Theoretical investigation of action potential duration dependence on extracellular Ca2+ in human cardiomyocytes
Theoretical investigation of action potential duration dependence on extracellular Ca2+ in human cardiomyocytes
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DOI：
10.1016/j.yjmcc.2008.12.002
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发表时间：
2009-03-01
影响因子：
5
通讯作者：
Severi, Stefano
中科院分区：
文献类型：
--
作者：
Grandi, Eleonora;Pasqualini, Francesco S.;Severi, Stefano
[Ca~(2+)](O)的降低延长了患者心肌细胞的AP和QT(C)间期。虽然这种现象在临床上与心律失常的发生有关，但其机制是违反直觉的，而且还不完全清楚。目的：探讨[Ca~(2+)](O)对动作电位时程的调控机制。在人类心肌细胞中。我们实现了人心室肌细胞的Ten Tusscher-Noble-Noble-Panfilov模型，并对快速和缓慢激活的延迟整流钾电流(I-Kr和I-Ks)和L型钙电流(I-Cal)的公式进行了修改，以纳入它们对细胞内或细胞外钙的敏感性。在临床相关的1-3 mm范围内，用原始模型和修改后的模型在可变的[Ca~(2+)]下进行模拟。原始模型的反应是动作电位时程缩短，使[Ca~(2+)](O)降低，与实验结果相反。K+电流对钙的依赖性不能再现动作电位时程与[钙](O)的反向关系。只有当I-Cal失活过程被改变时，通过增强其对钙的依赖性，模拟才能预测在较低的[Ca+](O)时时程延长。虽然钙依赖的i-Cal失活是主要机制，但通过Na+/Ca~(2+)交换和质膜Ca~(2+)-ATPase对电源性Ca~(2+)转运的继发性改变有助于逆转时程对[Ca~(2+)](O)的依赖性。这一理论研究指出，钙依赖的ICAL失活是动作电位依赖于[Ca~(2+)](O)的主要机制。改进后的模型更适合于分析钙离子水平变化时的复极机制。(C)2008 Elsevier Inc.保留所有权利。
Reduction in [Ca2+](o) prolongs the AP in ventricular cardiomyrocytes and the QT(c), interval in patients. Although this phenomenon is relevant to arrhythmogenesis in the clinical setting, its mechanisms are counterintuitive and incompletely understood. To evaluate in silico the mechanisms of APD modulation by [Ca2+](o). in human cardiomyrocytes. We implemented the Ten Tusscher-Noble-Noble-Panfilov model of the human ventricular myrocyte and modified the formulations of the rapidly and slowly activating delayed rectifier K+ currents (I-Kr and I-Ks) and L-type Ca2+ current (I-CaL) to incorporate their known sensitivity to intra- or extracellular Ca2+. Simulations were run with the original and modified models at variable [Ca2+], in the clinically relevant I to 3 mM range. The original model responds with APD shortening to decrease in [Ca2+](o), i.e. opposite to the experimental observations. Incorporation of Ca2+ dependency of K+ currents cannot reproduce the inverse relation between APD and [Ca2+](o). Only when I-CaL inactivation process was modified, by enhancing its dependency on Ca2+, simulations predict APD prolongation at lower [Ca2+](o). Although Ca2+-dependent I-CaL inactivation is the primary mechanism, secondary changes in electrogenic Ca2+ transport (by Na+/Ca2+ exchanger and plasmalemmal Ca2+-ATPase) contribute to the reversal of APD dependency on [Ca2+](o). This theoretical investigation points to Ca2+-dependent inactivation of ICaL as a mechanism primarily responsible for the dependency of APD on [Ca2+](o). The modifications implemented here make the model more suitable to analyze repolarization mechanisms when Ca2+ levels are altered. (C) 2008 Elsevier Inc. All rights reserved.