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Rate-Dependent Role of I_Kur in Human Atrial Repolarization and Atrial Fibrillation Maintenance.

ABSTRACT: The atrial-specific ultrarapid delayed rectifier K⁺ current (I_Kur) inactivates slowly but completely at depolarized voltages. The consequences for I_Kur rate-dependence have not been analyzed in detail and currently available mathematical action-potential (AP) models do not take into account experimentally observed I_Kur inactivation dynamics. Here, we developed an updated formulation of I_Kur inactivation that accurately reproduces time-, voltage-, and frequency-dependent inactivation. We then modified the human atrial cardiomyocyte Courtemanche AP model to incorporate realistic I_Kur inactivation properties. Despite markedly different inactivation dynamics, there was no difference in AP parameters across a wide range of stimulation frequencies between the original and updated models. Using the updated model, we showed that, under physiological stimulation conditions, I_Kur does not inactivate significantly even at high atrial rates because the transmembrane potential spends little time at voltages associated with inactivation. Thus, channel dynamics are determined principally by activation kinetics. I_Kur magnitude decreases at higher rates because of AP changes that reduce I_Kur activation. Nevertheless, the relative contribution of I_Kur to AP repolarization increases at higher frequencies because of reduced activation of the rapid delayed-rectifier current I_Kr. Consequently, I_Kur block produces dose-dependent termination of simulated atrial fibrillation (AF) in the absence of AF-induced electrical remodeling. The inclusion of AF-related ionic remodeling stabilizes simulated AF and greatly reduces the predicted antiarrhythmic efficacy of I_Kur block. Our results explain a range of experimental observations, including recently reported positive rate-dependent I_Kur-blocking effects on human atrial APs, and provide insights relevant to the potential value of I_Kur as an antiarrhythmic target for the treatment of AF.

SUBMITTER: Aguilar M

PROVIDER: S-EPMC5425383 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Rate-Dependent Role of IKur in Human Atrial Repolarization and Atrial Fibrillation Maintenance.

Aguilar Martin M Feng Jianlin J Vigmond Edward E Comtois Philippe P Nattel Stanley S

Biophysical journal 20170501 9

The atrial-specific ultrarapid delayed rectifier K+ current (IKur) inactivates slowly but completely at depolarized voltages. The consequences for IKur rate-dependence have not been analyzed in detail and currently available mathematical action-potential (AP) models do not take into account experimentally observed IKur inactivation dynamics. Here, we developed an updated formulation of IKur inactivation that accurately reproduces time-, volt ...[more]

PMID: 28494969

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Project description:Atrial fibrillation (AF) is a progressive arrhythmia for which current therapy is inadequate. During AF, rapid stimulation causes atrial remodeling that promotes further AF. The cellular signals that trigger this process remain poorly understood, however, and elucidation of these factors would likely identify new therapeutic targets. We have previously shown that immortalized mouse atrial (HL-1) myocytes subjected to 24 hr of rapid stimulation in culture undergo remodeling similar to that seen in animal models of atrial tachycardia (AT) and human AF. This preparation is devoid of confounding in vivo variables that can modulate gene expression (e.g., hemodynamics). Therefore, we investigated the transcriptional profile associated with early atrial cell remodeling. RNA was harvested from HL-1 cells cultured for 24 hr in the absence and presence of rapid stimulation and subjected to microarray analysis. Data were normalized using Robust Multichip Analysis (RMA), and genes exhibiting significant differential expression were identified using the Significance Analysis of Microarrays (SAM) method. Using this approach, 919 genes were identified that were significantly altered with rapid stimulation (763 up-regulated and 156 down-regulated). For many individual transcripts, changes typical of AF/AT were observed, with marked up-regulation of genes encoding BNP and ANP precursors, heat shock proteins, and MAP kinases, while novel signaling pathways and molecules were also identified. Both stress and survival response were evident, as well as up-regulation of multiple transcription factors. Genes were also functionally classified based on cellular component, biologic process, and molecular function using the Gene Ontology database to permit direct comparison of our data with other gene sets regulated in human AF and experimental AT. For broad categories of genes grouped by functional classification, there was striking conservation between rapidly stimulated HL-1 cells and AF/AT. Results were confirmed using real-time quantitative RT-PCR on 13 genes selected by physiological relevance in AF/AT and regulation in the microarray analysis (up, down, and nonregulated). Rapidly-stimulated atrial myocytes provide a complementary experimental paradigm to explore the initial cellular signals in AT remodeling to identify novel targets in the treatment of AF. Experiment Overall Design: HL-1 cell expression profile in vitro with and without rapid electric stimulation

Dataset Information

Rate-Dependent Role of I_Kur in Human Atrial Repolarization and Atrial Fibrillation Maintenance.

Publications

Rate-Dependent Role of I<sub>Kur</sub> in Human Atrial Repolarization and Atrial Fibrillation Maintenance.

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