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Simulation Study of the Arrhythmogenic Effects of Two Missense Mutations in Human Atrial Fibrillation

机译:两种畸形突变在人心房颤动中的血液发生影响的仿真研究

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Genetic mutations affecting genes encoding for ion channel protein structures have been associated with the presence of atrial fibrillation (AF) in healthy individuals. The aim of this study is to model and simulate the effects of two gain-of-function mutations found in literature, T895M and T436M, and affecting the rapid delayed rectifier potassium current. Courtemanche human atrial model has been chosen to reproduce myocytes behaviour and an optimization algorithm has been employed to fit model parameters to experimental data. Single cell and tissue patch simulations have been performed to study the effects of the two mutations in control, paroxysmal and permanent AF conditions, both in right and left atrium. 0D simulations revealed that both mutations cause an increase in IKr current, leading to action potential duration shortening and flattening of restitution curves, especially in presence of the mutation T895M. Initiation of a re-entrant activity in 2D simulations were possible both in case of T895M and T436M. The study reports the arrhythmogenicity of the two mutants and reveals T895M having a stronger effect with respect to T436M, in particular in control rather than in paroxysmal and permanent AF conditions. Differences in the dynamics of the two mutations highlight the importance of a patient-specific approach in planning targeted drug therapies.
机译:影响用于离子通道蛋白质结构的基因的基因突变已经与健康个体的心房颤动(AF)的存在有关。本研究的目的是模拟和模拟文献,T895M和T436M中的两个功能突变的影响,并影响快速延迟整流钾电流。本协议的人心房模型已选择再现肌细胞行为,并采用优化算法将模型参数适合实验数据。已经进行了单细胞和组织斑块模拟,以研究对照,阵发性和永久性AF条件中的两个突变,左侧和左心房的影响。 0d模拟显示,两个突变都会导致I增加 kr 电流,导致恢复曲线的动作潜在持续时间缩短和平整,特别是在突变T895M的情况下。在T895M和T436M的情况下,可以在2D模拟中启动再参赛剂活性。该研究报告了两个突变体的脑血管生成性,并揭示了对T436M具有更强的效果的T895M,特别是对照而不是在阵发性和永久性AF条件下。两种突变动态的差异突出了患者特异性方法在规划靶向药物疗法方面的重要性。

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