In silico investigation of a KCNQ1 mutation associated with short QT syndrome.
In silico investigation of a KCNQ1 mutation associated with short QT syndrome.
复制标题
DOI：
10.1038/s41598-017-08367-2
复制
发表时间：
2017-08-16
影响因子：
4.6
通讯作者：
Zhang H
中科院分区：
文献类型：
--
作者：
Adeniran I;Whittaker DG;El Harchi A;Hancox JC;Zhang H
短 QT 综合征 (SQTS) 是一种罕见疾病，其特征是心电图上的 QT 间期异常“短”，并且心律失常和猝死的易感性增加。这项模拟研究调查了多尺度人类心室模型中与 SQT2 相关的 V307L KCNQ1“功能获得”突变相关的心律失常动力学，该突变增加了慢延迟整流钾电流 (IK)。将概括野生型 (WT) 和 V307L 突变体 IK 动力学的马尔可夫链 (MC) 模型纳入人心室动作电位 (AP) 模型中，用于研究 QT 间期变化和心律失常底物。此外，还对 SQT2 条件下 QT 间期正常化和终止再进入所需的模拟 IK 抑制程度进行了量化。开发的 MC 模型准确地再现了与纯合子 (V307L) 和杂合子 (WT-V307L) 突变条件下 IK 动力学改变相关的 AP 缩短和有效不应期缩短，从而延长了 3D 人类心室模型的寿命和重新进入的主导频率。 IK 减少 58% 和 65% 分别足以终止 WT-V307L 和 V307L 条件下的再入。这项研究进一步证实了 V307L KCNQ1 突变与人类心室促心律失常之间的因果关系，并确立了部分抑制 IK 作为 SQT2 中潜在的抗心律失常策略。
Short QT syndrome (SQTS) is a rare condition characterized by abnormally ‘short’ QT intervals on the ECG and increased susceptibility to cardiac arrhythmias and sudden death. This simulation study investigated arrhythmia dynamics in multi-scale human ventricle models associated with the SQT2-related V307L KCNQ1 ‘gain-of-function’ mutation, which increases slow-delayed rectifier potassium current (IKs). A Markov chain (MC) model recapitulating wild type (WT) and V307L mutant IKs kinetics was incorporated into a model of the human ventricular action potential (AP) for investigation of QT interval changes and arrhythmia substrates. In addition, the degree of simulated IKs inhibition necessary to normalize the QT interval and terminate re-entry in SQT2 conditions was quantified. The developed MC model accurately reproduced AP shortening and reduced effective refractory period associated with altered IKs kinetics in homozygous (V307L) and heterozygous (WT-V307L) mutation conditions, which increased the lifespan and dominant frequency of re-entry in 3D human ventricle models. IKs reductions of 58% and 65% were sufficient to terminate re-entry in WT-V307L and V307L conditions, respectively. This study further substantiates a causal link between the V307L KCNQ1 mutation and pro-arrhythmia in human ventricles, and establishes partial inhibition of IKs as a potential anti-arrhythmic strategy in SQT2.
登录
查看更多内容
影响因子：
5.8
作者：
Duncan, R. S.;McPate, M. J.;Ridley, J. M.;Gao, Z.;James, A. F.;Leishman, D. J.;Leaney, J. L.;Witchel, H. J.;Hancox, J. C.
通讯作者：
Hancox, J. C.
影响因子：
4.3
作者：
Adeniran I;McPate MJ;Witchel HJ;Hancox JC;Zhang H
通讯作者：
Zhang H
影响因子：
5.5
作者：
Frea, Simone;Giustetto, Carla;Gaita, Fiorenzo
通讯作者：
Gaita, Fiorenzo
影响因子：
24
作者：
Mazzanti, Andrea;Kanthan, Ajita;Monteforte, Nicola;Memmi, Mirella;Bloise, Raffaella;Novelli, Valeria;Miceli, Carlotta;O'Rourke, Sean;Borio, Gianluca;Zienciuk-Krajka, Agnieszka;Curcio, Antonio;Surducan, Andreea Elena;Colombo, Mario;Napolitano, Carlo;Priori, Silvia G.
通讯作者：
Priori, Silvia G.
影响因子：
24
作者：
Giustetto, Carla;Schimpf, Rainer;Gaita, Fiorenzo
通讯作者：
Gaita, Fiorenzo