Microdomain-Specific Modulation of L-Type Calcium Channels Leads to Triggered Ventricular Arrhythmia in Heart Failure.
Microdomain-Specific Modulation of L-Type Calcium Channels Leads to Triggered Ventricular Arrhythmia in Heart Failure.
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DOI：
10.1161/circresaha.116.308698
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发表时间：
2016-09-30
影响因子：
20.1
通讯作者：
Gorelik J
中科院分区：
文献类型：
--
作者：
Sanchez-Alonso JL;Bhargava A;O'Hara T;Glukhov AV;Schobesberger S;Bhogal N;Sikkel MB;Mansfield C;Korchev YE;Lyon AR;Punjabi PP;Nikolaev VO;Trayanova NA;Gorelik J
补充数字内容可在文本中找到。继发于心肌细胞结构变化的Ca 2+信号复合物亚细胞靶向的破坏可能导致各种心脏疾病的病理生理学，包括心力衰竭（HF）和某些心律失常。探讨心力衰竭时心室L型钙通道（LTCCs）的微区靶向重构。应用超分辨扫描膜片钳技术、共聚焦显微镜和荧光显微镜观察单个LTCCs在正常和衰竭的人和大鼠心室肌细胞不同膜微区的分布。两种动物的膜结构破坏导致功能性LTCC从横小管（T-小管）的典型位置重新分布到肌膜的非天然嵴，在那里它们的开放概率显著增加（0.034±0.011对0.154±0.027，P<0.001）。高开放概率与增强非天然微区中钙-钙调蛋白激酶II介导的磷酸化有关，并导致伊卡，L窗口电流升高，这有助于早期后去极化的发展。开发了一种新的HF中LTCC功能模型;在用实验数据验证后，该模型用于确定HF诱导的T-小管损失如何导致LTCC功能改变和早期后去极化。HF心肌细胞模型，然后在三维左心室模型中实施，证明这种早期后除极可以传播和启动折返性心律失常。LTCC特性的微区靶向重构是可能在HF相关重构的设置中促成心室肌生成的途径中的重要事件。这超出了HF中电重构的经典概念，并为心血管疾病增加了新的维度。
Supplemental Digital Content is available in the text. Disruption in subcellular targeting of Ca2+ signaling complexes secondary to changes in cardiac myocyte structure may contribute to the pathophysiology of a variety of cardiac diseases, including heart failure (HF) and certain arrhythmias. To explore microdomain-targeted remodeling of ventricular L-type Ca2+ channels (LTCCs) in HF. Super-resolution scanning patch-clamp, confocal and fluorescence microscopy were used to explore the distribution of single LTCCs in different membrane microdomains of nonfailing and failing human and rat ventricular myocytes. Disruption of membrane structure in both species led to the redistribution of functional LTCCs from their canonical location in transversal tubules (T-tubules) to the non-native crest of the sarcolemma, where their open probability was dramatically increased (0.034±0.011 versus 0.154±0.027, P<0.001). High open probability was linked to enhance calcium–calmodulin kinase II–mediated phosphorylation in non-native microdomains and resulted in an elevated ICa,L window current, which contributed to the development of early afterdepolarizations. A novel model of LTCC function in HF was developed; after its validation with experimental data, the model was used to ascertain how HF-induced T-tubule loss led to altered LTCC function and early afterdepolarizations. The HF myocyte model was then implemented in a 3-dimensional left ventricle model, demonstrating that such early afterdepolarizations can propagate and initiate reentrant arrhythmias. Microdomain-targeted remodeling of LTCC properties is an important event in pathways that may contribute to ventricular arrhythmogenesis in the settings of HF-associated remodeling. This extends beyond the classical concept of electric remodeling in HF and adds a new dimension to cardiovascular disease.