Increased vulnerability of human ventricle to re-entrant excitation in hERG-linked variant 1 short QT syndrome.
Increased vulnerability of human ventricle to re-entrant excitation in hERG-linked variant 1 short QT syndrome.
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DOI：
10.1371/journal.pcbi.1002313
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发表时间：
2011-12
影响因子：
4.3
通讯作者：
Zhang H
中科院分区：
文献类型：
--
作者：
Adeniran I;McPate MJ;Witchel HJ;Hancox JC;Zhang H
短QT综合征（SQTS）是一种遗传异质性疾病，其特征是QT间期缩短，对心律失常和猝死的易感性增加。该模拟研究确定了SQTS的快速延迟整流钾电流（IKr）相关SQT 1变体中的致瘤机制。在再现关于N588 K突变对KCNH 2编码的hERG的影响的实验数据方面，发现马尔可夫链（MC）模型上级于Hodgkin-Huxley（HH）模型。然后将这些离子通道模型纳入人体心室动作电位（AP）模型，并纳入1D和2D理想化和现实的透壁心室组织模拟和3D解剖模型。在单细胞模型中，N588 K突变缩短了心室肌细胞90%复极时的AP持续时间（APD 90），并降低了AP期间的最大跨壁电压异质性（δV）。这导致APD 90和有效不应期（ERP）的跨壁异质性降低：预期是抗心律失常而非促心律失常的效应。然而，考虑到基于Tusscher-Noble-Noble-Panfilov心室模型的完整组织模型中IKr密度的跨壁异质性，N588 K突变不仅导致QT缩短和T波振幅增加，而且发现心室组织的某些局部区域的δV增加，导致组织对单向传导阻滞的脆弱性增加，并倾向于形成折返激发波。在2D和3D组织模型中，N588 K突变促进并维持折返激发波，这是由于维持折返所需的基底尺寸减小。因此，在SQT 1中，N588 K-hERG突变促进心室折返的启动和维持，增加了折返螺旋波的寿命和3D组织中涡卷波的稳定性。心脏性猝死可能发生在心脏组织病变的个体中，或在表面健康的受试者中，这些受试者患有“离子通道”蛋白的遗传缺陷，这增加了心律失常的风险，并与显著的发病率和死亡率相关。一种罕见但严重的遗传疾病是“短QT综合征”（SQTS）。虽然现在已知KCNH 2编码的N588 K-hERG突变与SQTS的主要（SQT 1）变体相关，但由于缺乏基因型准确的实验模型，室性心律失常的启动和持续机制仍不清楚。在这项研究中，我们使用了复杂的多尺度计算机模型的人类心室，以调查的促肾上腺皮质激素的影响N588 K hERG突变。研究发现，该突变加速了心室复极过程，在组织的某些局部区域产生了增强的电异质性，导致心律失常发生的风险增加。还发现加速心室复极减少了维持二维和三维折返回路所需的组织的基底尺寸。这项研究为理解SQT 1中hERG通道功能的变化如何导致这种遗传性心律失常综合征的室性心律失常风险加剧提供了新的机制见解。
The short QT syndrome (SQTS) is a genetically heterogeneous condition characterized by abbreviated QT intervals and an increased susceptibility to arrhythmia and sudden death. This simulation study identifies arrhythmogenic mechanisms in the rapid-delayed rectifier K+ current (IKr)-linked SQT1 variant of the SQTS. Markov chain (MC) models were found to be superior to Hodgkin-Huxley (HH) models in reproducing experimental data regarding effects of the N588K mutation on KCNH2-encoded hERG. These ionic channel models were then incorporated into human ventricular action potential (AP) models and into 1D and 2D idealised and realistic transmural ventricular tissue simulations and into a 3D anatomical model. In single cell models, the N588K mutation abbreviated ventricular cell AP duration at 90% repolarization (APD90) and decreased the maximal transmural voltage heterogeneity (δV) during APs. This resulted in decreased transmural heterogeneity of APD90 and of the effective refractory period (ERP): effects that are anticipated to be anti-arrhythmic rather than pro-arrhythmic. However, with consideration of transmural heterogeneity of IKr density in the intact tissue model based on the ten Tusscher-Noble-Noble-Panfilov ventricular model, not only did the N588K mutation lead to QT-shortening and increases in T-wave amplitude, but δV was found to be augmented in some local regions of ventricle tissue, resulting in increased tissue vulnerability for uni-directional conduction block and predisposing to formation of re-entrant excitation waves. In 2D and 3D tissue models, the N588K mutation facilitated and maintained re-entrant excitation waves due to the reduced substrate size necessary for sustaining re-entry. Thus, in SQT1 the N588K-hERG mutation facilitates initiation and maintenance of ventricular re-entry, increasing the lifespan of re-entrant spiral waves and the stability of scroll waves in 3D tissue. Sudden cardiac death may arise in individuals with diseased heart tissue, or in apparently healthy subjects who suffer from genetic defects in ‘ion channel’ proteins, which increase cardiac arrhythmia risk and are associated with significant morbidity and mortality. One rare, though serious, genetic condition is the ‘short QT syndrome’ (SQTS). Although it is now known that the KCNH2-encoded N588K-hERG mutation is associated with the main (SQT1) variant of the SQTS, the mechanisms by which ventricular arrhythmia is initiated and sustained are still unclear due to lack of genotypically accurate experimental models. In this study, we used sophisticated multi-scale computer models of human ventricles in order to investigate the pro-arrhythmic effects of the N588K hERG mutation. It was found that the mutation accelerated the ventricular repolarization process, produced augmented electrical heterogeneity in some local regions of the tissue, leading to increased risk of arrhythmia genesis. It was also found that accelerated ventricular repolarization reduced the substrate size of the tissue required to sustain re-entrant circuits in both two and three dimensions. This study provides new mechanistic insight into understanding of how changes to hERG channel function in SQT1 lead to exacerbated ventricular arrhythmia risk in this inherited arrhythmia syndrome.
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