Multiscale Modeling of Clotting Risk in Atrial Fibrillation

该项目将开发经过临床验证的心脏动力学多尺度模型，其中包括流体动力学、 机电耦合和流固耦合(FSI)模拟心内流动和血液 心房颤动(房颤)时的共凝集。房颤是美国最常见的持续性心律失常，与 有严重并发症，包括血栓栓塞症和中风。抗凝血通常被开给 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，将大多数房颤患者归类为中等风险。其核心是 这项研究的假设是，使用当前风险评估指标的治疗指南导致许多房颤患者 接受不必要的抗凝和不必要的血栓监测。这样做的长期目标是 研究旨在开发新的、广谱的方法来评估房颤患者的凝血风险，从而提供 个性化风险预测。这一提议的科学前提是，心房功能障碍的综合模型将 能够对房颤中的血流和凝血进行机械研究，最终促进个体化治疗。 在房颤中，大多数临床上有意义的血栓形成在左心耳(LAA)。LAA的解剖结构是 异质性很强，尽管越来越多的人认识到LAA的解剖结构会影响凝血风险， 目前的指南中没有考虑解剖学。计算机模型为研究影响提供了理想的平台 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的是 在脑室。此外，现有的心房FSI模型都不包括对左心耳的详细描述，这与 与主要的左房腔不同，脑室是高度小梁状的。这个项目的一个关键创新是它将 开发临床验证的心脏血流FSI模型，用于特定患者的LA解剖描述，包括 LAA的现实模型。这些模型将被扩展到包括凝血的生物物理详细模型 动力学和血块运输。本项目的目的是建立这些模型，并将其应用于研究 房颤两种治疗方法的血流和凝血动力学：(1)通过Watchman装置经皮LAA隔绝术 (2)在导管消融治疗中电隔离左心耳。在LAA排除的情况下， 与设备相关的血栓形成3.4%；因此，术后抗凝治疗目前用于 所有接受这些设备的患者。很少进行LAA的电隔离，因为担心 它对收缩血流和中风风险的影响，以及无法确定哪些患者将受益。 本项目开发的核心建模方法也可用于模拟血栓形成 在一系列重要的医疗条件下(静脉血栓栓塞症、深静脉血栓形成)，医疗器械 (人工心脏瓣膜、心脏辅助装置、下腔静脉滤器)和新型生物材料。归根结底，使用 该平台预计将作为非临床平台提交给FDA医疗器械开发工具计划 在监管提交中预测临床前设备性能的评估模型。

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.