Multiscale Modeling of Clotting Risk in Atrial Fibrillation

该项目将开发临床验证的心脏动力学多尺度模型，整合流体动力学， 机电耦合和流体-结构相互作用（FSI）来模拟心内流动和血液 心房颤动（AF）中的凝血。AF是美国最常见的持续性心律失常， 严重并发症包括血栓栓塞和中风抗凝剂通常用于 中风风险升高的患者。然而，目前的风险评估指标，缺乏个性化 根据心房结构或功能，将大多数AF患者归类为中度风险。核心 本研究的假设是，使用当前风险评估指标的治疗指南导致许多AF患者 接受不必要的抗凝治疗和不必要的血栓监测。长期目标是 研究是开发新的，广谱的方法来评估房颤的凝血风险， 个性化风险预测这项建议的科学前提是，心房功能障碍的综合模型将 能够对AF中的流动和凝血进行机制研究，最终促进个体化治疗。 在AF中，大多数具有临床意义的血栓形成于左心耳（LAA）。左心耳的解剖结构是 非常异质，尽管人们逐渐认识到左心耳解剖结构会影响凝血风险， 在当前指南中未考虑解剖结构。计算机模型为研究撞击提供了理想的平台 左心耳血流模式的结构和功能变化，但大多数现有的心脏流体动力学模型关注 在心室上此外，没有心房的现有FSI模型包括LAA的详细描述， 与主LA腔不同，心室高度小梁化。该项目的一个关键创新是， 在患者特定的左心房解剖结构描述中开发临床验证的血流FSI模型，包括 LAA的真实模型。这些模型将扩展到包括生物病理学详细的凝血模型 动力学和凝块运输。本项目旨在建立这些模型，并将其应用于研究 AF的两种治疗中的血流和凝血动力学：（1）通过WATCHMAN器械经皮LAA隔绝术 以及（2）在导管消融治疗中电隔离LAA。在左心耳封堵术的情况下， 器械相关血栓形成率为3.4%;因此，术后抗凝治疗目前用于 所有接受这些器械的患者。由于担心以下问题，很少对左心耳进行电隔离： 它对收缩期血流和中风风险的影响，以及无法确定哪些患者会受益。 在这个项目中开发的核心建模方法也可以用于模拟血栓形成 在一系列重要的医疗状况（静脉血栓栓塞、深静脉血栓形成）中，医疗器械 （人工心脏瓣膜、心室辅助装置、IVC过滤器）和新型生物材料。最终，模型使用 该平台预计将作为非临床项目提交给FDA医疗器械开发工具项目 评估模型，以预测监管提交文件中的临床前器械性能。

This project will develop clinically validated multiscale models of cardiac dynamics that integrate fluid dynamics, electromechanical coupling, and fluid-structure interaction (FSI) to simulate intracardiac flows and blood co-agulation in atrial fibrillation (AF). AF is the most common sustained arrhythmia in the U.S. and is associated with serious complications, including thromboembolism and stroke. Anticoagulation is commonly prescribed to patients who have an elevated stroke risk. However, current risk assessment indices, which lack individualization based upon atrial structure or function, classify most AF patients as being at intermediate risk. The core hypothesis of this research is that treatment guidelines using current risk assessment metrics result in many AF patients receiving unneeded anticoagulation and unnecessary monitoring for thrombosis. The long-term objective of this research is to develop new, broad-spectrum approaches to clotting risk assessment in AF that provide personalized risk prediction. The scientific premise of this proposal is that comprehensive models of atrial dysfunction will enable mechanistic studies of flow and clotting in AF that will ultimately facilitate individualized treatment. In AF, most clinically significant thrombi form in the left atrial appendage (LAA). The anatomy of the LAA is extremely heterogeneous, and although there is an emerging appreciation that LAA anatomy affects clotting risk, anatomy is not considered in current guidelines. Computer models provide ideal platforms for studying the impact of structural and functional variations on LAA flow patterns, but most existing cardiac fluid dynamics models focus on the ventricles. Further, no existing FSI model of the atria includes a detailed description of the LAA, which, like the ventricles and unlike the main LA cavity, is highly trabeculated. A key innovation of this project is that it will develop clinically validated FSI models of cardiac flow in patient-specific descriptions of LA anatomies, including realistic models of the LAA. These models will be extended to include biophysically detailed models of coagulation dynamics and clot transport. This project aims both to establish these models and also to apply them to study flows and clotting dynamics in two therapies for AF: (1) percutaneous LAA exclusion via the WATCHMAN device and (2) electrically isolating the LAA in catheter ablation therapy. In the case of LAA exclusion, the incidence of device-associated thrombosis is 3.4%; consequently, post-operative anticoagulation therapy is currently used in all patients receiving these devices. Electrical isolation of the LAA is rarely performed because of concerns about its effect on systolic flow and stroke risk, and the inability to identify patients who would benefit. The core modeling approaches developed in this project can also be deployed to simulate thrombogenesis in a range of significant medical conditions (venous thromboembolism, deep vein thrombosis), medical devices (prosthetic heart valves, ventricular assist devices, IVC filters), and novel biomaterials. Ultimately, models using this platform are expected to be submitted to the FDA Medical Device Development Tools program as non-clinical assessment models to predict pre-clinical device performance in regulatory submissions.