Proarrhythmic and antiarrhythmic actions of ion channel blockers on arrhythmias in the heart: model study.
Proarrhythmic and antiarrhythmic actions of ion channel blockers on arrhythmias in the heart: model study.
复制标题
离子通道阻滞剂对心律失常的促心律失常和抗心律失常作用：模型研究。
作者：
T. Chay
我们解释了为什么1)一些I类和IV类抗心律失常药物可以发挥致心律失常作用，2)一些III类药物能有效地控制折返性心律失常，3)周期长度(CL)振荡参与终止或启动折返性心律失常。为了解释这些现象，我们采用了以下三种方法：分叉分析、仿真和模型构建。在Beeler-Reuters模型中，抗心律失常药物通过改变Na+、Ca~(2+)、时变延迟整流和时无关内向整流K+通道的最大电导来模拟，模型细胞呈环状排列。分叉分析预测，存在一个临界环大小(CRS)，在该临界环大小时，无限环行为突然破裂。通道阻滞剂可通过不同的方式影响CRS：Na+和Ca~(2+)阻滞剂缩短CRS，延迟整流性K~+通道阻滞剂和内向K~+通道阻滞剂延长CRS。这种差异解释了为什么一些抗心律失常药物是促心律失常药物(即缩短CRS)，而另一些药物是抗心律失常药物(即延长CRS)。然后使用模拟来研究药物如何影响CRS附近的折返性心律。我们发现，在这个区域，CL、传导速度和动作电位时程都变得振荡。随着环尺寸的减小，振荡的模式变得更加复杂。当环收缩到一定大小时，再入不能再持续，在几个振荡周期后它就会终止。为了解释化学发光振荡的基本机制，我们构造了一个包含低阈值快内向电流和高阈值慢内向电流的最小模型。在这个模型中，我们证明了两种不同的激活和失活动力学的内向电流引起了CL振荡。我们的结果从理论上解释了Frame‘s群在犬房三尖瓣环上的实验结果，即IC类药物可使非持续性短暂折返产生稳定折返，而III类药物可使CL产生复杂的振荡。我们的结果也支持Frame组的结果，即在“可调”三尖瓣环中，随着可激发间隙的缩短，CL振荡变得更加复杂，其周期也变得更短。
We explain why 1) some class I and IV antiarrhythmia drugs could exert proarrhythmic action, 2) some class III drugs are effective in controlling reentrant arrhythmias, and 3) cycle length (CL) oscillation is involved in the termination or initiation of reentry. To explain these phenomena, we employ the following three means: bifurcation analysis, simulation, and model construction. Antiarrhythmia drugs are modeled by varying maximal conductances of Na+, Ca2+, and time-dependent delayed rectifying and time-independent inward rectifying K+ channels in the Beeler-Reuter model, where the model cells are arranged in a ring. Bifurcation analysis predicts that there is a critical ring size (CRS) at which infinite ring behavior suddenly breaks down. Channel blockers can affect CRS in different manners: Na+ and Ca2+ blockers shorten CRS, whereas delayed rectifying K+ channel blockers and the inward K+ channel blockers lengthen CRS. This differential explains why some antiarrhythmia drugs are proarrhythmic (i.e., shorten CRS) whereas others are antiarrhythmic (i.e., lengthen CRS). Simulation is then used to investigate how the drugs affect reentrant rhythms in the neighborhood of the CRS. We find that, in this region, CL, conduction velocity, and action potential duration become oscillatory. As ring size shrinks, the pattern of the oscillation becomes more complex. When the ring shrinks to a certain size, reentry can no longer be sustained, and it terminates after a few oscillatory cycles. To explain the basic mechanism involved in CL oscillation, we then construct a minimal model that contains a low-threshold fast inward current and a high-threshold slow inward current. With this model, we show that the two inward currents, with vastly different activation and inactivation kinetics, cause CL oscillations. Our results thus give theoretical explanations for the experimental finding of Frame's group in canine atrial tricuspid ring in vitro that class IC drugs can bring about stable reentry from nonsustained transient reentry, whereas class III drugs transform stable reentry to complex oscillations in CL. Our results also support the result of Frame's group, in that, in "adjustable" tricuspid rings, CL oscillation becomes more complex and its period becomes shorter as an excitable gap is shortened.