Hashambhoy Yasmin L, Winslow Raimond L, Greenstein Joseph L
Department of Biomedical Engineering, Institute for Computational Medicine, TheJohns Hopkins University, Baltimore, MD 21218, USA.
Annu Int Conf IEEE Eng Med Biol Soc. 2011;2011:4665-8. doi: 10.1109/IEMBS.2011.6091155.
Cardiac voltage-gated Na(+) channels underlie membrane depolarization during the upstroke of the action potential (AP). These channels also exhibit a late, slowly-inactivating component of current (late I(Na)) that may be enhanced under pathological conditions such as heart failure, and may therefore promote AP prolongation and increase the likelihood of arrhythmia. Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) functionally modifies Na(+) channels, however it remains unclear if the CaMKII-dependent changes in late I(Na) are a major contributor to cellular arrhythmias such as early after depolarizations (EADs). In this study we develop a model of I(Na), including CaMKII-dependent effects, based on experimental measurements. The Na(+) channel model is incorporated into a computational model of the whole myocyte which describes excitation-contraction coupling via stochastic simulation of individual Ca(2+) release sites. Simulations suggest that relatively small augmentation of late I(Na) is sufficient to significantly prolong APs and lead to the appearance of EADs.
心脏电压门控钠通道是动作电位（AP）上升支期间膜去极化的基础。这些通道还表现出一种延迟的、缓慢失活的电流成分（延迟钠电流，late I(Na)），在诸如心力衰竭等病理条件下该成分可能增强，因此可能促进动作电位延长并增加心律失常的可能性。钙/钙调蛋白依赖性蛋白激酶II（CaMKII）在功能上修饰钠通道，然而尚不清楚CaMKII依赖性的延迟钠电流变化是否是诸如早期后去极化（EADs）等细胞心律失常的主要促成因素。在本研究中，我们基于实验测量结果开发了一个包含CaMKII依赖性效应的延迟钠电流模型。钠通道模型被纳入整个心肌细胞的计算模型中，该模型通过对单个钙释放位点的随机模拟来描述兴奋 - 收缩偶联。模拟结果表明，延迟钠电流相对较小的增强就足以显著延长动作电位并导致早期后去极化的出现。
