Quantifying arrhythmic long QT effects of hydroxychloroquine and azithromycin with whole-heart optical mapping and simulations.
Quantifying arrhythmic long QT effects of hydroxychloroquine and azithromycin with whole-heart optical mapping and simulations.
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DOI：
10.1016/j.hroo.2021.06.008
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发表时间：
2021-08
期刊：
影响因子：
--
通讯作者：
Fenton FH
中科院分区：
文献类型：
--
作者：
Uzelac I;Kaboudian A;Iravanian S;Siles-Paredes JG;Gumbart JC;Ashikaga H;Bhatia N;Gilmour RF Jr;Cherry EM;Fenton FH
2020年3月，羟氯喹（HCQ）单独或联合阿奇霉素（AZM）在许多国家被批准作为COVID-19的治疗药物。这种疗法被证明是无效的，具有长QT和致命的心律失常风险，说明了确定重新利用药物的新安全性的挑战。研究HCQ和AZM（联合和单独）与高剂量HCQ在COVID-19临床试验中的预防作用和机制。使用离体Langendorff灌注的豚鼠（GP）心脏中的电压敏感染料的光学映射以及GP Luo-Rudy和人O 'Hara-Virag-Varro-Rudy模型的数值模拟，对细胞和组织中的Epi、Endo和M细胞，结合药物对细胞膜离子电流的影响，定量HCQ和AZM的促炎作用。在实验中，HCQ单独和与AZM组合通过延长动作电位时程和增加跨心脏的动作电位（AP）复极的空间离散度而导致长QT间期，从而导致促心律失常的不一致交替。AZM单独使用时，AP形状的三角测量较少，因此具有较小的放射性效应。数学心脏模型不能再现实验观察到的大多数心脏效应。在公共卫生危机期间，可以通过替代实验和计算方法更好地评估新药物和重新用途药物的风险和益处，以确定预防机制。光学标测是一个有效的框架，适用于研究药物对心脏细胞膜离子通道在细胞水平和心律失常机制在组织和整个器官水平的不利影响。
In March 2020, hydroxychloroquine (HCQ) alone or combined with azithromycin (AZM) was authorized as a treatment for COVID-19 in many countries. The therapy proved ineffective with long QT and deadly cardiac arrhythmia risks, illustrating challenges to determine the new safety profile of repurposed drugs. To investigate proarrhythmic effects and mechanism of HCQ and AZM (combined and alone) with high doses of HCQ as in the COVID-19 clinical trials. Proarrhythmic effects of HCQ and AZM are quantified using optical mapping with voltage-sensitive dyes in ex vivo Langendorff-perfused guinea pig (GP) hearts and with numerical simulations of a GP Luo-Rudy and a human O’Hara-Virag-Varro-Rudy models, for Epi, Endo, and M cells, in cell and tissue, incorporating the drug’s effect on cell membrane ionic currents. Experimentally, HCQ alone and combined with AZM leads to long QT intervals by prolonging the action potential duration and increased spatial dispersion of action potential (AP) repolarization across the heart, leading to proarrhythmic discordant alternans. AZM alone had a lesser arrhythmic effect with less triangulation of the AP shape. Mathematical cardiac models fail to reproduce most of the arrhythmic effects observed experimentally. During public health crises, the risks and benefits of new and repurposed drugs could be better assessed with alternative experimental and computational approaches to identify proarrhythmic mechanisms. Optical mapping is an effective framework suitable to investigate the drug’s adverse effects on cardiac cell membrane ionic channels at the cellular level and arrhythmia mechanisms at the tissue and whole-organ level.
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影响因子：
10.8
作者：
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发表时间：
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影响因子：
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