Quantitative cross-species translators of cardiac myocyte electrophysiology: Model training, experimental validation, and applications.
Quantitative cross-species translators of cardiac myocyte electrophysiology: Model training, experimental validation, and applications.
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DOI：
10.1126/sciadv.abg0927
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发表时间：
2021-11-19
期刊：
影响因子：
13.6
通讯作者：
Grandi E
中科院分区：
文献类型：
--
作者：
Morotti S;Liu C;Hegyi B;Ni H;Fogli Iseppe A;Wang L;Pritoni M;Ripplinger CM;Bers DM;Edwards AG;Grandi E
翻译发现：我们提出了定量工具，映射跨物种的心肌细胞生理学和药理学。动物实验是评价新型治疗化合物的心脏功效和安全性的关键。然而，调节兴奋-收缩偶联机制的种间差异可能会限制实验结果从动物模型到人类生理学的转化，并破坏药物疗效和安全性的评估。在这里，我们建立了一套翻译器，用于定量绘制跨物种心室肌细胞的电生理反应。我们使用广泛的数据集训练这些统计算子，该数据集通过模拟我们在小鼠、兔和人类中的动作电位和Ca 2+瞬变的生物药理学详细计算模型的群体获得。然后，我们根据描述对刺激的反应的实验数据测试了我们的翻译器，例如离子通道阻滞，心跳率的变化和β-肾上腺素能激发。我们证明，这种方法非常适合于预测不同物种或实验条件下的扰动效应，并建议将其整合到机制研究和药物开发管道中。
Found in translation: We present quantitative tools that map cardiac myocyte physiology and pharmacology across species. Animal experimentation is key in the evaluation of cardiac efficacy and safety of novel therapeutic compounds. However, interspecies differences in the mechanisms regulating excitation-contraction coupling can limit the translation of experimental findings from animal models to human physiology and undermine the assessment of drugs’ efficacy and safety. Here, we built a suite of translators for quantitatively mapping electrophysiological responses in ventricular myocytes across species. We trained these statistical operators using a broad dataset obtained by simulating populations of our biophysically detailed computational models of action potential and Ca2+ transient in mouse, rabbit, and human. We then tested our translators against experimental data describing the response to stimuli, such as ion channel block, change in beating rate, and β-adrenergic challenge. We demonstrate that this approach is well suited to predicting the effects of perturbations across different species or experimental conditions and suggest its integration into mechanistic studies and drug development pipelines.
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