Mechanisms of altered excitation-contraction coupling in canine tachycardia-induced heart failure, II -: Model studies
Mechanisms of altered excitation-contraction coupling in canine tachycardia-induced heart failure, II -: Model studies
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DOI：
10.1161/01.res.84.5.571
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发表时间：
1999-03-19
影响因子：
20.1
通讯作者：
O'Rourke, B
中科院分区：
文献类型：
--
作者：
Winslow, RL;Rice, J;O'Rourke, B
在失败的人心室肌细胞中测量的Ca 2+瞬变表现出振幅降低、舒张减慢和频率依赖性减弱。在配套文章（O 'Rourke B，Kass DA，Tomaselli GF，Kaab S，Tunin R，Marban E.犬心动过速心脏兴奋-收缩偶联改变的机制：实验研究。Circ Res，1999年; 84：562-570），O 'Rourke等人表明，在从经受心动过速起搏方案的犬心脏分离的肌细胞中记录的Ca 2+瞬变表现出类似的反应。对这些衰竭心脏中的蛋白质水平的分析表明，SR Ca 2 + ATP酶和受磷蛋白平均降低28%，Na+/Ca 2+交换器（NCX）蛋白平均增加104%。在这篇文章中，我们提出了一个模型的犬心肌中层心室动作电位和Ca 2+瞬变。该模型用于估计心力衰竭中NCX和SR Ca 2 + ATP酶的功能上调和下调的程度，使用从2个不同的实验方案获得的数据。使用这些实验方案获得的平均SR Ca 2 + ATP酶功能下调的模型估计值为49%和62%，平均NCX功能上调范围的模型估计值为38%和75%。电压钳Ca 2+瞬变的模拟表明，这种变化足以解释衰竭犬心脏中Ca 2+瞬变的幅度减小、形状改变和松弛减慢。模型分析还表明，改变表达的Ca 2+处理蛋白发挥了重要作用，延长动作电位持续时间在失败的犬心肌细胞。
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, Kaab S, Tunin R, Marban 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.