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

Henggui Zhang, Clifford J. Garratt, Jiujiang Zhu, Arun V. Holden

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Abstract

Objectives: Although previous studies in dogs have indicated a minimal role for changes in IK1 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 IK1, 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. (ICaL, Ito, IK1, and INa) (AF-1) and Workman et al. (ICaL, Ito, and IK1) (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 APD90. With the AF-1 remodeled parameters, there is a 62% reduction in APD90 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 ICaL, IK1, or Ito alone result in APD90 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 APD90 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 ICaL or IK1 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 IK1 has a greater influence on atrial APD in the human model.
Original languageEnglish
Pages (from-to)493-502
Number of pages10
JournalCardiovascular Research
Volume66
Issue number3
DOIs
StatePublished - 1 Jun 2005

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Atrial Fibrillation
Action Potentials
Up-Regulation
Ion Channels
Computer Simulation
Dogs
Ions
Calcium

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Zhang, Henggui; Garratt, Clifford J.; Zhu, Jiujiang; Holden, Arun V. / Role of up-regulation of IK1 in action potential shortening associated with atrial fibrillation in humans.

In: Cardiovascular Research, Vol. 66, No. 3, 01.06.2005, p. 493-502.

Research output: Contribution to journalArticle

@article{3831b7a8fc21487b89e62f6b4c2ab50c,
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abstract = "Objectives: Although previous studies in dogs have indicated a minimal role for changes in IK1 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 IK1, 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. (ICaL, Ito, IK1, and INa) (AF-1) and Workman et al. (ICaL, Ito, and IK1) (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 APD90. With the AF-1 remodeled parameters, there is a 62% reduction in APD90 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 ICaL, IK1, or Ito alone result in APD90 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 APD90 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 ICaL or IK1 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 IK1 has a greater influence on atrial APD in the human model.",
author = "Henggui Zhang and Garratt, {Clifford J.} and Jiujiang Zhu and Holden, {Arun V.}",
year = "2005",
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Role of up-regulation of IK1 in action potential shortening associated with atrial fibrillation in humans. / Zhang, Henggui; Garratt, Clifford J.; Zhu, Jiujiang; Holden, Arun V.

In: Cardiovascular Research, Vol. 66, No. 3, 01.06.2005, p. 493-502.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Role of up-regulation of IK1 in action potential shortening associated with atrial fibrillation in humans

AU - Zhang,Henggui

AU - Garratt,Clifford J.

AU - Zhu,Jiujiang

AU - Holden,Arun V.

PY - 2005/6/1

Y1 - 2005/6/1

N2 - Objectives: Although previous studies in dogs have indicated a minimal role for changes in IK1 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 IK1, 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. (ICaL, Ito, IK1, and INa) (AF-1) and Workman et al. (ICaL, Ito, and IK1) (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 APD90. With the AF-1 remodeled parameters, there is a 62% reduction in APD90 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 ICaL, IK1, or Ito alone result in APD90 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 APD90 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 ICaL or IK1 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 IK1 has a greater influence on atrial APD in the human model.

AB - Objectives: Although previous studies in dogs have indicated a minimal role for changes in IK1 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 IK1, 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. (ICaL, Ito, IK1, and INa) (AF-1) and Workman et al. (ICaL, Ito, and IK1) (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 APD90. With the AF-1 remodeled parameters, there is a 62% reduction in APD90 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 ICaL, IK1, or Ito alone result in APD90 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 APD90 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 ICaL or IK1 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 IK1 has a greater influence on atrial APD in the human model.

U2 - 10.1016/j.cardiores.2005.01.020

DO - 10.1016/j.cardiores.2005.01.020

M3 - Article

VL - 66

SP - 493

EP - 502

JO - Cardiovascular Research

T2 - Cardiovascular Research

JF - Cardiovascular Research

SN - 0008-6363

IS - 3

ER -