Abstract：
OBJECTIVE: Personalized 3D computer models of atria have been extensively implemented in the last yearsas a tool to facilitate the understanding of the mechanisms underlying different forms of arrhythmia, such as atrial fibrillation (AF). Meanwhile, genetic mutations acting on potassium channel dynamics were demonstrated to induce fibrillatory episodes in asymptomatic patients. This research study aims at assessing the effects and the atrial susceptibility to AF of three gain-of-function mutations - namely, KCNH2 T895M, KCNH2 T436M, and KCNE3-V17M - associated with AF outbreaks, using highly detailed 3D atrial models with realistic wall thickness and heterogenous histological properties.
METHODS: The 3D atrial model was generated by reconstructing segmented anatomical structures from CT scans of an AF patient. Modified versions of the Courtemanche human atrial myocyte model were used to reproduce the electrophysiological activity of the WT and of the three mutant cells. Ectopic foci (EF) were simulated in sixteen locations across the atrial mesh using an S1-S2 protocol with two S2 basic cycle lengths (BCL) and eleven coupling intervals in order to induce arrhythmias.
RESULTS: The three genetic mutations at 3D level reduced the APD90. The KCNE3-V17M mutation provoked the highest shortening (55 % in RA and LA with respect to WT), followed by KCNH2 T895M (14 % in RA and 18 % LA with respect to WT)and KCNH2 T436M (7 % in RA and 9 % LA with respect to WT). The KCNE3-V17M mutation led to arrhythmia in 67 % of the cases simulated and in 94 % of ectopic foci considered, at S2 BCL equal to 100 ms. The KCNH2 T436M and KCNH2 T895M mutations increased the vulnerability to AF in a similar way, leading to arrhythmic episodes in 7 % of the simulated conditions, at S2 BCL set to 160 ms. Overall, 60 % of the arrhythmic events generated arise in the left atrium. Spiral waves, multiple rotors and disordered electrical pattern were elicited in the presence of the KCNE3-V17M mutation, exhibiting an instantaneous mean frequency of 7.6 Hz with a mean standard deviation of 1.12 Hz. The scroll waves induced in the presence of the KCNH2 T436M and KCNH2 T895M mutations showed steadiness and regularity with an instantaneous mean frequencies in the range of 4.9 - 5.1 Hz and a mean standard deviation within 0.19 - 0.53 Hz.
CONCLUSIONS: The pro-arrhythmogenicity of the KCNE3-V17M, KCNH2 T895M and KCNH2 T436M mutations was studied and proved on personalized 3D cardiac models. The three genetic mutations were demonstrated to increase the predisposition of atrial tissue to the formation of AF-susceptible substrate in different ways based on their effects on electrophysiological properties of the atria.
METHODS: The 3D atrial model was generated by reconstructing segmented anatomical structures from CT scans of an AF patient. Modified versions of the Courtemanche human atrial myocyte model were used to reproduce the electrophysiological activity of the WT and of the three mutant cells. Ectopic foci (EF) were simulated in sixteen locations across the atrial mesh using an S1-S2 protocol with two S2 basic cycle lengths (BCL) and eleven coupling intervals in order to induce arrhythmias.
RESULTS: The three genetic mutations at 3D level reduced the APD90. The KCNE3-V17M mutation provoked the highest shortening (55 % in RA and LA with respect to WT), followed by KCNH2 T895M (14 % in RA and 18 % LA with respect to WT)and KCNH2 T436M (7 % in RA and 9 % LA with respect to WT). The KCNE3-V17M mutation led to arrhythmia in 67 % of the cases simulated and in 94 % of ectopic foci considered, at S2 BCL equal to 100 ms. The KCNH2 T436M and KCNH2 T895M mutations increased the vulnerability to AF in a similar way, leading to arrhythmic episodes in 7 % of the simulated conditions, at S2 BCL set to 160 ms. Overall, 60 % of the arrhythmic events generated arise in the left atrium. Spiral waves, multiple rotors and disordered electrical pattern were elicited in the presence of the KCNE3-V17M mutation, exhibiting an instantaneous mean frequency of 7.6 Hz with a mean standard deviation of 1.12 Hz. The scroll waves induced in the presence of the KCNH2 T436M and KCNH2 T895M mutations showed steadiness and regularity with an instantaneous mean frequencies in the range of 4.9 - 5.1 Hz and a mean standard deviation within 0.19 - 0.53 Hz.
