Luo Cunjin, Wang Kuanquan, Zhang Henggui
School of Computer Science and Technology, Harbin Institute of Technology (HIT), Harbin, China.
School of Physics and Astronomy, The University of Manchester, Manchester, United Kingdom.
PLoS One. 2017 Jun 20;12(6):e0179515. doi: 10.1371/journal.pone.0179515. eCollection 2017.
Short QT syndrome (SQTS) is an inherited disorder associated with abnormally abbreviated QT intervals and an increased incidence of atrial and ventricular arrhythmias. SQT1 variant (linked to the rapid delayed rectifier potassium channel current, IKr) of SQTS, results from an inactivation-attenuated, gain-of-function mutation (N588K) in the KCNH2-encoded potassium channels. Pro-arrhythmogenic effects of SQT1 have been well characterized, but less is known about the possible pharmacological antiarrhythmic treatment of SQT1. Therefore, this study aimed to assess the potential effects of E-4031, disopyramide and quinidine on SQT1 using a mathematical model of human ventricular electrophysiology.
The ten Tusscher et al. biophysically detailed model of the human ventricular action potential (AP) was modified to incorporate IKr Markov chain (MC) formulations based on experimental data of the kinetics of the N588K mutation of the KCNH2-encoded subunit of the IKr channels. The modified ventricular cell model was then integrated into one-dimensional (1D) strand, 2D regular and realistic tissues with transmural heterogeneities. The channel-blocking effect of the drugs on ion currents in healthy and SQT1 cells was modeled using half-maximal inhibitory concentration (IC50) and Hill coefficient (nH) values from literatures. Effects of drugs on cell AP duration (APD), effective refractory period (ERP) and pseudo-ECG traces were calculated. Effects of drugs on the ventricular temporal and spatial vulnerability to re-entrant excitation waves were measured. Re-entry was simulated in both 2D regular and realistic ventricular tissue.
At the single cell level, the drugs E-4031 and disopyramide had hardly noticeable effects on the ventricular cell APD at 90% repolarization (APD90), whereas quinidine caused a significant prolongation of APD90. Quinidine prolonged and decreased the maximal transmural AP heterogeneity (δV); this led to the decreased transmural heterogeneity of APD across the 1D strand. Quinidine caused QT prolongation and a decrease in the T-wave amplitude, and increased ERP and decreased temporal susceptibility of the tissue to the initiation of re-entry and increased the minimum substrate size necessary to prevent re-entry in the 2D regular model, and further terminated re-entrant waves in the 2D realistic model. Quinidine exhibited significantly better therapeutic effects on SQT1 than E-4031 and disopyramide.
The simulated pharmacological actions of quinidine exhibited antiarrhythmic effects on SQT1. This study substantiates a causal link between quinidine and QT interval prolongation in SQT1 and suggests that quinidine may be a potential pharmacological agent for treating SQT1 patients.
短QT综合征（SQTS）是一种遗传性疾病，与QT间期异常缩短以及心房和心室心律失常的发生率增加有关。SQTS的SQT1变异型（与快速延迟整流钾通道电流IKr相关）是由KCNH2编码的钾通道中的失活减弱、功能获得性突变（N588K）引起的。SQT1的促心律失常作用已得到充分表征，但关于SQT1可能的药理学抗心律失常治疗知之甚少。因此，本研究旨在使用人心室电生理学数学模型评估E-4031、丙吡胺和奎尼丁对SQT1的潜在影响。
对Ten Tusscher等人的人心室动作电位（AP）生物物理详细模型进行修改，以纳入基于IKr通道KCNH2编码亚基N588K突变动力学实验数据的IKr马尔可夫链（MC）公式。然后将修改后的心室细胞模型整合到具有跨壁异质性的一维（1D）肌束、二维规则和真实组织中。使用文献中的半数最大抑制浓度（IC50）和希尔系数（nH）值对药物对健康细胞和SQT1细胞中离子电流的阻断作用进行建模。计算药物对细胞动作电位持续时间（APD）、有效不应期（ERP）和伪心电图轨迹的影响。测量药物对心室对折返兴奋波的时间和空间易损性的影响。在二维规则和真实心室组织中模拟折返。
在单细胞水平，药物E-4031和丙吡胺对90%复极化时的心室细胞APD（APD90）几乎没有明显影响，而奎尼丁导致APD90显著延长。奎尼丁延长并降低了最大跨壁AP异质性（δV）；这导致跨1D肌束的APD跨壁异质性降低。奎尼丁导致QT延长和T波振幅降低，并增加ERP，降低组织对折返起始的时间易感性，并增加二维规则模型中防止折返所需的最小底物大小，并在二维真实模型中进一步终止折返波。奎尼丁对SQT1的治疗效果明显优于E-4031和丙吡胺。
奎尼丁的模拟药理作用对SQT1表现出抗心律失常作用。本研究证实了奎尼丁与SQT1中QT间期延长之间的因果关系，并表明奎尼丁可能是治疗SQT1患者的潜在药物。
