Growth and Remodelling in the Porcine Heart-- Pushing Mathematics through Experiments

心血管疾病（CVD）是英国乃至全世界致残和死亡的主要原因，每年造成的经济影响估计为190亿英镑。获得性心脏病（例如可导致心肌梗死的冠状动脉心脏病）的流行，特别是在老年人口中，意味着这是我们社会中主要的公共卫生问题。对心血管疾病进行更有效的临床管理仍有很大的空间，部分原因是症状与病因之间的相关性较差。在开发新颖和创新的解决方案以实现针对患者的干预方面存在着巨大的潜力，这些解决方案已经在其他临床要求高的专业中取得了更好的结果。计算模型为心脏力学的正逆分析提供了一个平台。软组织建模能够整合多标量结构功能和FSI，并为研究基于cvd的患者特异性干预提供了新的机会，并且已经被用于提高对心肌梗死的认识，评估新型移植物材料和评估动脉粥样硬化动脉对斑块的脆弱性。这种模拟的价值是通过本构模型准确代表组织行为的函数。现有的模型考虑了组织的各向异性、超弹性反应，但对生长和重塑（G&R）和数据衍生的年龄特异性行为的研究有限。最近的成人心肌实验研究也证明了粘弹性组织特性的重要性，这在心脏建模中通常被忽视。这项研究将提供基于实验的粘弹性G&R定律，提高年龄特异性心脏组织行为模拟的准确性。随着计算能力的提高，这是实现患者特异性心脏治疗的重要一步。我们设计了一个实验程序，提供数据，以产生新的G&R本构律，从猪组织跨越6个G&R阶段。我们将测量关键的结构参数，包括胶原蛋白和心肌细胞纤维的取向和分散，以及生物力学参数，包括双轴、简单剪切和应力松弛。我们还将对这些组织进行生物化学和生物学分析，以便对人类研究进行交叉定位。这些数据将基于格拉斯哥小组开发的框架，生成新的本构模型。利用基于结构的HO本构法，结合心脏主动收缩和FSI，成功地模拟了三维动态有限应变LV力学。我们将通过获取猪体内超声数据对新的G&R定律进行假设检验，从而推导出p-v曲线、血流量和压力。我们还将把这种行为映射到人类成熟的相应阶段。与现有的国际心脏组织建模能力相比，基于实验的G&R定律将代表着重大进展。它应该使实现针对特定患者的手术的目标更接近，从而使获得性心脏病和其他心血管疾病得到更有效的治疗。我们的工作也将为后续关注G&R在疾病进展中的研究和潜在的临床干预奠定基础和参考。我们的方法将为其他人提供一个平台，在更广泛的研究领域利用这些原则和方法，其中可能包括监测和管理一般心脏病的进展。我们的工作也将有助于全球学术基础和应用科学，以及转化（医疗保健）领域。我们将提供第一个实验和理论相结合的方法来研究天然猪心脏的G&R，建立一个结构和生物力学变化的数据库，并将其映射到人类生理学，这将为进一步的研究提供支持。

Cardiovascular disease (CVD) is the leading cause of disability and death in the UK and worldwide, with an estimated £19bn annual economic impact. The prevalence of acquired heart disease (e.g. coronary heart disease, which can lead to myocardial infarction), particularly in the elderly population, means that this is the dominant public health problem in our society. Scope remains for more effective clinical management of CVDs, in part due to the poor correlation between symptoms and causation. Significant potential exists in developing novel and innovative solutions to lead towards patient-specific interventions, which have already achieved enhanced outcomes within other clinically-demanding specialities. Computational modelling provides a platform for forward and inverse analysis of cardiac mechanics. Soft tissue modelling enables integration of multi-scalar structure-function and FSI, and presents an emerging opportunity for investigating CVD-based, patient-specific interventions and is already being exploited to improve knowledge of myocardial infarction, evaluation of novel graft materials and assessing the vulnerabilities of atherosclerotic arteries to the plaque. The value of such simulations is a function of accurately representing tissue behaviour, via constitutive models. Existing models consider the tissue's anisotropic, hyperelastic response, but with limited studies on growth and remodelling (G&R) and data derived age-specific behaviour. Recent adult myocardium experimental studies also demonstrated the importance of viscoelastic tissue properties, which are generally ignored in heart modelling. This study will deliver experimentally based G&R laws with viscoelasticity that increase the accuracy of age-specific, cardiac tissue-behaviour simulations. Twinned with increasing computational capabilities, this is an important next-step towards realising patient-specific cardiac treatments. We have designed an experimental programme that provides data for generating new G&R constitutive laws, from porcine tissue across 6 G&R stages. We will measure critical structural parameters including collagen and cardiomyocyte fibre orientation and dispersion, and biomechanical parameters including bi-axial, simple shear and stress-relaxation. We will also biochemically and biologically analysis these tissues, to allow cross-mapping to human studies. These data will then enable generation of new constitutive models, based on the framework developed by the Glasgow group. These have been used successfully to simulate the 3D dynamic finite strain LV mechanics, using the structure-based HO constitutive law, coupled with cardiac active contraction and FSI. We will hypothesis-test the new G&R laws by acquiring in vivo porcine ultrasound data, to allow derivation of p-v curves, blood flow rate and pressure. We will also map this behaviour to equivalent phases of human maturation. The experimentally based G&R laws will represent significant progress versus the existing international capabilities of modelling in cardiac tissues. It should bring nearer the ambition of achieving patient-specific surgeries to enable more effective treatment of acquired heart disease and other CVDs. Our work will also set a foundation and reference for subsequent studies focused on G&R in disease progressions and potential clinical intervention. Our approach will provide a platform for others to exploit these principles and methodologies across a broader research area, which could include monitoring and managing progression of general heart diseases. Our work will also contribute towards worldwide academic basic and applied sciences, as well as the translational (healthcare) domain. We will provide the first combined experimental and theoretical approach to G&R of a natural porcine heart, establishing a database of structural and biomechanical changes mapped to human physiology, which will be available for interrogation to support further research.