Gibb W J, Wagner M B, Lesh M D
Cardiovascular Research Institute, University of California, San Francisco 94143.
J Theor Biol. 1994 Jun 7;168(3):245-57. doi: 10.1006/jtbi.1994.1106.
Under certain conditions, drugs that partially block transmembrane potassium currents in ventricular myocytes predispose patients to ventricular tachyarrhythmias. Although the precise mechanisms by which potassium blockade initiates tachyarrhythmias are unknown, it is believed that early afterdepolarizations (EADs) may play a role. Using the Luo-Rudy kinetic model of the ventricular action potential, we examine the effect of potassium blockade on the likelihood of observing triggered cardiac activity in a system of two coupled kinetic patches. We found that (i) phase 2 EADs are capable of triggering full action potentials in neighboring tissue if the patches are separated by a relatively large resistive barrier, and (ii) partial potassium blockade can either increase or decrease triggering probabilities depending on coupling resistivity. To understand the dynamic contribution of potassium blockade to triggered activity, the two-patch model is decomposed into two single patches. In one of the patches we compute the stability properties of simulated EADs (arising from phase 2 of the ventricular action potential) as a function of potassium blockade. The EAD stability properties are then related to the frequency-amplitude response of the neighboring patch. From the analysis of the decomposed system we found (iii) that increases in triggering probabilities brought about by potassium blockade may result from frequency and amplitude shifts of stable EAD oscillations. The first finding suggests a mechanism by which potassium blockade could induce EAD-triggered arrhythmias within the setting of chronic myocardial infarction. The second and third findings may partially explain why potassium blockade is antiarrhythmic in some patients, and proarrhythmic in others.
在某些情况下，部分阻断心室肌细胞跨膜钾电流的药物会使患者易患室性快速心律失常。尽管钾离子阻断引发快速心律失常的确切机制尚不清楚，但人们认为早期后除极（EADs）可能起了作用。利用心室动作电位的Luo-Rudy动力学模型，我们研究了钾离子阻断对在两个耦合动力学膜片系统中观察到触发心脏活动可能性的影响。我们发现：（i）如果膜片被相对较大的电阻性屏障隔开，2期EADs能够在相邻组织中触发完整的动作电位；（ii）部分钾离子阻断根据耦合电阻性的不同，可能增加或降低触发概率。为了理解钾离子阻断对触发活动的动态贡献，将双膜片模型分解为两个单膜片。在其中一个膜片中，我们计算模拟EADs（由心室动作电位的2期产生）的稳定性特性作为钾离子阻断的函数。然后将EAD的稳定性特性与相邻膜片的频率-振幅响应联系起来。通过对分解系统的分析，我们发现：（iii）钾离子阻断导致触发概率增加可能是由稳定EAD振荡的频率和振幅变化引起的。第一个发现提示了一种机制，通过该机制钾离子阻断可能在慢性心肌梗死情况下诱发EAD触发的心律失常。第二个和第三个发现可能部分解释了为什么钾离子阻断在一些患者中具有抗心律失常作用，而在另一些患者中则具有促心律失常作用。
