Aguilar Martin, Feng Jianlin, Vigmond Edward, Comtois Philippe, Nattel Stanley
Research Center, Montreal Heart Institute, Université de Montréal, Montreal, Québec, Canada; Department of Pharmacology and Physiology/Institute of Biomedical Engineering, Université de Montréal, Montreal, Québec, Canada.
Bristol-Myers Squibb, Wallingford, Connecticut.
Biophys J. 2017 May 9;112(9):1997-2010. doi: 10.1016/j.bpj.2017.03.022.
The atrial-specific ultrarapid delayed rectifier K current (I) inactivates slowly but completely at depolarized voltages. The consequences for I rate-dependence have not been analyzed in detail and currently available mathematical action-potential (AP) models do not take into account experimentally observed I inactivation dynamics. Here, we developed an updated formulation of I inactivation that accurately reproduces time-, voltage-, and frequency-dependent inactivation. We then modified the human atrial cardiomyocyte Courtemanche AP model to incorporate realistic I inactivation properties. Despite markedly different inactivation dynamics, there was no difference in AP parameters across a wide range of stimulation frequencies between the original and updated models. Using the updated model, we showed that, under physiological stimulation conditions, I does not inactivate significantly even at high atrial rates because the transmembrane potential spends little time at voltages associated with inactivation. Thus, channel dynamics are determined principally by activation kinetics. I magnitude decreases at higher rates because of AP changes that reduce I activation. Nevertheless, the relative contribution of I to AP repolarization increases at higher frequencies because of reduced activation of the rapid delayed-rectifier current I. Consequently, I block produces dose-dependent termination of simulated atrial fibrillation (AF) in the absence of AF-induced electrical remodeling. The inclusion of AF-related ionic remodeling stabilizes simulated AF and greatly reduces the predicted antiarrhythmic efficacy of I block. Our results explain a range of experimental observations, including recently reported positive rate-dependent I-blocking effects on human atrial APs, and provide insights relevant to the potential value of I as an antiarrhythmic target for the treatment of AF.
心房特异性超快速延迟整流钾电流（I）在去极化电压下缓慢但完全失活。I的频率依赖性后果尚未得到详细分析，目前可用的数学动作电位（AP）模型未考虑实验观察到的I失活动力学。在此，我们开发了一种I失活的更新公式，该公式能准确再现时间、电压和频率依赖性失活。然后，我们对人类心房心肌细胞库尔特曼奇AP模型进行了修改，以纳入实际的I失活特性。尽管失活动力学明显不同，但在广泛的刺激频率范围内，原始模型和更新模型的AP参数并无差异。使用更新后的模型，我们表明，在生理刺激条件下，即使在高心房率时I也不会显著失活，因为跨膜电位在与失活相关的电压下停留的时间很少。因此，通道动力学主要由激活动力学决定。由于AP变化减少了I的激活，I的幅度在较高频率时降低。然而，由于快速延迟整流电流I的激活减少，I对AP复极化的相对贡献在较高频率时增加。因此，在不存在房颤诱导的电重构的情况下，I阻断可产生剂量依赖性的模拟房颤（AF）终止。纳入与房颤相关的离子重构可稳定模拟房颤，并大大降低预测的I阻断抗心律失常疗效。我们的结果解释了一系列实验观察结果，包括最近报道的I阻断对人类心房AP的正频率依赖性效应，并提供了与I作为治疗房颤的抗心律失常靶点的潜在价值相关的见解。
