Instituto de Investigación Interuniversitario en Bioingeniería y Tecnología Orientada al Ser Humano (I3BH), Universitat Politècnica de València (UPV), Camino de Vera s/n, 46022 Valencia, Spain.
Prog Biophys Mol Biol. 2011 Oct;107(1):60-73. doi: 10.1016/j.pbiomolbio.2011.06.012. Epub 2011 Jul 3.
Several mathematical models of rabbit ventricular action potential (AP) have been proposed to investigate mechanisms of arrhythmias and excitation-contraction coupling. Our study aims at systematically characterizing how ionic current properties modulate the main cellular biomarkers of arrhythmic risk using two widely-used rabbit ventricular models, and comparing simulation results using the two models with experimental data available for rabbit. A sensitivity analysis of AP properties, Ca²⁺ and Na⁺ dynamics, and their rate dependence to variations (±15% and ±30%) in the main transmembrane current conductances and kinetics was performed using the Shannon et al. (2004) and the Mahajan et al. (2008a,b) AP rabbit models. The effects of severe transmembrane current blocks (up to 100%) on steady-state AP and calcium transients, and AP duration (APD) restitution curves were also simulated using both models. Our simulations show that, in both virtual rabbit cardiomyocytes, APD is significantly modified by most repolarization currents, AP triangulation is regulated mostly by the inward rectifier K⁺ current (I(K1)) whereas APD rate adaptation as well as Na⁺ rate dependence is influenced by the Na⁺/K⁺ pump current (I(NaK)). In addition, steady-state Ca²⁺ levels, APD restitution properties and Ca²⁺ rate dependence are strongly dependent on I(NaK), the L-Type Ca²⁺ current (I(CaL)) and the Na⁺/Ca²⁺ exchanger current (I(NaCa)), although the relative role of these currents is markedly model dependent. Furthermore, our results show that simulations using both models agree with many experimentally-reported electrophysiological characteristics. However, our study shows that the Shannon et al. model mimics rabbit electrophysiology more accurately at normal pacing rates, whereas Mahajan et al. model behaves more appropriately at faster rates. Our results reinforce the usefulness of sensitivity analysis for further understanding of cellular electrophysiology and validation of cardiac AP models.
已有几种兔心室动作电位（AP）的数学模型被提出，以研究心律失常和兴奋-收缩偶联的机制。我们的研究旨在使用两种广泛使用的兔心室模型系统地描述离子电流特性如何调节心律失常风险的主要细胞生物标志物，并将两种模型的模拟结果与兔的实验数据进行比较。使用 Shannon 等人（2004 年）和 Mahajan 等人（2008a,b）的兔 AP 模型，对 AP 特性、Ca²⁺和 Na⁺动力学及其对主要跨膜电流电导和动力学变化（±15%和±30%）的速率依赖性进行了敏感性分析。还使用两种模型模拟了严重的跨膜电流阻断（高达 100%）对稳态 AP 和钙瞬变以及 AP 时程（APD）复恢曲线的影响。我们的模拟结果表明，在两种虚拟兔心肌细胞中，APD 主要受大多数复极电流的影响，AP 三角化主要受内向整流钾电流（I(K1)）调节，而 APD 速率适应以及 Na⁺速率依赖性受钠钾泵电流（I(NaK)）影响。此外，稳态 Ca²⁺水平、APD 复恢特性和 Ca²⁺速率依赖性强烈依赖于 I(NaK)、L 型 Ca²⁺电流（I(CaL)）和 Na⁺/Ca²⁺交换器电流（I(NaCa)），尽管这些电流的相对作用在很大程度上取决于模型。此外，我们的研究结果表明，两种模型的模拟结果与许多实验报告的电生理特性一致。然而，我们的研究表明，Shannon 等人的模型在正常起搏率下更能模拟兔的电生理特性，而 Mahajan 等人的模型在更快的速率下表现得更合适。我们的研究结果进一步证实了敏感性分析在深入了解细胞电生理和验证心脏 AP 模型方面的有用性。
