Predictive multiscale modeling of atrial fibrillation for therapy development

描述（由申请人提供）：心房颤动（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。由于房颤有多种变体，是多因素的，并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，部分原因是由于体内全心房电生理成像固有的技术困难。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进行了一些早期的多尺度建模，但社区将从一个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。该项目的总体目标是开发一个多尺度建模框架，以评估潜在的药理学和基于设备的房颤治疗。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控制阵发性、持续性和慢性房颤存在常见人类离子通道多态性的情况下的疗效。具体来说，我们的目标是：1。开发一个简单的、可扩展的框架，能够对人体心房进行建模。2. 实现心房颤动的多尺度模型，代表疾病的多种状态。3. 获取普通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. 结合离子通道基因多态性的真实心房模型预测房颤药理学控制效果。该项目将产生一个可扩展的、开源的房颤建模框架，它不仅有助于测试离子通道多态性背景下的药理学功效的具体问题，而且还有助于建模社区在很大程度上研究围绕房颤及其治疗的大量问题。

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. PUBLIC HEALTH RELEVANCE: (Using no more than two or three sentences, describe the relevance of this research to public health.) Atrial fibrillation is the most common sustained cardiac arrhythmia in the United States and the rest of the developed world, and has serious mortality and morbidity. Because atrial fibrillation is very difficult and expensive to study comprehensively in large-animal models, the research community would benefit greatly from a systematic computational modeling framework with which to illuminate the many facets of this complex disorder. The overall goal of this project is to develop such a multiscale modeling framework, which will enable the evaluation of potential pharmacological and device-based atrial fibrillation therapies.