Department of Internal Medicine III, University Hospital Heidelberg, Heidelberg, Germany.
Theoretical Biology and Bioinformatics, Utrecht University, Utrecht, The Netherlands.
PLoS One. 2013 Dec 20;8(12):e83179. doi: 10.1371/journal.pone.0083179. eCollection 2013.
Inhibition of the atrial ultra-rapid delayed rectifier potassium current (I Kur) represents a promising therapeutic strategy in the therapy of atrial fibrillation. However, experimental and clinical data on the antiarrhythmic efficacy remain controversial. We tested the hypothesis that antiarrhythmic effects of I Kur inhibitors are dependent on kinetic properties of channel blockade. A mathematical description of I Kur blockade was introduced into Courtemanche-Ramirez-Nattel models of normal and remodeled atrial electrophysiology. Effects of five model compounds with different kinetic properties were analyzed. Although a reduction of dominant frequencies could be observed in two dimensional tissue simulations for all compounds, a reduction of spiral wave activity could be only be detected in two cases. We found that an increase of the percent area of refractory tissue due to a prolongation of the wavelength seems to be particularly important. By automatic tracking of spiral tip movement we find that increased refractoriness resulted in rotor extinction caused by an increased spiral-tip meandering. We show that antiarrhythmic effects of I Kur inhibitors are dependent on kinetic properties of blockade. We find that an increase of the percent area of refractory tissue is the underlying mechanism for an increased spiral-tip meandering, resulting in the extinction of re-entrant circuits.
抑制心房超快延迟整流钾电流（I Kur）代表了治疗心房颤动的一种有前途的治疗策略。然而，关于抗心律失常疗效的实验和临床数据仍然存在争议。我们检验了这样一个假设，即 I Kur 抑制剂的抗心律失常作用取决于通道阻滞的动力学特性。将 I Kur 阻滞的数学描述引入到正常和重构心房电生理学的 Courtemanche-Ramirez-Nattel 模型中。分析了五种具有不同动力学特性的模型化合物的作用。尽管在所有化合物的二维组织模拟中都可以观察到主导频率的降低，但仅在两种情况下可以检测到螺旋波活动的降低。我们发现，由于波长的延长而导致的不应期组织百分比的增加似乎特别重要。通过对螺旋尖端运动的自动跟踪，我们发现增加的不应期导致由于螺旋尖端蜿蜒增加而导致的转子熄灭。我们表明，I Kur 抑制剂的抗心律失常作用取决于阻滞的动力学特性。我们发现，不应期组织百分比的增加是螺旋尖端蜿蜒增加的潜在机制，导致折返电路的熄灭。
