药物化合物对人类长 QT 综合征心肌细胞搏动率变化的影响。
The Effects of Pharmacological Compounds on Beat Rate Variations in Human Long QT-Syndrome Cardiomyocytes.
机构信息
Institute of Biomedical Technology, University of Tampere, Tampere, Finland.
BioMediTech, Tampere, Finland.
出版信息
Stem Cell Rev Rep. 2016 Dec;12(6):698-707. doi: 10.1007/s12015-016-9686-0.
Healthy human heart rate fluctuates overtime showing long-range fractal correlations. In contrast, various cardiac diseases and normal aging show the breakdown of fractal complexity. Recently, it was shown that human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) intrinsically exhibit fractal behavior as in humans. Here, we investigated the fractal complexity of hiPSC-derived long QT-cardiomyocytes (LQT-CMs). We recorded extracellular field potentials from hiPSC-CMs at baseline and under the effect of various compounds including β-blocker bisoprolol, ML277, a specific and potent I current activator, as well as JNJ303, a specific I blocker. From the peak-to-peak-intervals, we determined the long-range fractal correlations by using detrended fluctuation analysis. Electrophysiologically, the baseline corrected field potential durations (cFPDs) were more prolonged in LQT-CMs than in wildtype (WT)-CMs. Bisoprolol did not have significant effects to the cFPD in any CMs. ML277 shortened cFPD in a dose-dependent fashion by 11 % and 5-11 % in WT- and LQT-CMs, respectively. JNJ303 prolonged cFPD in a dose-dependent fashion by 22 % and 7-13 % in WT- and LQT-CMs, respectively. At baseline, all CMs showed fractal correlations as determined by short-term scaling exponent α. However, in all CMs, the α was increased when pharmacological compounds were applied indicating of breakdown of fractal complexity. These findings suggest that the intrinsic mechanisms contributing to the fractal complexity are not altered in LQT-CMs. The modulation of I channel and β1-adrenoreceptors by pharmacological compounds may affect the fractal complexity of the hiPSC-CMs.
健康人心率随时间波动，表现出长程分形相关性。相比之下，各种心脏疾病和正常衰老表现出分形复杂性的破坏。最近，研究表明人类诱导多能干细胞衍生的心肌细胞（hiPSC-CMs）在内在表现出分形行为，与人类相似。在这里，我们研究了 hiPSC 衍生的长 QT 心肌细胞（LQT-CMs）的分形复杂性。我们在基线和各种化合物作用下记录 hiPSC-CMs 的细胞外场电位，包括β受体阻滞剂比索洛尔、特定且强效的 I 电流激活剂 ML277 以及特定的 I 通道阻滞剂 JNJ303。从峰峰值间隔，我们使用去趋势波动分析确定长程分形相关性。电生理上，LQT-CMs 的基线校正场电位持续时间（cFPD）比 WT-CMs 更长。比索洛尔对任何 CMs 的 cFPD 都没有显著影响。ML277 以剂量依赖的方式缩短 cFPD，在 WT-CMs 和 LQT-CMs 中分别缩短 11%和 5-11%。JNJ303 以剂量依赖的方式延长 cFPD，在 WT-CMs 和 LQT-CMs 中分别延长 22%和 7-13%。在基线时，所有 CMs 的短期标度指数 α 均表现出分形相关性。然而，在用药物化合物处理后，所有 CMs 的 α 均增加，表明分形复杂性的破坏。这些发现表明，导致分形复杂性的内在机制在 LQT-CMs 中没有改变。I 通道和β1-肾上腺素受体的药理学调节可能会影响 hiPSC-CMs 的分形复杂性。
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