Properties and ionic mechanisms of action potential adaptation, restitution, and accommodation in canine epicardium
Properties and ionic mechanisms of action potential adaptation, restitution, and accommodation in canine epicardium
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DOI：
10.1152/ajpheart.01216.2008
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发表时间：
2009-04-01
影响因子：
4.8
通讯作者：
Rudy, Yoram
中科院分区：
文献类型：
--
作者：
Decker, Keith F.;Heijman, Jordi;Rudy, Yoram
德克尔KF，海曼J，席尔瓦JR，洪德TJ，鲁迪Y.犬心外膜动作电位适应、恢复和调节的特性和离子机制。Am J Physiol Heart Circ Physiol 296：H1017-H1026，2009.首次发表于2009年1月23日; doi：10.1152/ajpheart.01216.2008。心肌细胞的计算模型是理解心律失常离子机制的重要工具。这项工作提出了一种新的犬心外膜肌细胞模型，再现了广泛的实验观察到的心脏细胞和组织的频率依赖性行为，包括动作电位（AP）持续时间（APD）的适应，恢复和调节。模型行为取决于4-氨基吡啶敏感的瞬时外向电流（I-to 1），延迟整流钾电流（I-Ks），L型钙通道电流（I-Ca，I-L）的慢成分，和Na+-K+泵电流（I-NaK）的更新配方拟合犬心室肌细胞的数据。我们发现，I-to 1在增强峰值I-Ca，I-L和肌浆网Ca 2+释放传播AP中发挥有限的作用，但调制APD恢复的时间过程。IKs在短舒张间期的APD缩短中起重要作用，尽管在较长周期长度的AP复极中作用有限。此外，我们还发现I-Ca、I-L在APD的调节和APD恢复的速率依赖性中起着关键作用。Ca ~（2+）通过I-Ca、I-L快速进入，促进Na ~+-Ca ~（2+）交换器Ca ~（2+）的排出和Na ~+的进入，进而促进Na ~+通过I-Na ~（2+）K的排出。APD调节的结果，这种增加外向I-NaK。我们的模拟结果为确定心脏对快速和不规则起搏频率的反应（例如，心律失常）。准确模拟率依赖性现象，并增加其机制基础的理解，将导致更现实的多细胞模拟心律失常和分子治疗靶点的识别。
Decker KF, Heijman J, Silva JR, Hund TJ, Rudy Y. Properties and ionic mechanisms of action potential adaptation, restitution, and accommodation in canine epicardium. Am J Physiol Heart Circ Physiol 296: H1017-H1026, 2009. First published January 23, 2009; doi:10.1152/ajpheart.01216.2008.-Computational models of cardiac myocytes are important tools for understanding ionic mechanisms of arrhythmia. This work presents a new model of the canine epicardial myocyte that reproduces a wide range of experimentally observed rate-dependent behaviors in cardiac cell and tissue, including action potential (AP) duration (APD) adaptation, restitution, and accommodation. Model behavior depends on updated formulations for the 4-aminopyridine-sensitive transient outward current (I-to1), the slow component of the delayed rectifier K+ current (I-Ks), the L-type Ca2+ channel current (I-Ca,I-L), and the Na+-K+ pump current (I-NaK) fit to data from canine ventricular myocytes. We found that I-to1 plays a limited role in potentiating peak I-Ca,I-L and sarcoplasmic reticulum Ca2+ release for propagated APs but modulates the time course of APD restitution. IKs plays an important role in APD shortening at short diastolic intervals, despite a limited role in AP repolarization at longer cycle lengths. In addition, we found that I-Ca,I-L plays a critical role in APD accommodation and rate dependence of APD restitution. Ca2+ entry via I-Ca,I-L at fast rate drives increased Na+-Ca2+ exchanger Ca2+ extrusion and Na+ entry, which in turn increases Na+ extrusion via outward I-NaK. APD accommodation results from this increased outward I-NaK. Our simulation results provide valuable insight into the mechanistic basis of rate-dependent phenomena important for determining the heart's response to rapid and irregular pacing rates (e.g., arrhythmia). Accurate simulation of rate-dependent phenomena and increased understanding of their mechanistic basis will lead to more realistic multicellular simulations of arrhythmia and identification of molecular therapeutic targets.