Predictive multiscale modeling of atrial fibrillation for therapy development

描述（由申请人提供）：房颤（AF）是美国和其他发达国家最常见的持续性心律失常，具有严重的发病率和死亡率。由于AF具有几种变体，是多因素的，并且随着时间的推移而演变，因此在大型动物模型中进行全面研究非常困难和昂贵，部分原因是体内成像全心房电生理学的固有技术困难。预测多尺度计算模型有可能填补这一研究空白。虽然我们和其他人已经对AF进行了一些早期多尺度建模，但社区将从系统的建模框架中受益匪浅，该框架可以阐明这种复杂疾病的许多方面。本项目的总体目标是开发一个多尺度建模框架，以评价潜在的药理学和基于器械的房颤治疗。除了开发这样一个建模系统，作为其治疗设计效用的概念验证，我们将收集和利用细胞电生理数据来预测药物在常见的人类离子通道多态性存在下控制阵发性、持续性和慢性AF的疗效。具体来说，我们的目标是：1。开发一个简单的，可扩展的框架，能够模拟人类心房。2.实现心房颤动的多尺度模型，以代表该疾病的多种状态。3.目的：获得常见离子通道基因多态性对药物-通道相互作用影响的电生理数据. 4.预测药物在具有离子通道基因多态性的真实心房模型中控制房颤的有效性。该项目将产生一个可扩展的，开源的房颤建模框架，这将是有用的，不仅要测试在离子通道多态性的背景下药理学疗效的具体问题，但也为广大的建模社区，以调查大量的问题围绕房颤及其治疗。

DESCRIPTION (provided by applicant): Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in the United States and the rest of the developed world, and has serious morbidity and mortality. Because AF has several variants, is multi- factorial, and evolves over time, it is very difficult and expensive to study comprehensively in large-animal models, in part due to the inherent technical difficulties of imaging whole-atria electrophysiology in vivo. Predictive multiscale computational modeling has the potential to fill this research void. While we and others have performed some early-stage multiscale modeling of AF, the community would benefit greatly from a systematic modeling framework with which to illuminate the many facets of this complex disorder. The overall goal of this project is to develop a multiscale modeling framework that will enable the evaluation of potential pharmacological and device-based atrial fibrillation therapies. In addition to developing such a modeling system, as a proof-of-concept of its therapy-design utility we will collect and utilize cellular electrophysiological data to predict the efficacy of pharmacological agents at controlling paroxysmal, persistent, and chronic AF in the presence of common human ion-channel polymorphisms. Specifically, we aim: 1. To develop a straightforward, extensible framework capable of modeling the human atria. 2. To implement a multiscale model of atrial fibrillation representing the multiple states of the disorder. 3. To acquire electrophysiological data of the impact of common ion channel gene polymorphisms on drug- channel interactions. 4. To predict pharmacological AF control efficacy in the realistic atrial model(s) with incorporated ion channel gene polymorphisms. This project will produce an extensible, open-source atrial fibrillation modeling framework that will be useful not only to test the specific question of pharmacological efficacy in the context of ion channel polymorphisms, but also for the modeling community at large to investigate the vast array of issues surrounding atrial fibrillation and its therapy.