Research Collaboration Visit to the Auckland Bioengineering Institute, New Zealand.

尽管经过了一个多世纪的研究，人们对心律失常的机制仍知之甚少。即使是现代实验方法也不能提供足够的时间和空间分辨率来追踪心脏组织样本中纤颤发展的细节，更不用说体内的心脏了。人类遗传学的进步提供了某些基因对细胞活动影响的信息，但不能解释纤维性颤动产生的最终机制。因此，对于一些遗传性心脏病，首先出现的症状是死亡。数学建模和心脏电活动的最新现实计算机模拟的结合大大提高了我们对心脏颤动和心源性猝死的理解，并且随着我们接近全心脏建模的最终目标，预计计算机建模或计算机“测试”的影响将显著增加。由于每个细胞需要大量的方程以及所需的巨大的空间和时间尺度，从生物物理和解剖学角度模拟心脏动作电位在心脏中的传播在计算上是昂贵的。因此，通过通用数学模型分析获得的任何见解都是非常有价值的，因为它倾向于揭示通用机制，而不像直接的计算机模拟，它只提供对特定参数和初始条件选择有效的答案，并依赖于计算机模型的准确性。请注意，尽管经过了几十年的稳步发展，计算机模型在宏观尺度上仍然具有定性而非定量的预测能力，例如，对于整个心脏或整个心脏腔。我们在耗散涡动力学的渐近分析方面的最新进展揭示了涡与激发层厚度急剧变化相互作用的新现象。这种心脏再入与尖锐解剖特征的相互作用，如胸廓肌和心房终末嵴，可导致已建立的再入定位与最初定位相比发生相当大的位移。在Belousov-Zhabotinski反应实验中证实了对涡流漂移的渐近理论预测，并在计算机模拟中验证了各种细胞激励模型，从极其简化的“概念”模型到现实的离子动力学模型，以及从人工理想几何形状到现实的人体解剖结构的组织几何形状。更好地理解这一现象可能对临床有重要意义，例如选择治疗房颤的个体消融策略。到目前为止，对所识别的新现象的验证仅在人类心房的单一模型上完成，并且在考虑实验测试和临床意义之前，需要对各种心脏MRI解剖模型进行广泛的测试，以了解其普遍影响的程度。该计划的目的是访问新西兰奥克兰生物工程研究所（ABI），该研究所是心脏和心血管系统研究领域的国际领先机构，集仪器开发、实验测量和建模于一体。ABI心血管磁共振（CMR）成像组获得最详细的心脏几何形状和组织微观结构模型。这次访问将形成比从远处可行的更密切的合作，并提供在最新的解剖学和生物物理现实模型中对新现象进行详尽测试的可能性。申请人参加心脏生理组研讨会（2016年8月23日，韩国首尔）将获得额外的好处，这将是一个独特的机会，与该领域的世界领导者讨论我们最近的发现和未来的研究方向。

Despite over a century's study, the mechanisms of cardiac arrhythmias are poorly understood. Even modern experimental methods do not provide sufficient temporal and spacial resolution to trace down fine details of fibrillation development in samples of cardiac tissue, not to mention the heart in vivo. Advances in human genetics provide information on the impact of certain genes on cellular activity, but do not explain the resultant mechanisms by which fibrillation arises. Thus, for some genetic cardiac diseases, the first presenting symptom is death.Combination of mathematical modelling and the latest realistic computer simulations of electrical activity in the heart have much advanced our understanding of heart fibrillation and sudden cardiac death, and the impact of in-silico modelling, or indeed in-silico "testing", is expected to increase significantly as we approach the ultimate goal of the whole-heart modelling. Biophysically and anatomically realistic simulation of cardiac action potential propagation through the heart is computationally expensive due to the huge number of equations per cell and the vast spacial and temporal scales required. Therefore any insights that can be obtained through generic mathematical model analysis is very valuable, as it tends to reveal generic mechanisms, unlike direct computer simulations, which provide answers valid only for a specific choice of parameters and initial conditions and depend on the computer model accuracy. Note that despite of the decades of steady progress, computer models still have qualitative rather than quantitative predictive power on the macroscopic scale, e.g. where whole heart or a whole chamber of the heart are concerned. Our recent progress in asymptotic analysis of dissipative vortices dynamics has revealed a new phenomenon of the vortices interaction with sharp variations of thickness in excitable layer. Such interaction of cardiac re-entry with sharp anatomical features, as e.g. pectinate muscles and terminal crest in atria, can cause considerable displacement of established localisation of re-entry compared to where it was first localised. The asymptotic theory prediction of the vortices drift caused by interaction with sharp thickness variations in a layer has been confirmed in experiments with Belousov-Zhabotinski reaction, and verified in computer simulations with a variety of cell excitation models, from extremely simplified "conceptual" models to realistic ionic kinetics models, and for tissue geometries from artificial idealised geometries to a realistic anatomy of human atria. A better underestanding of this phenomenon may have significant implications in clinics, say for chosing an individual ablation strategy for treatment of atrial fibrillation.Validation of the identified new phenomenon has so far been done only on a single model of human atrium, and understanding of to what extent the effect is universal requires extensive testing on a wide variety of cardiac MRI anatomy models, before experimental testing and clinical implications can be considered. The aim of the proposed project is to visit the Auckland Bioengineering Institute (ABI), New Zealand, which is an international leader in the heart and cardiovascular system research that combines instrumentation development, experimental measurements and modelling. ABI cardiovascular magnetic resonance (CMR) imaging group obtains most detail models of heart geometry and tissue microstructure. This visit will forge a closer collaboration than it is feasible from a distance, and provide a possibility of exhaustive testing of the new phenomenon in the most up-to-date anatomically and biophysically realistic models. An extra benefit will be provided by the applicant's participation in Cardiac Physiome Workshop (23 August 2016, Seoul, Korea), which will be a unique opportunity to discuss our recent findings and future directions of research with the world leaders in the field.