Sohnis Family Research Laboratory for Cardiac Electrophysiology and Regenerative Medicine, The Rappaport Faculty of Medicine and Research Institute, Technion - Israel Institute of Technology, Haifa, Israel.
Sohnis Family Research Laboratory for Cardiac Electrophysiology and Regenerative Medicine, The Rappaport Faculty of Medicine and Research Institute, Technion - Israel Institute of Technology, Haifa, Israel; Cardiolology Department, Rambam Health Care Campus, Haifa, Israel.
J Mol Cell Cardiol. 2023 Oct;183:42-53. doi: 10.1016/j.yjmcc.2023.08.003. Epub 2023 Aug 12.
Among the monogenic inherited causes of atrial fibrillation is the short QT syndrome (SQTS), a rare channelopathy causing atrial and ventricular arrhythmias. One of the limitations in studying the mechanisms and optimizing treatment of SQTS-related atrial arrhythmias has been the lack of relevant human atrial tissues models.
To generate a unique model to study SQTS-related atrial arrhythmias by combining the use of patient-specific human induced pluripotent stem cells (hiPSCs), atrial-specific differentiation schemes, two-dimensional tissue modeling, optical mapping, and drug testing.
SQTS (N588K KCNH2 mutation), isogenic-control, and healthy-control hiPSCs were coaxed to differentiate into atrial cardiomyocytes using a retinoic-acid based differentiation protocol. The atrial identity of the cells was confirmed by a distinctive pattern of MLC2v downregulation, connexin 40 upregulation, shorter and triangular-shaped action potentials (APs), and expression of the atrial-specific acetylcholine-sensitive potassium current. In comparison to the healthy- and isogenic control cells, the SQTS-hiPSC atrial cardiomyocytes displayed abbreviated APs and refractory periods along with an augmented rapidly activating delayed-rectifier potassium current (I). Optical mapping of a hiPSC-based atrial tissue model of the SQTS displayed shortened APD and altered biophysical properties of spiral waves induced in this model, manifested by accelerated spiral-wave frequency and increased rotor curvature. Both AP shortening and arrhythmia irregularities were reversed by quinidine and vernakalant treatment, but not by sotalol.
Patient-specific hiPSC-based atrial cellular and tissue models of the SQTS were established, which provide examples on how this type of modeling can shed light on the pathogenesis and pharmacological treatment of inherited atrial arrhythmias.
心房颤动的单基因遗传性病因之一是短 QT 综合征（SQTS），这是一种罕见的通道病，可引起心房和心室心律失常。研究 SQTS 相关心房性心律失常的机制和优化治疗方法的一个限制因素是缺乏相关的人类心房组织模型。
通过结合使用患者特异性人诱导多能干细胞（hiPSC）、心房特异性分化方案、二维组织建模、光学映射和药物测试，生成一种独特的模型来研究 SQTS 相关的心房性心律失常。
将 SQTS（N588K KCNH2 突变）、同基因对照和健康对照 hiPSC 用视黄酸基分化方案诱导向心房肌细胞分化。通过 MLC2v 下调、连接蛋白 40 上调、较短的三角形动作电位（AP）和心房特异性乙酰胆碱敏感钾电流的表达，证实了细胞的心房特性。与健康对照和同基因对照细胞相比，SQTS-hiPSC 心房肌细胞显示出 APs 缩短和不应期延长，以及快速激活延迟整流钾电流（I）增强。SQTS 基于 hiPSC 的心房组织模型的光学映射显示 APD 缩短和螺旋波的生物物理特性改变，表现为螺旋波频率加快和旋转曲率增加。奎尼丁和 vernakalant 治疗可逆转 AP 缩短和心律失常不规则性，但索他洛尔不能。
建立了 SQTS 的基于患者特异性 hiPSC 的心房细胞和组织模型，为这种建模类型如何阐明遗传性心房性心律失常的发病机制和药物治疗提供了范例。
