Dynamical mechanisms of phase-2 early afterdepolarizations in human ventricular myocytes: insights from bifurcation analyses of two mathematical models
Dynamical mechanisms of phase-2 early afterdepolarizations in human ventricular myocytes: insights from bifurcation analyses of two mathematical models
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DOI：
10.1152/ajpheart.00115.2016
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发表时间：
2017-01-01
影响因子：
4.8
通讯作者：
Shibamoto, Toshishige
中科院分区：
文献类型：
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作者：
Kurata, Yasutaka;Tsumoto, Kunichika;Shibamoto, Toshishige
早期去极化后（EAD）被认为是长QT综合征室性心律失常的一个原因。我们利用两种人类心室肌细胞模型，从理论上研究了延迟型K（+）通道电流、l型Ca2+通道电流（I-CaL）、Na+ /Ca2+交换电流（I-NCX）、Na+ -K+泵电流（I-NaK）、细胞内Ca2+ (Ca-i)通过肌浆网（SR）处理和细胞内Na+浓度（Na-i）对2期EADs的起始、终止和调制的快速（I-Kr）和慢速（I-Ks）成分。通过计算平衡点、极限环（LCs）和分岔点作为参数的函数，探讨了模型细胞动力学行为的分岔结构。通过数值模拟再现了EADs。结果表明：1)IKs和/或IKr的降低或ICaL的增加导致EAD的产生，中间心肌细胞模型对EAD的产生特别敏感；EADs的参数区域与稳定lc的区域重叠。2)检测到IKs激活依赖型和ICaL失活依赖型两种类型的EADs（终止机制）；EAD的形成并不一定需要ik。3)抑制INCX通过促进Ca2+依赖性的ICaL失活来抑制EADs。4) Cai动力学（SR Ca2+处理）和Nai通过调节ICaL、INCX和INaK强烈影响模型细胞的分叉和EAD的产生。在稳态和动态状态下，随着Cai和Nai的变化，ead的参数区域会发生位移，通常与稳定lc的参数区域重叠。5)心动过缓相关的EADs诱导主要是由于较低起搏速率下的Nai降低。本研究表明，分岔分析使我们能够更深入地了解EAD形成的动力学机制。我们通过对人心室肌细胞（HVM）模型的分岔分析，研究了2期早期后去极化（EAD）的机制。有节奏hvm的EAD形成基本依赖于非有节奏hvm的分岔现象，但在静止和动态状态下受到细胞内离子浓度的强烈影响。EAD一代不一定需要i - k。
Early afterdepolarization (EAD) is known as a cause of ventricular arrhythmias in long QT syndromes. We theoretically investigated how the rapid (I-Kr) and slow (I-Ks) components of delayed-rectifier K (+) channel currents, L-type Ca2+ channel current (I-CaL), Na+ /Ca2+ exchanger current (I-NCX), Na+ -K+ pump current (I-NaK), intracellular Ca2+ (Ca-i) handling via sarcoplasmic reticulum (SR), and intracellular Na+ concentration (Na-i) contribute to initiation, termination, and modulation of phase-2 EADs, using two human ventricular myocyte models. Bifurcation structures of dynamical behaviors in model cells were explored by calculating equilibrium points, limit cycles (LCs), and bifurcation points as functions of parameters. EADs were reproduced by numerical simulations. The results are summarized as follows: 1) decreasing IKs and/or IKr or increasing ICaL led to EAD generation, to which mid-myocardial cell models were especially susceptible; the parameter regions of EADs overlapped the regions of stable LCs. 2) Two types of EADs (termination mechanisms), IKs activation-dependent and ICaL inactivation-dependent EADs, were detected; IKs was not necessarily required for EAD formation. 3) Inhibiting INCX suppressed EADs via facilitating Ca2+ -dependent ICaL inactivation. 4) Cai dynamics (SR Ca2+ handling) and Nai strongly affected bifurcations and EAD generation in model cells via modulating ICaL, INCX, and INaK. Parameter regions of EADs, often overlapping those of stable LCs, shifted depending on Cai and Nai in stationary and dynamic states. 5) Bradycardia-related induction of EADs was mainly due to decreases in Nai at lower pacing rates. This study demonstrates that bifurcation analysis allows us to understand the dynamical mechanisms of EAD formation more profoundly.NEW & NOTEWORTHY We investigated mechanisms of phase-2 early afterdepolarization (EAD) by bifurcation analyses of human ventricular myocyte (HVM) models. EAD formation in paced HVMs basically depended on bifurcation phenomena in non-paced HVMs, but was strongly affected by intracellular ion concentrations in stationary and dynamic states. EAD generation did not necessarily require I-Ks.