Trigger vs. Substrate: Multi-Dimensional Modulation of QT-Prolongation Associated Arrhythmic Dynamics by a hERG Channel Activator.
Trigger vs. Substrate: Multi-Dimensional Modulation of QT-Prolongation Associated Arrhythmic Dynamics by a hERG Channel Activator.
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DOI：
10.3389/fphys.2017.00757
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发表时间：
2017
影响因子：
4
通讯作者：
Benson AP
中科院分区：
文献类型：
--
作者：
Colman MA;Perez Alday EA;Holden AV;Benson AP
背景：细胞水平的动作电位时程延长导致的心电图QT间期延长与心律失常的易感性增加有关。与QT延长相关的心律失常的药物治疗通常是通过尝试将APD值恢复到可控范围、逆转对钙离子依赖的后除极(心律失常触发因素)的易感性以及与APD值延长相关的跨室壁复极离散度(心律失常底物)的增加来实现的。然而，这种药理调节已被证明效果有限。要了解药物调节的综合功能影响，需要同时研究触发因素和底物。方法：我们利用人的心室动作电位模型，结合随机三维时空钙动力学模型，并修改参数以模拟延长的QT条件，在计算机方法中实现了多尺度(细胞和组织)。我们使用这些模型来检测HERG激动剂MC-II-157C将动作电位恢复到可控范围的效果，检测其对心律失常触发物和底物的影响，以及这些心律失常触发物和底物之间的相互作用。结果：QT延长条件促进了快速起搏时后除极下自发释放事件的发生。MC-II-157c延长QT可缩短动作电位时程，抑制后除极的发展，减少后除极在单细胞中表现为触发活动的可能性。在组织中，QT延长导致复极的跨壁离散度增加，表现为单向传导阻滞的易损窗口增加。在某些情况下，MC-II-157c通过对INA的影响进一步增加了易受攻击的窗口。MC-II-157C的随机释放事件调制和跨室壁复极调制弥散的组合导致了一种综合行为，其中心律失常触发减少，但心律失常底物增加，导致对心律失常的可变和非线性总体易感性。结论：触发物减少与底物增加的相对平衡是MC-II-157c对QT间期延长所致心律失常易感性的多维调节作用的基础。
Background: Prolongation of the QT interval of the electrocardiogram (ECG), underlain by prolongation of the action potential duration (APD) at the cellular level, is linked to increased vulnerability to cardiac arrhythmia. Pharmacological management of arrhythmia associated with QT prolongation is typically achieved through attempting to restore APD to control ranges, reversing the enhanced vulnerability to Ca2+-dependent afterdepolarisations (arrhythmia triggers) and increased transmural dispersion of repolarisation (arrhythmia substrate) associated with APD prolongation. However, such pharmacological modulation has been demonstrated to have limited effectiveness. Understanding the integrative functional impact of pharmacological modulation requires simultaneous investigation of both the trigger and substrate. Methods: We implemented a multi-scale (cell and tissue) in silico approach using a model of the human ventricular action potential, integrated with a model of stochastic 3D spatiotemporal Ca2+ dynamics, and parameter modification to mimic prolonged QT conditions. We used these models to examine the efficacy of the hERG activator MC-II-157c in restoring APD to control ranges, examined its effects on arrhythmia triggers and substrates, and the interaction of these arrhythmia triggers and substrates. Results: QT prolongation conditions promoted the development of spontaneous release events underlying afterdepolarisations during rapid pacing. MC-II-157c applied to prolonged QT conditions shortened the APD, inhibited the development of afterdepolarisations and reduced the probability of afterdepolarisations manifesting as triggered activity in single cells. In tissue, QT prolongation resulted in an increased transmural dispersion of repolarisation, which manifested as an increased vulnerable window for uni-directional conduction block. In some cases, MC-II-157c further increased the vulnerable window through its effects on INa. The combination of stochastic release event modulation and transmural dispersion of repolarisation modulation by MC-II-157c resulted in an integrative behavior wherein the arrhythmia trigger is reduced but the arrhythmia substrate is increased, leading to variable and non-linear overall vulnerability to arrhythmia. Conclusion: The relative balance of reduced trigger and increased substrate underlies a multi-dimensional role of MC-II-157c in modulation of cardiac arrhythmia vulnerability associated with prolonged QT interval.
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影响因子：
20.1
作者：
Glukhov AV;Fedorov VV;Lou Q;Ravikumar VK;Kalish PW;Schuessler RB;Moazami N;Efimov IR
通讯作者：
Efimov IR
影响因子：
3.7
作者：
Alday EA;Ni H;Zhang C;Colman MA;Gan Z;Zhang H
通讯作者：
Zhang H
影响因子：
4.3
作者：
Alday EA;Colman MA;Langley P;Zhang H
通讯作者：
Zhang H
影响因子：
4.3
作者：
Alday EA;Colman MA;Langley P;Butters TD;Higham J;Workman AJ;Hancox JC;Zhang H
通讯作者：
Zhang H
影响因子：
2.9
作者：
Benson, Alan P.;Halley, Graeme;Holden, Arun V.
通讯作者：
Holden, Arun V.