CONCLUSIONS: The pro-arrhythmogenicity of the KCNE3-V17M, KCNH2 T895M and KCNH2 T436M mutations was studied and proved on personalized 3D cardiac models. The three genetic mutations were demonstrated to increase the predisposition of atrial tissue to the formation of AF-susceptible substrate in different ways based on their effects on electrophysiological properties of the atria.
摘要：
目的：心房的个性化3D计算机模型在过去的一年中已被广泛实施，这是一种工具，可以帮助人们理解不同形式的心律失常的潜在机制。如心房颤动（AF）。同时,研究表明,在无症状患者中,作用于钾离子通道动力学的基因突变可诱发纤颤发作.这项研究旨在评估三种功能获得突变对房颤的影响和心房易感性-即KCNH2T895M,KCNH2T436M,和KCNE3-V17M-与AF爆发相关，使用具有真实壁厚和异质组织学特性的高度详细的3D心房模型。
方法：通过重建房颤患者CT扫描的分段解剖结构，生成三维心房模型。Courtemanche人心房肌细胞模型的修改版本用于再现WT和三个突变细胞的电生理活性。使用具有两个S2基本周期长度（BCL）和11个耦合间隔的S1-S2协议在心房网格上的16个位置模拟异位灶（EF），以诱发心律失常。
结果：3D水平的三个基因突变降低了APD90。KCNE3-V17M突变引起最高的缩短（RA和LA相对于WT为55％），其次是KCNH2T895M(在RA中为14%,在WT中为18%LA)和KCNH2T436M(在RA中为7%,在WT中为9%LA)。KCNE3-V17M突变导致67%的模拟病例和94%的异位病灶出现心律失常，在S2处BCL等于100ms。KCNH2T436M和KCNH2T895M突变以类似的方式增加了对AF的脆弱性，在7%的模拟条件下导致心律失常发作，在S2BCL设置为160ms。总的来说,产生的心律失常事件的60％发生在左心房。螺旋波,在KCNE3-V17M突变的存在下引起多个转子和无序的电模式，表现出7.6Hz的瞬时平均频率和1.12Hz的平均标准偏差。在KCNH2T436M和KCNH2T895M突变存在下诱导的滚动波显示出稳定性和规律性，瞬时平均频率在4.9-5.1Hz范围内，平均标准偏差在0.19-0.53Hz内。
结论：KCNE3-V17M的致心律失常性，在个性化3D心脏模型上研究并证明KCNH2T895M和KCNH2T436M突变。根据对心房电生理特性的影响，证明了这三种基因突变以不同的方式增加了心房组织对AF易感底物形成的易感性。
方法：通过重建房颤患者CT扫描的分段解剖结构，生成三维心房模型。Courtemanche人心房肌细胞模型的修改版本用于再现WT和三个突变细胞的电生理活性。使用具有两个S2基本周期长度（BCL）和11个耦合间隔的S1-S2协议在心房网格上的16个位置模拟异位灶（EF），以诱发心律失常。
结果：3D水平的三个基因突变降低了APD90。KCNE3-V17M突变引起最高的缩短（RA和LA相对于WT为55％），其次是KCNH2T895M(在RA中为14%,在WT中为18%LA)和KCNH2T436M(在RA中为7%,在WT中为9%LA)。KCNE3-V17M突变导致67%的模拟病例和94%的异位病灶出现心律失常，在S2处BCL等于100ms。KCNH2T436M和KCNH2T895M突变以类似的方式增加了对AF的脆弱性，在7%的模拟条件下导致心律失常发作，在S2BCL设置为160ms。总的来说,产生的心律失常事件的60％发生在左心房。螺旋波,在KCNE3-V17M突变的存在下引起多个转子和无序的电模式，表现出7.6Hz的瞬时平均频率和1.12Hz的平均标准偏差。在KCNH2T436M和KCNH2T895M突变存在下诱导的滚动波显示出稳定性和规律性，瞬时平均频率在4.9-5.1Hz范围内，平均标准偏差在0.19-0.53Hz内。
结论：KCNE3-V17M的致心律失常性，在个性化3D心脏模型上研究并证明KCNH2T895M和KCNH2T436M突变。根据对心房电生理特性的影响，证明了这三种基因突变以不同的方式增加了心房组织对AF易感底物形成的易感性。
