Calcium-Voltage Coupling in the Genesis of Early and Delayed Afterdepolarizations in Cardiac Myocytes
Calcium-Voltage Coupling in the Genesis of Early and Delayed Afterdepolarizations in Cardiac Myocytes
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DOI：
10.1016/j.bpj.2015.03.011
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发表时间：
2015-04-21
影响因子：
3.4
通讯作者：
Qu, Zhilin
中科院分区：
文献类型：
--
作者：
Song, Zhen;Ko, Christopher Y.;Qu, Zhilin
早期后除极（埃兹）和延迟后除极（DAD）是已知可引起心律失常的电压振荡。埃兹主要由动作电位（AP）复极化相的电压振荡驱动，而DAD则由阿托洛尔期间自发钙（Ca）释放驱动。因为电压和钙是双向耦合的，它们调节彼此的行为，并且新的AP和钙循环动力学可以从这种耦合中出现。在这项研究中，我们进行了计算机模拟，使用AP模型与详细的时空钙循环纳入随机开放的钙通道和ryanodine受体的影响，钙电压耦合EAD和DAD的动力学。在小鼠心室肌细胞中的实验补充了模拟。我们表明：（1）由于钙离子对离子电流特性的复杂作用，导致Ryanodine受体泄漏和/或肌浆网/内质网Ca ATP酶活性增加而引起的钙瞬变既可促进EAD，也可抑制EAD，（2）自发钙波对埃兹也有复杂作用，但没有I-Ca、I-L的参与，不能诱发显著幅度的埃兹; 3）AP持续时间的延长和埃兹的发生通过增加细胞内Ca负荷促进DAD的发生，并确定了DAD的两种机制，即，Ca波依赖性和Ca波独立性;和4）Ca电压耦合促进复杂的EAD模式，例如对于单独电压驱动的埃兹未观察到的EAD交替。总之，钙-电压耦合结合电压和钙循环的非线性动力学行为在产生实验观察到的心肌细胞中复杂的EAD和DAD动力学中起关键作用，其机制复杂但可分析。
Early afterdepolarizations (EADs) and delayed afterdepolarizations (DADs) are voltage oscillations known to cause cardiac arrhythmias. EADs are mainly driven by voltage oscillations in the repolarizing phase of the action potential (AP), while DADs are driven by spontaneous calcium (Ca) release during diastole. Because voltage and Ca are bidirectionally coupled, they modulate each other's behaviors, and new AP and Ca cycling dynamics can emerge from this coupling. In this study, we performed computer simulations using an AP model with detailed spatiotemporal Ca cycling incorporating stochastic openings of Ca channels and ryanodine receptors to investigate the effects of Ca-voltage coupling on EAD and DAD dynamics. Simulations were complemented by experiments in mouse ventricular myocytes. We show that: 1) alteration of the Ca transient due to increased ryanodine receptor leakiness and/or sarco/endoplasmic reticulum Ca ATPase activity can either promote or suppress EADs due to the complex effects of Ca on ionic current properties; 2) spontaneous Ca waves also exhibit complex effects on EADs, but cannot induce EADs of significant amplitude without the participation of I-Ca,I-L; 3) lengthening AP duration and the occurrence of EADs promote DADs by increasing intracellular Ca loading, and two mechanisms of DADs are identified, i.e., Ca-wave-dependent and Ca-wave-independent; and 4) Ca-voltage coupling promotes complex EAD patterns such as EAD alternans that are not observed for solely voltage-driven EADs. In conclusion, Ca-voltage coupling combined with the nonlinear dynamical behaviors of voltage and Ca cycling play a key role in generating complex EAD and DAD dynamics observed experimentally in cardiac myocytes, whose mechanisms are complex but analyzable.