PDF(Pubmed)
Abstract：
Genetic mutations in genes encoding for potassium channel protein structures have been recently associated with episodes of atrial fibrillation in asymptomatic patients. The aim of this study is to investigate the potential arrhythmogenicity of three gain-of-function mutations related to atrial fibrillation-namely, KCNH2 T895M, KCNH2 T436M, and KCNE3-V17M-using modeling and simulation of the electrophysiological activity of the heart. A genetic algorithm was used to tune the parameters\' value of the original ionic currents to reproduce the alterations experimentally observed caused by the mutations. The effects on action potentials, ionic currents, and restitution properties were analyzed using versions of the Courtemanche human atrial myocyte model in different tissues: pulmonary vein, right, and left atrium. Atrial susceptibility of the tissues to spiral wave generation was also investigated studying the temporal vulnerability. The presence of the three mutations resulted in an overall more arrhythmogenic substrate. Higher current density, action potential duration shortening, and flattening of the restitution curves were the major effects of the three mutations at the single-cell level. The genetic mutations at the tissue level induced a higher temporal vulnerability to the rotor\'s initiation and progression, by sustaining spiral waves that perpetuate until the end of the simulation. The mutation with the highest pro-arrhythmic effects, exhibiting the widest sustained VW and the smallest meandering rotor\'s tip areas, was KCNE3-V17M. Moreover, the increased susceptibility to arrhythmias and rotor\'s stability was tissue-dependent. Pulmonary vein tissues were more prone to rotor\'s initiation, while in left atrium tissues rotors were more easily sustained. Re-entries were also progressively more stable in pulmonary vein tissue, followed by the left atrium, and finally the right atrium. The presence of the genetic mutations increased the susceptibility to arrhythmias by promoting the rotor\'s initiation and maintenance. The study provides useful insights into the mechanisms underlying fibrillatory events caused by KCNH2 T895M, KCNH2 T436M, and KCNE3-V17M and might aid the planning of patient-specific targeted therapies.
摘要：
最近，编码钾离子通道蛋白结构的基因中的基因突变与无症状患者的心房颤动发作有关。这项研究的目的是研究与心房颤动相关的三种功能获得突变的潜在心律失常性，即KCNH2T895M,KCNH2T436M,和KCNE3-V17M-使用心脏电生理活动的建模和仿真。使用遗传算法来调整原始离子电流的参数值，以重现由突变引起的实验观察到的变化。对动作电位的影响，离子电流，使用Courtemanche人心房肌细胞模型在不同组织中的版本分析了恢复特性：肺静脉，对,左心房.还研究了组织对螺旋波产生的心房敏感性，研究了时间脆弱性。三个突变的存在导致总体上更多的致心律失常底物。更高的电流密度，动作电位持续时间缩短，恢复曲线的平坦化是三种突变在单细胞水平上的主要影响。在组织水平的基因突变诱导了一个更高的时间脆弱性的转子的启动和进展，通过维持螺旋波一直持续到模拟结束。具有最高致心律失常作用的突变，表现出最宽的持续大众和最小的曲折转子尖端区域，是KCNE3-V17M.此外，对心律失常的易感性增加和转子的稳定性是组织依赖性的。肺静脉组织更容易发生转子的启动，而在左心房组织中，转子更容易维持。再次进入肺静脉组织也逐渐更稳定，其次是左心房,最后是右心房。基因突变的存在通过促进转子的启动和维持增加了对心律失常的易感性。该研究为KCNH2T895M引起的纤维化事件的潜在机制提供了有用的见解，KCNH2T436M,和KCNE3-V17M，可能有助于规划患者特异性靶向治疗。
