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首页> 外文期刊>European Biophysics Journal >Quantitative prediction of the arrhythmogenic effects of de novo hERG mutations in computational models of human ventricular tissues
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Quantitative prediction of the arrhythmogenic effects of de novo hERG mutations in computational models of human ventricular tissues

机译：在人类心室组织计算模型中从头hERG突变的心律失常作用的定量预测

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Mutations to hERG which result in changes to the rapid delayed rectifier current I _(Kr) can cause long and short QT syndromes and are associated with an increased risk of cardiac arrhythmias. Experimental recordings of I _(Kr) reveal the effects of mutations at the channel level, but how these changes translate to the cell and tissue levels remains unclear. We used computational models of human ventricular myocytes and tissues to predict and quantify the effects that de novo hERG mutations would have on cell and tissue electrophysiology. Mutations that decreased I _(Kr) maximum conductance resulted in an increased cell and tissue action potential duration (APD) and a long QT interval on the electrocardiogram (ECG), whereas those that caused a positive shift in the inactivation curve resulted in a decreased APD and a short QT. Tissue vulnerability to re-entrant arrhythmias was correlated with transmural dispersion of repolarisation, and any change to this vulnerability could be inferred from the ECG QT interval or T wave peak-to-end time. Faster I _(Kr) activation kinetics caused cell APD alternans to appear over a wider range of pacing rates and with a larger magnitude, and spatial heterogeneity in these cellular alternans resulted in discordant alternans at the tissue level. Thus, from channel kinetic data, we can predict the tissue-level electrophysiological effects of any hERG mutations and identify how the mutation would manifest clinically, as either a long or short QT syndrome with or without an increased risk of alternans and re-entrant arrhythmias.
机译：hERG突变导致快速延迟的整流器电流I _（Kr）发生变化，可能导致长QT综合征和短期QT综合征，并伴有心律不齐的风险增加。 I_（Kr）的实验记录揭示了通道水平上突变的影响，但这些变化如何转化为细胞和组织水平仍不清楚。我们使用人类心室肌细胞和组织的计算模型来预测和量化从头hERG突变对细胞和组织电生理的影响。降低I _（Kr）最大电导率的突变导致增加的细胞和组织动作电位持续时间（APD）和较长的心电图（ECG）QT间隔，而那些引起失活曲线呈正向偏移的突变导致降低APD和简短的QT。折返性心律失常的组织脆弱性与复极的透壁散布有关，对此脆弱性的任何改变都可以从ECG QT间隔或T波峰到峰时间推断出来。更快的I_（Kr）活化动力学导致细胞APD交替蛋白出现在更宽的起搏速率范围内，并且幅度更大，并且这些细胞交替蛋白的空间异质性导致组织水平的交替蛋白。因此，从通道动力学数据中，我们可以预测任何hERG突变的组织水平的电生理效应，并确定该突变在临床上将如何表现出来，无论是长QT综合征还是短QT综合征，伴或不伴交替性和再入性心律不齐的风险增加。

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