Interactions between calcium-induced arrhythmia triggers and the electrophysiological-anatomical substrate underlying the induction of atrial fibrillation
Interactions between calcium-induced arrhythmia triggers and the electrophysiological-anatomical substrate underlying the induction of atrial fibrillation
复制标题
DOI：
10.1113/jp285740
复制
发表时间：
2024-02-19
影响因子：
5.5
通讯作者：
Aslanidi，Oleg V.
中科院分区：
文献类型：
--
作者：
Colman，Michael A.;Varela，Marta;Aslanidi，Oleg V.
摘要心房颤动（AF）是最常见的心律失常，由自发性局灶性兴奋和折返引起。肺静脉（PV）袖中的自发电放电与AF生成有关。本模拟研究的目的是确定确定肺静脉中AF触发点定位的机制及其对AF发生的贡献。使用了一种新型犬心房生物物理模型，该模型将随机自发亚细胞Ca 2+释放事件（SCRE）与离子特性的区域电生理异质性以及心房解剖结构、微结构和斑片状纤维化的详细三维模型相结合。模拟强调了与周围心房相比PV细胞中较小的内向整流钾电流（IK 1）的重要性，这使得SCRE更容易导致诱导触发活动的延迟后去极化。肌浆网Ca ~（2+）负荷对触发活性的依赖性有显著性变化。与单细胞相比，该特征在3D组织中更为突出（Δ半最大[Ca 2 +]SR= 58 μMvs.）。22 μM）。在3D心房纳入电异质性，激励优先出现从PV区域。这些触发的局灶性兴奋导致左心房短暂性折返。增加纤维化斑块促进局灶性兴奋和波破裂的局部出现，这对产生AF样模式的影响比PV更大。因此，IK 1降低、静息膜电位负性降低以及纤维化诱导的电紧张性负荷变化都有助于自发性局灶性触发出现复杂的兴奋模式。但是这种局部化的机制还有待阐明。我们应用了多尺度计算建模方法来阐明潜在的机制心房的肺静脉区域中的肌细胞具有较小的负静息膜电位和降低的时间非依赖性钾电流;我们证明这两个因素都促进了单细胞和组织的触发活动。2较小的负静息膜电位也有助于快钠电流的异质失活，这可以使类似折返的兴奋模式出现，而没有传统的传导阻滞。
AbstractAtrial fibrillation (AF) is the most common cardiac arrhythmia and is sustained by spontaneous focal excitations and re‐entry. Spontaneous electrical firing in the pulmonary vein (PV) sleeves is implicated in AF generation. The aim of this simulation study was to identify the mechanisms determining the localisation of AF triggers in the PVs and their contribution to the genesis of AF. A novel biophysical model of the canine atria was used that integrates stochastic, spontaneous subcellular Ca2+release events (SCRE) with regional electrophysiological heterogeneity in ionic properties and a detailed three‐dimensional model of atrial anatomy, microarchitecture and patchy fibrosis. Simulations highlighted the importance of the smaller inward rectifier potassium current (IK1) in PV cells compared to the surrounding atria, which enabled SCRE more readily to result in delayed‐afterdepolarisations that induced triggered activity. There was a leftward shift in the dependence of the probability of triggered activity on sarcoplasmic reticulum Ca2+load. This feature was accentuated in 3D tissue compared to single cells (Δ half‐maximal [Ca2+]SR= 58 μMvs. 22 μM). In 3D atria incorporating electrical heterogeneity, excitations preferentially emerged from the PV region. These triggered focal excitations resulted in transient re‐entry in the left atrium. Addition of fibrotic patches promoted localised emergence of focal excitations and wavebreaks that had a more substantial impact on generating AF‐like patterns than the PVs. Thus, a reducedIK1, less negative resting membrane potential, and fibrosis‐induced changes of the electrotonic load all contribute to the emergence of complex excitation patterns from spontaneous focal triggers.Key pointsFocal excitations in the atria are most commonly associated with the pulmonary veins, but the mechanisms for this localisation are yet to be elucidated.We applied a multi‐scale computational modelling approach to elucidate the mechanisms underlying such localisations.Myocytes in the pulmonary vein region of the atria have a less negative resting membrane potential and reduced time‐independent potassium current; we demonstrate that both of these factors promote triggered activity in single cells and tissues.The less negative resting membrane potential also contributes to heterogeneous inactivation of the fast sodium current, which can enable re‐entrant‐like excitation patterns to emerge without traditional conduction block.