Fibrillatory activity in cardiac reaction-diffusion models with time-varying parameters

上下文 房颤(房颤)是最常见的心律失常，也是卒中的主要原因。我的研究项目包括在心房的计算机模型中模拟这些节律紊乱，以深入了解它们的机制，并调查促进它们发生的因素。心脏电活动可以通过反应扩散系统来数学描述，反应扩散系统将从离子通道到器官解剖的生物数据整合在一起。一些模型参数(如离子通道电导)可能受外部因素的调节，如自主神经系统通过释放乙酰胆碱(ACh)来调节。我们将在计算环境中，以时变ACh动作为范例，研究参数随时间变化如何影响房性心律失常的易感性和随后的纤颤动力学。 具体目标 我们将研究胆碱能房颤，这是一种与心脏组织中ACh浓度不均一相关的房颤形式。这将为我们提供一个生理学相关的框架来研究时变参数(ACh浓度)的瞬时和长期影响。我们的短期目标是： (1)建立胆碱能房颤的计算机模型。将创建一个3D犬房模型。将开发通过自动调整局部ACh浓度来分配异质复极化属性的算法。将设计和研究ACh变化(ACh释放和降解)的时间分布。 (2)模拟随时间变化的ACh浓度调制的房颤动力学。在模型中将诱发房颤发作，并将评估房颤启动的易感性。研究ACh变化的不同时空分布对房颤动力学的影响：ACh不均匀的位置和大小、ACh变化的峰值和时间常数以及复极梯度将发生变化。 (3)使用波长测量监测纤颤活动。复极化属性可以在空间和时间上改变，并且在比节拍短的时间尺度上改变。这些变化将通过瞬时测量激发波的空间范围(即波长)来评估。为此，一种新的计算技术将被开发、验证并应用于胆碱能房颤。 原创性和意义 以前的模型有恒定的参数。我们将研究时变参数如何触发更复杂的房颤动力学或导致房颤自我终止。这可能有助于解释自主神经活动在房颤中的重要性。应用范围不仅限于胆碱能房颤；细胞参数的外部控制可以通过使用光遗传学技术引入的光敏通道来实现。从计算的角度来看，开发的新的建模工具将为进一步研究房颤的异质致心律失常底物奠定基础。

CONTEXT Atrial fibrillation (AF) is the most frequent arrhythmia and a major cause of stroke. My research program involves simulating these rhythm disorders in computer models of the atria to get insights into their mechanisms and investigate the factors promoting their occurrence. Cardiac electrical activity can be mathematically described by reaction-diffusion systems that integrate biological data from ion channel to organ anatomy. Some model parameters (e.g. ion channel conductances) may be regulated by external factors, e.g. by the autonomic nervous system through acetylcholine (ACh) release. We are going to study in a computational environment how time-dependent variation of parameters affects the vulnerability to atrial arrhythmias and the ensuing fibrillatory dynamics, using time-varying ACh action as a paradigm. SPECIFIC AIMS We will investigate cholinergic AF, a form of AF associated with heterogeneity in ACh concentration in the cardiac tissue. This will provide us a physiologically-relevant framework to study the transient and long-term effects of a time-varying parameter (ACh concentration). Our short-term aims are: (1) To develop a computer model of cholinergic AF. A 3D canine atrial model will be created. Algorithms will be developed to assign heterogeneous repolarization properties by automatically adjusting local ACh concentration. Temporal profiles of ACh variation (ACh release and degradation) will be designed and investigated. (2) To simulate AF dynamics modulated by time-dependent ACh concentration. AF episodes will be induced in the model and the vulnerability to AF initiation will be assessed. The effect of different spatiotemporal profiles of ACh variation on AF dynamics will be studied: the position and size of ACh inhomogeneity, the peak value and time constants of ACh variation, and repolarization gradients will be varied. (3) To monitor fibrillatory activity using a wavelength measure. Repolarization properties may change both in space and time and at a time scale shorter than a beat. These changes will be assessed by an instantaneous measure of the spatial extent of excitation waves (i.e. wavelength). For that purpose, a new computational technique will be developed, validated, and applied to cholinergic AF. ORIGINALITY AND SIGNIFICANCE Previous models had constant parameters. We are going to investigate how time-varying parameters may trigger a more complex AF dynamics or lead to AF self-termination. This may help explain the importance of autonomic activity in AF. Applications extend beyond cholinergic AF; external control of cell parameters may be achieved through light-sensitive channels introduced using optogenetics techniques. From a computational viewpoint, the new modeling tools developed will form the basis for further studies on heterogeneous arrhythmogenic substrates for AF.