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

具有时变参数的心脏反应扩散模型中的颤动活动

• 批准号: RGPIN-2015-05658
• 负责人: Jacquemet, Vincent
• 金额: $ 3.21万
• 依托单位: Université de Montréal
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2019
• 资助国家: 加拿大
• 起止时间: 2019-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=688784
• 关键词: Fibrillatory; activity; cardiac; reaction; diffusion

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.

心房颤动（AF）是最常见的心律失常，也是中风的主要原因。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，以深入了解其机制并调查促进其发生的因素。心脏电活动可以通过反应扩散系统进行数学描述，该系统将生物数据从离子通道整合到器官解剖结构。一些模型参数（例如离子通道电导）可由外部因素调节，例如由自主神经系统通过乙酰胆碱（ACh）释放调节。我们将在计算环境中研究参数的时间依赖性变化如何影响房性心律失常的脆弱性和随后的抑制动力学，使用时变ACh作用作为范例。具体目的 * 我们将研究胆碱能AF，一种与心脏组织中ACh浓度不均一性相关的AF形式。这将为我们提供一个生理相关的框架来研究随时间变化的参数（乙酰胆碱浓度）的瞬态和长期影响。我们的近期目标是：（1）建立胆碱能房颤的计算机模型。将开发算法，通过自动调节局部ACh浓度来分配异质复极特性。将设计和研究乙酰胆碱变化（乙酰胆碱释放和降解）的时间曲线。(2)模拟由时间依赖性ACh浓度调制的AF动力学。将在模型中诱导AF发作，并评估AF启动的脆弱性。将研究ACh变化的不同时空分布对AF动力学的影响：ACh不均匀性的位置和大小、ACh变化的峰值和时间常数以及复极梯度将发生变化。*** (3)使用波长测量来监测反射活动。复极特性可以在空间和时间上以及在短于搏动的时间尺度上改变。这些变化将通过激发波空间范围（即波长）的瞬时测量来评估。为此，将开发、验证一种新的计算技术，并将其应用于胆碱能AF。** * 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AF动力学或导致AF自终止。这可能有助于解释AF中自主活动的重要性。应用范围超出胆碱能AF;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AF的非均质产酶底物奠定基础。