Gemmell Philip, Burrage Kevin, Rodriguez Blanca, Quinn T Alexander
Department of Computer Science, University of Oxford, Oxford, United Kingdom.
Department of Computer Science, University of Oxford, Oxford, United Kingdom ; School of Mathematical Sciences, Queensland University of Technology, Brisbane, Australia.
PLoS One. 2014 Feb 28;9(2):e90112. doi: 10.1371/journal.pone.0090112. eCollection 2014.
Variability is observed at all levels of cardiac electrophysiology. Yet, the underlying causes and importance of this variability are generally unknown, and difficult to investigate with current experimental techniques. The aim of the present study was to generate populations of computational ventricular action potential models that reproduce experimentally observed intercellular variability of repolarisation (represented by action potential duration) and to identify its potential causes. A systematic exploration of the effects of simultaneously varying the magnitude of six transmembrane current conductances (transient outward, rapid and slow delayed rectifier K(+), inward rectifying K(+), L-type Ca(2+), and Na(+)/K(+) pump currents) in two rabbit-specific ventricular action potential models (Shannon et al. and Mahajan et al.) at multiple cycle lengths (400, 600, 1,000 ms) was performed. This was accomplished with distributed computing software specialised for multi-dimensional parameter sweeps and grid execution. An initial population of 15,625 parameter sets was generated for both models at each cycle length. Action potential durations of these populations were compared to experimentally derived ranges for rabbit ventricular myocytes. 1,352 parameter sets for the Shannon model and 779 parameter sets for the Mahajan model yielded action potential duration within the experimental range, demonstrating that a wide array of ionic conductance values can be used to simulate a physiological rabbit ventricular action potential. Furthermore, by using clutter-based dimension reordering, a technique that allows visualisation of multi-dimensional spaces in two dimensions, the interaction of current conductances and their relative importance to the ventricular action potential at different cycle lengths were revealed. Overall, this work represents an important step towards a better understanding of the role that variability in current conductances may play in experimentally observed intercellular variability of rabbit ventricular action potential repolarisation.
在心脏电生理学的各个层面都可观察到变异性。然而，这种变异性的潜在原因及重要性通常尚不明确，且难以用当前的实验技术进行研究。本研究的目的是生成计算性心室动作电位模型群体，这些模型能重现实验观察到的复极化过程中的细胞间变异性（以动作电位时程表示），并确定其潜在原因。我们在两个兔特异性心室动作电位模型（香农等人和马哈詹等人的模型）中，于多个心动周期长度（400、600、1000毫秒）下，系统地探究了同时改变六种跨膜电流电导（瞬时外向电流、快速和慢速延迟整流钾电流、内向整流钾电流、L型钙电流以及钠/钾泵电流）大小的影响。这是通过专门用于多维参数扫描和网格执行的分布式计算软件来完成的。在每个心动周期长度下，为两个模型都生成了15,625个参数集的初始群体。将这些群体的动作电位时程与兔心室肌细胞的实验得出范围进行比较。香农模型的1352个参数集和马哈詹模型的779个参数集产生的动作电位时程在实验范围内，这表明可以使用多种离子电导值来模拟生理性兔心室动作电位。此外，通过使用基于杂波的维度重排技术（一种能在二维中可视化多维空间的技术），揭示了电流电导之间的相互作用及其在不同心动周期长度下对心室动作电位的相对重要性。总体而言，这项工作朝着更好地理解电流电导变异性可能在实验观察到的兔心室动作电位复极化细胞间变异性中所起的作用迈出了重要一步。
