Complex electrophysiological remodeling in postinfarction ischemic heart failure
Complex electrophysiological remodeling in postinfarction ischemic heart failure
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DOI：
10.1073/pnas.1718211115
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发表时间：
2018-03-27
影响因子：
11.1
通讯作者：
Chen-Izu, Ye
中科院分区：
文献类型：
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作者：
Hegyi, Bence;Bossuyt, Julie;Chen-Izu, Ye
心肌梗死（MI）后心力衰竭（HF）与心律失常的高发生率相关。治疗策略的发展需要详细了解电生理重构。然而，缺血性HF中离子电流的变化仍然不完全清楚，特别是在平移大动物模型中。在这里，我们系统地测量心肌梗死后HF的猪模型中梗死边缘和远端区域的心室肌细胞中的主要离子电流。我们记录了八个离子电流在细胞的动作电位（AP）在生理相关的条件下使用（自我）AP钳顺序解剖。与健康对照组相比，HF远端区心肌细胞的迟发Na+电流、Ca 2+激活的K+电流、Ca 2+激活的Cl-电流增加，快速延迟整流K+电流减少，Na+/Ca 2+交换电流改变。HF边缘区心肌细胞也出现上述变化，但同时伴有L型Ca ~（2+）电流减少、内向整流性K ~+电流减少和Ca ~（2+）释放依赖性延迟后除极。我们的数据显示，任何单个电流的变化都相对较小，但综合影响改变了内向电流和外向电流之间的平衡，缩短了边界区的AP，但延长了偏远区的AP。MI后HF的这种差异性重构增加了AP复极的不均匀性，这可能增强了致心律失常底物。我们全面的研究结果提供了一个机制框架，了解为什么单通道阻滞剂可能无法抑制心律失常，并强调需要考虑丰富的画面和整合的许多离子电流在设计治疗策略治疗心律失常的HF。
Heart failure (HF) following myocardial infarction (MI) is associated with high incidence of cardiac arrhythmias. Development of therapeutic strategy requires detailed understanding of electrophysiological remodeling. However, changes of ionic currents in ischemic HF remain incompletely understood, especially in translational large-animal models. Here, we systematically measure the major ionic currents in ventricular myocytes from the infarct border and remote zones in a porcine model of post-MI HF. We recorded eight ionic currents during the cell's action potential (AP) under physiologically relevant conditions using (self)AP-clamp sequential dissection. Compared with healthy controls, HF-remote zone myocytes exhibited increased late Na+ current, Ca2+-activated K+ current, Ca2+-activated Cl- current, decreased rapid delayed rectifier K+ current, and altered Na+/Ca2+ exchange current profile. In HF-border zone myocytes, the above changes also occurred but with additional decrease of L-type Ca2+ current, decrease of inward rectifier K+ current, and Ca2+ release-dependent delayed after-depolarizations. Our data reveal that the changes in any individual current are relatively small, but the integrated impacts shift the balance between the inward and outward currents to shorten AP in the border zone but prolong AP in the remote zone. This differential remodeling in post-MI HF increases the inhomogeneity of AP repolarization, which may enhance the arrhythmogenic substrate. Our comprehensive findings provide a mechanistic framework for understanding why single-channel blockers may fail to suppress arrhythmias, and highlight the need to consider the rich tableau and integration of many ionic currents in designing therapeutic strategies for treating arrhythmias in HF.