A computational model of fibrosis and the cardiac conduction system: the next generation of virtual heart models for research and teaching

纤维化和心脏传导系统的计算模型：用于研究和教学的下一代虚拟心脏模型

• 批准号: NC/Y500598/1
• 金额: $ 17.2万
• 依托单位: University of Leeds
• 依托单位国家: 英国
• 项目类别: Training Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=NC%2FY500598%2F1
• 关键词: computational; model; fibrosis; cardiac; conduction

The proliferation of fibrosis is observed in various cardiovascular diseases (CVDs) and has been linked to arrhythmias, the irregular rhythm of the heart. However, the precise mechanisms through which fibrosis promotes arrhythmia are not yet fully understood. Current computational models of fibrosis lack sophistication, failing to capture the underlying electrical heterogeneity. Developing an advanced computational model of fibrosis would enable detailed simulation studies and reveal novel mechanistic insights. Additionally, the cardiac conduction system (CCS) governs the normal excitation of the heart, and its remodelling can directly lead to arrhythmias. However, few, if any, computational models incorporate detailed electrophysiologically-anatomical representations of the CCS due to challenges in imaging and segmenting this system from anatomical data.Atrial fibrillation (AF), the most prevalent sustained cardiac arrhythmia, becomes increasingly challenging to treat and manage as it progresses to a chronic condition, associated with electrical and structural remodelling. Fibrosis plays a significant role in this progression, particularly in the emergence of complex excitation patterns in chronic AF. The CCS is critical in the transmission of electrical excitation from the atria to the ventricles, making it a crucial factor in understanding how AF impairs cardiac function.To underpin improved diagnostic and treatment strategies in the future, understanding the roles of fibrosis and the CCS in the development and progression of AF is essential. This project aims to develop a novel computational model of fibrosis, integrating it into a comprehensive whole-heart model with the CCS. The resulting tool will support future animal-free research and will be applied in his project to address fundamental questions regarding the mechanisms of AF.The project brings together a team of computational modellers and experimentalists with a wealth of models, data, and experience to deliver on its objectives:Objective 1: Develop and validate detailed and specific models that integrate electrophysiological and anatomical features of different forms of fibrosis, building upon our novel approach for modelling heterogeneous cellular coupling.Objective 2: Investigate the fundamental mechanisms by which fibrosis promotes arrhythmia triggers and substrate using the developed model.Objective 3: Explore how fibrosis contributes to trigger and substrate in AF by applying the models alongside reconstructed human atria and fibrosis maps.Objective 4: Integrate these models into our whole-heart model and develop a robust simulation capable of considering structural remodelling and simulating normal and abnormal activation patterns.Objective 5: Investigate the interaction between AF, the CCS, and ventricular function using the comprehensive whole-heart model.

在各种心血管疾病（cvd）中观察到纤维化的增殖，并与心律失常（心律不规律）有关。然而，纤维化促进心律失常的确切机制尚不完全清楚。目前的纤维化计算模型缺乏复杂性，无法捕捉潜在的电异质性。开发一种先进的纤维化计算模型将使详细的模拟研究和揭示新的机制见解成为可能。此外，心脏传导系统（CCS）控制着心脏的正常兴奋，其重构可直接导致心律失常。然而，由于在成像和从解剖数据中分割该系统方面的挑战，很少（如果有的话）计算模型包含CCS的详细电生理解剖表示。房颤（AF）是最常见的持续性心律失常，随着其发展为与电和结构重构相关的慢性疾病，治疗和管理变得越来越具有挑战性。纤维化在这一过程中起着重要作用，特别是在慢性房颤复杂兴奋模式的出现中。CCS在从心房到心室的电兴奋传递中起着关键作用，使其成为了解房颤如何损害心功能的关键因素。为了支持未来改进的诊断和治疗策略，了解纤维化和CCS在房颤发生和进展中的作用是必不可少的。本项目旨在开发一种新的纤维化计算模型，并将其与CCS整合到一个全面的全心脏模型中。由此产生的工具将支持未来的无动物研究，并将应用于他的项目中，以解决有关af机制的基本问题。该项目汇集了一个由计算建模师和实验家组成的团队，他们拥有丰富的模型、数据和经验，以实现其目标。开发和验证详细和特定的模型，整合不同形式的纤维化的电生理和解剖特征，建立在我们模拟异质细胞耦合的新方法之上。目的2：利用所建立的模型研究纤维化促进心律失常触发和底物的基本机制。目的3：通过将模型与重建的人心房和纤维化图一起应用，探讨纤维化如何促进房颤的触发和底物。目标4：将这些模型整合到我们的全心模型中，并开发一个能够考虑结构重塑和模拟正常和异常激活模式的鲁棒模拟。目的5：采用全心综合模型研究AF、CCS和心室功能之间的相互作用。