Sher Anna A, Cooling Michael T, Bethwaite Blair, Tan Jefferson, Peachey Tom, Enticott Colin, Garic Slavisa, Gavaghan David J, Noble Denis, Abramson David, Crampin Edmund J
Department of Physiology, Anatomy and Genetics, University of Oxford, UK.
Annu Int Conf IEEE Eng Med Biol Soc. 2010;2010:1498-502. doi: 10.1109/IEMBS.2010.5626841.
Cardiovascular diseases are the major cause of death in the developed countries. Identifying key cellular processes involved in generation of the electrical signal and in regulation of signal transduction pathways is essential for unraveling the underlying mechanisms of heart rhythm behavior. Computational cardiac models provide important insights into cardiovascular function and disease. Sensitivity analysis presents a key tool for exploring the large parameter space of such models, in order to determine the key factors determining and controlling the underlying physiological processes. We developed a new global sensitivity analysis tool which implements the Morris method, a global sensitivity screening algorithm, onto a Nimrod platform, which is a distributed resources software toolkit. The newly developed tool has been validated using the model of IP3-calcineurin signal transduction pathway model which has 30 parameters. The key driving factors of the IP3 transient behaviour have been calculated and confirmed to agree with previously published data. We next demonstrated the use of this method as an assessment tool for characterizing the structure of cardiac ionic models. In three latest human ventricular myocyte models, we examined the contribution of transmembrane currents to the shape of the electrical signal (i.e. on the action potential duration). The resulting profiles of the ionic current balance demonstrated the highly nonlinear nature of cardiac ionic models and identified key players in different models. Such profiling suggests new avenues for development of methodologies to predict drug action effects in cardiac cells.
心血管疾病是发达国家的主要死因。识别参与电信号产生和信号转导通路调节的关键细胞过程对于阐明心律行为的潜在机制至关重要。计算心脏模型为心血管功能和疾病提供了重要见解。敏感性分析是探索此类模型大参数空间的关键工具，以便确定决定和控制潜在生理过程的关键因素。我们开发了一种新的全局敏感性分析工具，该工具将全局敏感性筛选算法莫里斯方法应用于分布式资源软件工具包Nimrod平台。新开发的工具已使用具有30个参数的IP3-钙调神经磷酸酶信号转导通路模型进行了验证。已计算出IP3瞬态行为的关键驱动因素，并证实与先前发表的数据一致。接下来，我们展示了该方法作为表征心脏离子模型结构的评估工具的用途。在三个最新的人类心室肌细胞模型中，我们研究了跨膜电流对电信号形状（即动作电位持续时间）的贡献。由此产生的离子电流平衡概况证明了心脏离子模型的高度非线性性质，并确定了不同模型中的关键因素。这种概况分析为开发预测药物在心脏细胞中作用效果的方法提供了新途径。
