Role of up-regulation of IK1 in action potential shortening associated with atrial fibrillation in humans

被引:93
作者
Zhang, HG
Garratt, CJ
Zhu, JJ
Holden, AV
机构
[1] Univ Manchester, Sch Phys & Astron, Biol Phys Grp, Manchester M60 1QD, Lancs, England
[2] Manchester Royal Infirm, Manchester Heart Ctr, Manchester M13 9WL, Lancs, England
[3] Univ Leeds, Sch Biomed Sci, Leeds LS2 9JT, W Yorkshire, England
基金
英国工程与自然科学研究理事会;
关键词
human atrial fibrillation; remodeling; mathematical modeling;
D O I
10.1016/j.cardiores.2005.01.020
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Objectives: Although previous studies in dogs have indicated a minimal role for changes in I-K1 in the shortening of action potential duration (APD) associated with atrial fibrillation (AF), in humans, there is evidence for significant AF-induced up-regulation of this current. In this computer model study, we investigated the relative contributions of the remodeling of I-K1, L-type calcium current, and other remodeled ionic channel currents to AF-induced APD reduction in human atrium. Methods: Two computer models of electrical activity of human atrial cell were modified by incorporating experimental data of AF-induced changes in human atrial ionic channel conductance and kinetics reported by Bosch et al. (I-CaL, I-to, I-K1, and I-Na) (AF-1) and Workman et al. (I-CaL, I-to, and I-K1) (AF-2). The roles and relative importance of individually remodeled ion channels in the APD reduction in human atrium were evaluated by the removal and exclusive methods, in which remodeling of specific currents was omitted, or considered in isolation, in the two models. Results: When tested together, previously reported AF-induced changes in sarcolemmal ion currents result in marked shortening of atrial APD(90). With the AF-1 remodeled parameters, there is a 62% reduction in APD(90) for the Nygren et al. model, and a 68% reduction for the Courtemanche et al. model, which are comparable to experimental results of 60% reduction seen in humans. When tested individually, AF-1-induced changes in I-CaL, I-K1, or I-to alone result in APD(90) reduction of 20%, 64%, and -10%, respectively, for the Nygren et al. model, and 27%, 40%, and 11.6%, respectively, for the Courtemanche et al. model. With the AF-2 remodeled parameters, there is a 47% reduction in APD(90) for the Nygren et al. model and a 49% reduction for the Courtemanche et al. model, which are also comparable to experimental results of 45% reduction. When tested individually, AF-2-induced changes in I-CaL or I-K1 alone result in APD90 reduction of 20% and 40%, respectively, for the Nygren et al. model, and 14% and 21%, respectively, for the Courtemanche et al. model. Conclusion: Previously reported changes in L-type Ca2+ current are insufficient to account for the observed reduction in atrial APD associated with persistent AF. Up-regulation of I-K1 has a greater influence on atrial APD in the human model. (c) 2005 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.
引用
收藏
页码:493 / 502
页数:10
相关论文
共 26 条
[1]   Ionic mechanisms of electrical remodeling in human atrial fibrillation [J].
Bosch, RF ;
Zeng, XR ;
Grammer, JB ;
Popovic, K ;
Mewis, C ;
Kühlkamp, V .
CARDIOVASCULAR RESEARCH, 1999, 44 (01) :121-131
[2]   Ionic mechanisms underlying human atrial action potential properties: insights from a mathematical model [J].
Courtemanche, M ;
Ramirez, RJ ;
Nattel, S .
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY, 1998, 275 (01) :H301-H321
[3]   Human inward rectifier potassium channels in chronic and postoperative atrial fibrillation [J].
Dobrev, D ;
Wettwer, E ;
Kortner, A ;
Knaut, M ;
Schüler, S ;
Ravens, U .
CARDIOVASCULAR RESEARCH, 2002, 54 (02) :397-404
[4]   Gap junctions in cardiovascular disease [J].
Jongsma, HJ ;
Wilders, R .
CIRCULATION RESEARCH, 2000, 86 (12) :1193-1197
[5]   Stable microreentrant sources as a mechanism of atrial fibrillation in the isolated sheep heart [J].
Mandapati, R ;
Skanes, A ;
Chen, J ;
Berenfeld, O ;
Jalife, J .
CIRCULATION, 2000, 101 (02) :194-199
[6]  
Mansour M, 2001, CIRCULATION, V103, P2631
[7]  
Moe G K, 1968, J Electrocardiol, V1, P145
[8]   Basic mechanisms of atrial fibrillation - Very new insights into very old ideas [J].
Nattel, S ;
Li, D ;
Yue, L .
ANNUAL REVIEW OF PHYSIOLOGY, 2000, 62 :51-77
[9]   New ideas about atrial fibrillation 50 years on [J].
Nattel, S .
NATURE, 2002, 415 (6868) :219-226
[10]   Simulations of the human atrial action potential [J].
Nygren, A ;
Leon, LJ ;
Giles, WR .
PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY OF LONDON SERIES A-MATHEMATICAL PHYSICAL AND ENGINEERING SCIENCES, 2001, 359 (1783) :1111-1125