Department of Pharmacology, University of California, Davis, 451 Health Sciences Dr, GBSF Room 3513, Davis, CA 95616-8636, USA.
Circ Res. 2011 Oct 14;109(9):1055-66. doi: 10.1161/CIRCRESAHA.111.253955. Epub 2011 Sep 15.
Understanding atrial fibrillation (AF) requires integrated understanding of ionic currents and Ca2+ transport in remodeled human atrium, but appropriate models are limited.
To study AF, we developed a new human atrial action potential (AP) model, derived from atrial experimental results and our human ventricular myocyte model.
Atria versus ventricles have lower I(K1), resulting in more depolarized resting membrane potential (≈7 mV). We used higher I(to,fast) density in atrium, removed I(to,slow), and included an atrial-specific I(Kur). I(NCX) and I(NaK) densities were reduced in atrial versus ventricular myocytes according to experimental results. SERCA function was altered to reproduce human atrial myocyte Ca2+ transients. To simulate chronic AF, we reduced I(CaL), I(to), I(Kur) and SERCA, and increased I(K1),I(Ks) and I(NCX). We also investigated the link between Kv1.5 channelopathy, [Ca2+]i, and AF. The sinus rhythm model showed a typical human atrial AP morphology. Consistent with experiments, the model showed shorter APs and reduced AP duration shortening at increasing pacing frequencies in AF or when I(CaL) was partially blocked, suggesting a crucial role of Ca2+ and Na+ in this effect. This also explained blunted Ca2+ transient and rate-adaptation of [Ca2+]i and [Na+]i in chronic AF. Moreover, increasing [Na+]i and altered I(NaK) and I(NCX) causes rate-dependent atrial AP shortening. Blocking I(Kur) to mimic Kv1.5 loss-of-function increased [Ca2+]i and caused early afterdepolarizations under adrenergic stress, as observed experimentally.
Our study provides a novel tool and insights into ionic bases of atrioventricular AP differences, and shows how Na+ and Ca2+ homeostases critically mediate abnormal repolarization in AF.
理解心房颤动（AF）需要综合了解重构人心房中的离子电流和 Ca2+转运，但合适的模型有限。
为了研究 AF，我们开发了一种新的人心房动作电位（AP）模型，该模型源自心房实验结果和我们的人心室肌细胞模型。
与心室相比，心房的 I(K1)较低，导致静息膜电位更去极化（≈7 mV）。我们在心房中使用更高的 Ito,fast 密度，去除 Ito,slow，并包括心房特异性 I(Kur)。根据实验结果，I(NCX)和 I(NaK)密度在心房肌细胞中降低。SERCA 功能改变以重现人心房肌细胞 Ca2+瞬变。为了模拟慢性 AF，我们降低了 I(CaL)、I(to)、I(Kur)和 SERCA，增加了 I(K1)、I(Ks)和 I(NCX)。我们还研究了 Kv1.5 通道病、[Ca2+]i 和 AF 之间的联系。窦性节律模型显示出典型的人心房 AP 形态。与实验一致，该模型在 AF 或部分阻断 I(CaL)时显示出较短的 AP 和减少的 AP 持续时间缩短，这表明 Ca2+和 Na+在这种效应中起关键作用。这也解释了慢性 AF 中 Ca2+瞬变和[Ca2+]i 和[Na+]i 的速率适应性变钝。此外，增加[Na+]i 和改变 I(NaK)和 I(NCX)会导致心房 AP 随时间缩短。模拟 Kv1.5 功能丧失的阻断 I(Kur)增加了 [Ca2+]i，并在肾上腺素应激下引起早期后除极，这与实验观察结果一致。
我们的研究为房室 AP 差异的离子基础提供了一种新的工具和见解，并表明 Na+和 Ca2+稳态如何在 AF 中关键调节异常复极。
