Early afterdepolarizations promote transmural reentry in ischemic human ventricles with reduced repolarization reserve.
Early afterdepolarizations promote transmural reentry in ischemic human ventricles with reduced repolarization reserve.
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DOI：
10.1016/j.pbiomolbio.2016.01.008
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发表时间：
2016-01
影响因子：
3.8
通讯作者：
Rodriguez B
中科院分区：
文献类型：
--
作者：
Dutta S;Mincholé A;Zacur E;Quinn TA;Taggart P;Rodriguez B
急性缺血是心律失常猝死的主要原因，钾电流阻滞剂进一步促进了这一过程。电紧张性电流引起的缺血区周围的大折返和早期后除极(EADS)被认为是动物和分离细胞研究中的潜在机制。然而，室性和人类特有的心律失常机制以及复极储备对其的调节仍不清楚。本论文的目的是揭示钾电流(IKR)阻滞剂在急性局部缺血的人心室肌中调节心律失常风险的多尺度机制。通过整合冠状动脉闭塞引起的电生理离子改变的实验知识，构建了一个人体急性局部缺血的生物物理详细模型。通过确定在缺血边缘区域异位后再入的易损窗口(VW)来评估心律失常的风险。在缺血区周围的大范围折返是人类缺血区的主要折返机制，由于ATP敏感性钾电流(IK(ATP))的激活而增加了复极储备。减少30%的IKR导致的耐火度延长4%抵消了宏观再入的建立，并减少了再入的VW(23.5%)。然而，尽管不应期进一步延长，但复极储备的进一步减少(50%IKR减少)抗心律失常作用较差。这是由于在缺血边缘区域建立了由电子触发的EADS实现的跨壁折返。EADs的产生是由于复极过程中长时间注入的低幅值电渗性电流引起的L型钙电流(ICAL)的再激活。在一个复极储备减少的局部缺血人心室模型中，电子触发的EADS被认为是促进室壁内折返的一种潜在机制。
Acute ischemia is a major cause of sudden arrhythmic death, further promoted by potassium current blockers. Macro-reentry around the ischemic region and early afterdepolarizations (EADs) caused by electrotonic current have been suggested as potential mechanisms in animal and isolated cell studies. However, ventricular and human-specific arrhythmia mechanisms and their modulation by repolarization reserve remain unclear. The goal of this paper is to unravel multiscale mechanisms underlying the modulation of arrhythmic risk by potassium current (IKr) block in human ventricles with acute regional ischemia. A human ventricular biophysically-detailed model, with acute regional ischemia is constructed by integrating experimental knowledge on the electrophysiological ionic alterations caused by coronary occlusion. Arrhythmic risk is evaluated by determining the vulnerable window (VW) for reentry following ectopy at the ischemic border zone. Macro-reentry around the ischemic region is the main reentrant mechanism in the ischemic human ventricle with increased repolarization reserve due to the ATP-sensitive potassium current (IK(ATP)) activation. Prolongation of refractoriness by 4% caused by 30% IKr reduction counteracts the establishment of macro-reentry and reduces the VW for reentry (by 23.5%). However, a further decrease in repolarization reserve (50% IKr reduction) is less anti-arrhythmic despite further prolongation of refractoriness. This is due to the establishment of transmural reentry enabled by electrotonically-triggered EADs in the ischemic border zone. EADs are produced by L-type calcium current (ICaL) reactivation due to prolonged low amplitude electrotonic current injected during the repolarization phase. Electrotonically-triggered EADs are identified as a potential mechanism facilitating intramural reentry in a regionally-ischemic human ventricles model with reduced repolarization reserve.