Winslow R L, Rice J, Jafri S, Marbán E, O'Rourke B
Department of Biomedical Engineering, Center for Computational Medicine and Biology, The Johns Hopkins University School of Medicine , Baltimore, MD 21205, USA.
Circ Res. 1999 Mar 19;84(5):571-86. doi: 10.1161/01.res.84.5.571.
Ca2+ transients measured in failing human ventricular myocytes exhibit reduced amplitude, slowed relaxation, and blunted frequency dependence. In the companion article (O'Rourke B, Kass DA, Tomaselli GF, Kääb S, Tunin R, Marbán E. Mechanisms of altered excitation-contraction coupling in canine tachycardia-induced heart, I: experimental studies. Circ Res. 1999;84:562-570), O'Rourke et al show that Ca2+ transients recorded in myocytes isolated from canine hearts subjected to the tachycardia pacing protocol exhibit similar responses. Analyses of protein levels in these failing hearts reveal that both SR Ca2+ ATPase and phospholamban are decreased on average by 28% and that Na+/Ca2+ exchanger (NCX) protein is increased on average by 104%. In this article, we present a model of the canine midmyocardial ventricular action potential and Ca2+ transient. The model is used to estimate the degree of functional upregulation and downregulation of NCX and SR Ca2+ ATPase in heart failure using data obtained from 2 different experimental protocols. Model estimates of average SR Ca2+ ATPase functional downregulation obtained using these experimental protocols are 49% and 62%. Model estimates of average NCX functional upregulation range are 38% and 75%. Simulation of voltage-clamp Ca2+ transients indicates that such changes are sufficient to account for the reduced amplitude, altered shape, and slowed relaxation of Ca2+ transients in the failing canine heart. Model analyses also suggest that altered expression of Ca2+ handling proteins plays a significant role in prolongation of action potential duration in failing canine myocytes.
在衰竭的人类心室肌细胞中测量到的Ca2+瞬变表现出振幅降低、松弛减慢以及频率依赖性减弱。在同期发表的文章中（奥罗克B、卡斯DA、托马塞利GF、卡布S、图宁R、马尔班E。犬快速性心律失常诱导性心肌病中兴奋-收缩偶联改变的机制，I：实验研究。《循环研究》。1999年；84：562 - 570），奥罗克等人表明，从经历快速起搏方案的犬心脏分离的心肌细胞中记录到的Ca2+瞬变表现出类似的反应。对这些衰竭心脏中蛋白质水平的分析显示，肌浆网Ca2+ATP酶和受磷蛋白平均降低了28%，而钠/钙交换体（NCX）蛋白平均增加了104%。在本文中，我们提出了一个犬心外膜下心室动作电位和Ca2+瞬变的模型。该模型用于利用从2种不同实验方案获得的数据估计心力衰竭时NCX和肌浆网Ca2+ATP酶功能上调和下调的程度。使用这些实验方案获得的肌浆网Ca2+ATP酶功能平均下调的模型估计值分别为49%和62%。NCX功能平均上调范围的模型估计值为38%和75%。电压钳Ca2+瞬变的模拟表明，这些变化足以解释衰竭犬心脏中Ca2+瞬变的振幅降低、形状改变和松弛减慢。模型分析还表明，Ca2+处理蛋白表达的改变在衰竭犬心肌细胞动作电位持续时间延长中起重要作用。
