Mechanistic investigations of structure-function interplay as causal

肥厚型心肌病（HCM）是最常见的遗传性心脏病之一，也是青年人心脏性猝死的主要原因。急性心肌缺血，即心肌供血突然短缺，被广泛认为是HCM中致死性心律失常的一个因素，但临床指南中仍然缺乏对缺血的评估。这部分是因为对HCM中缺血与其他疾病特征的相互作用知之甚少，这限制了对缺血风险的尝试，影响了心电图（ECG）上临床显著缺血的诊断，目的和目的本研究旨在利用多尺度心脏电生理技术研究心肌缺血在HCM中的作用建模和模拟，为风险分层、ECG诊断和抗心律失常治疗提供信息。目的是：（i）研究HCM中缺血与其他疾病特征（离子重塑和纤维化）相互作用以调节缺血风险的机制（ii）研究与运动时发生的正常变化相比，HCM中缺血如何在ECG上表现出来，以改善应激ECG中缺血的诊断（iii）研究雷诺嗪（一种抗心绞痛药物）对HCM中缺血风险的影响，以确定可能从治疗中获益的患者亚组。缺血作为一个动态过程，在细胞水平和空间范围上具有不同的严重程度。考虑到这种复杂性，以及HCM中离子重塑和纤维化严重程度的现有变异性，以及固有的群体电生理变异性，提出了重大的科学计算挑战。这些挑战是解决使用一种新的GPU心脏电生理学求解器。此外，该研究使用新方法将膜片钳，灌注和ECG数据结合起来，以告知和验证计算模型，将调查限制在临床相关病例中。这为更准确的“数字孪生”模拟铺平了道路，该模拟将药物治疗应用于HCM模型人群，并将其应用于计算机临床试验，用于抗肿瘤药物开发。与EPSRC战略保持一致拟议的研究扩展了EPSRC资助的数学生物学和非线性系统领域研究的当前组合。它与医疗保健技术优化治疗的重大挑战密切相关（"及时准确诊断、分层、预测建模和实时，基于证据的决策“）和新的计算和数学科学的交叉能力（“计算机模拟和仿真”）。合作者与Betty拉曼教授建立了合作关系（牛津临床磁共振研究中心）获取灌注成像数据，Raffaele Coppini教授（佛罗伦萨大学）获得人类HCM细胞测量的独特途径，Rafael Sachetto教授（联邦大学圣若昂del-Rei）的技术专长，以及Hugh Watkins教授（拉德克利夫医学系）和Iacopo Olivotto教授（Careggi大学医院）的临床HCM专长。

BackgroundHypertrophic cardiomyopathy (HCM) is one of the most common genetic heart diseases and a leading cause of sudden cardiac death in the young. Acute myocardial ischaemia, where there is a sudden shortage of blood supply to the heart muscle, is widely acknowledged as a contributor to lethal arrhythmias in HCM, yet the assessment of ischaemia remains absent from clinical guidelines. This is in part because the interactions that ischaemia has with other disease features in HCM are poorly understood, which limits attempts to characterise arrhythmic risk, affects the diagnosis of clinically significant ischaemia on electrocardiography (ECG), and constrains the development of novel antiarrhythmic pharmacologic therapies.Aims and ObjectivesThe research aims to investigate the role of myocardial ischaemia in HCM using multiscale cardiac electrophysiology modelling and simulation, to inform risk stratification, ECG diagnosis and antiarrhythmic therapy. The objectives are to:(i) investigate the mechanisms by which ischaemia interacts with other disease features in HCM (ionic remodelling and fibrosis) to modulate arrhythmic risk(ii) investigate how ischaemia manifests on the ECG in HCM in comparison to normal changes that occur with exercise, to improve the diagnosis of ischaemia on stress ECG(iii) investigate the effects of ranolazine (an antianginal drug) on arrhythmic risk in HCM, to identify patient subgroups likely to benefit from treatmentNovelty of Research MethodologyThe research includes ischaemia as a novel factor in simulations of HCM ventricles. Ischaemia, as a dynamic process, has variable severity at a cellular level and spatial extent. Accounting for this complexity, alongside existing variability in the severity of ionic remodelling and fibrosis in HCM, and intrinsic population electrophysiological variability, imposes significant scientific computing challenges. These challenges are addressed using a novel GPU cardiac electrophysiology solver. Additionally, the research uses novel methods to combine patch-clamp, perfusion and ECG data to inform and validate the computational models, constraining the investigations to clinically relevant cases. This paves the way for more accurate 'digital twin' simulations, which with the application of drug therapy to the HCM population of models, moves towards in silico clinical trials for antiarrhythmic drug development.Alignment with EPSRC strategiesThe proposed research extends the current portfolio of EPSRC funded research in the areas of Mathematical Biology and Non-linear Systems. It aligns closely with Healthcare Technologies Grand Challenges for Optimising Treatment ('technologies for timely and accurate diagnosis, stratification, predictive modelling, and real-time, evidence-based decision making') and the Cross-Cutting Capabilities on Novel Computational and Mathematical Sciences ('in silico modelling and simulation').CollaboratorsCollaborations are established with Prof. Betty Raman (Oxford Centre for Clinical Magnetic Resonance Research) for access to perfusion imaging data, Prof. Raffaele Coppini (University of Florence) for unique access to human HCM cellular measurements, Prof. Rafael Sachetto (Federal University of São João del-Rei) for technical expertise, and Prof. Hugh Watkins (Radcliffe Department of Medicine) and Prof. Iacopo Olivotto (Careggi University Hospital) for clinical HCM expertise.