AF) is the commonest cardiac arrhythmia. Developing effective and safe anti-AF drugs remains unmet. Atrial-selective blocking the ultra-rapid delayed rectifier potassium current (IKur) and sodium channel (INa) was recently reported to be potentially effective in the treatment of AF. We used computational models of human atria to assess the antiarrhythmic effects of IKur and INa blocks on human atria. A mathematical model of IKur channel block was developed to describe the blocking effects of acacetin, an IKur-selective blocker. INa blockade was simulated using the guarded-receptor model. The effects of these channel blocks were simulated using mathematical models of human atrial myocytes and tissue. Applying acacetin rendered significant APD prolongation (by 29.3 ms at 1 Hz). The INa blocker significantly reduced peak INa at fast pacing rates, but produced no effect at 1 Hz in both atria and ventricles. Combined actions of the two drugs further decreased peak INa and prolonged APD at a fast pacing rate. These effects were also demonstrated in two-dimensional simulations, where combined blockers showed reduced the life span of re-entrant excitation waves, exerting synergistic antiarrhythmic effects in the human atria, indicating that combined blocks of IKur and INa may be a valuable strategy for the treatment of AF.
UR - https://www.scopus.com/pages/publications/85016098385
M3 - 会议稿件
AN - SCOPUS:85016098385
T3 - Computing in Cardiology
SP - 837
EP - 840
BT - Computing in Cardiology Conference, CinC 2016
A2 - Murray, Alan
PB - IEEE Computer Society
T2 - 43rd Computing in Cardiology Conference, CinC 2016
Y2 - 11 September 2016 through 14 September 2016
ER -