Mechanisms of atrial fibrillation termination by pure sodium channel blockade in an ionically-realistic mathematical model
Mechanisms of atrial fibrillation termination by pure sodium channel blockade in an ionically-realistic mathematical model
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DOI：
10.1161/01.res.0000160709.49633.2b
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发表时间：
2005-03-18
影响因子：
20.1
通讯作者：
Jalife, J
中科院分区：
文献类型：
--
作者：
Kneller, J;Kalifa, J;Jalife, J
Na+通道阻断抗心律失常药物终止心房颤动（AF）的机制仍不清楚。经典的“前导圈”理论表明，Na+通道封锁应该（如果有的话）促进重返。我们使用基于离子的迷走性 AF 数学模型来评估在持续性心律失常期间应用纯 Na+ 电流 (I-Na) 抑制的效果。在控制条件下，AF 由 1 或 2 个主导螺旋波维持，并在动作电位持续时间 (APD) 离散度的临界水平上进行颤动传播。 I-Na 抑制随着阻滞的增加而逐渐终止 AF，在 65% 阻滞时终止所有 AF。在 1:1 传导过程中，I-Na 抑制可降低 APD（在 4 Hz 和 60% 阻断时降低 13%）、传导速度（降低 37%）和折返波长（降低 24%）。在 AF 期间，I-Na 抑制增加了主转子的尺寸并降低了再入率（例如，在 60% I-Na 抑制时主频率降低了 33%），同时减少了波断产生的次级小波。三种机制导致模型中 I-Na 块诱导 AF 终止：（1）旋转中心扩大超出计算基底的能力； (2) 对功能性障碍物的锚定减少，边界处的蜿蜒和消失增加； (3)减少可以提供新的主转子的次级小波的数量。离体绵羊心脏的光学图谱证实，河豚毒素剂量依赖性地终止 AF，同时产生类似于数学模型中 I-Na 抑制的定性效果。我们得出的结论是，纯 I-Na 抑制可终止 AF，产生与之前的临床和实验观察结果一致的激活变化。这些结果提供了对 I 类抗心律失常药物诱导 AF 终止的先前神秘机制的见解。
The mechanisms by which Na+-channel blocking antiarrhythmic drugs terminate atrial fibrillation (AF) remain unclear. Classical "leading-circle" theory suggests that Na+-channel blockade should, if anything, promote re-entry. We used an ionically-based mathematical model of vagotonic AF to evaluate the effects of applying pure Na+-current (I-Na) inhibition during sustained arrhythmia. Under control conditions, AF was maintained by 1 or 2 dominant spiral waves, with fibrillatory propagation at critical levels of action potential duration (APD) dispersion. I-Na inhibition terminated AF increasingly with increasing block, terminating all AF at 65% block. During 1:1 conduction, I-Na inhibition reduced APD (by 13% at 4 Hz and 60% block), conduction velocity (by 37%), and re-entry wavelength (by 24%). During AF, I-Na inhibition increased the size of primary rotors and reduced re-entry rate (eg, dominant frequency decreased by 33% at 60% I-Na inhibition) while decreasing generation of secondary wavelets by wavebreak. Three mechanisms contributed to I-Na block-induced AF termination in the model: (1) enlargement of the center of rotation beyond the capacity of the computational substrate; (2) decreased anchoring to functional obstacles, increasing meander and extinction at boundaries; and (3) reduction in the number of secondary wavelets that could provide new primary rotors. Optical mapping in isolated sheep hearts confirmed that tetrodotoxin dose-dependently terminates AF while producing effects qualitatively like those of I-Na inhibition in the mathematical model. We conclude that pure I-Na inhibition terminates AF, producing activation changes consistent with previous clinical and experimental observations. These results provide insights into previously enigmatic mechanisms of class I antiarrhythmic drug-induced AF termination.