Modelling the human heart: an integrated experimental and computational study

人类心脏建模：综合实验和计算研究

• 批准号: BB/J017272/1
• 负责人: Jonathan Kentish
• 金额: $ 82.46万
• 依托单位: King's College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2012
• 资助国家: 英国
• 起止时间: 2012 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FJ017272%2F1
• 关键词: Modelling; human; heart; integrated; experimental

The proposed project will provide new experimental data from human hearts that will be used to make a realistic computer model of the human heart. Heart disease is the main cause of mortality in the developed world. This disease is characterised by a reduced ability of the heart to pump blood, due to changes to the mechanical and electrical properties of heart cells. However, despite extensive experimental studies, the complicated sequence of events leading from altered function at the cellular level to life-threatening pump failure remains poorly understood. This situation has motivated rapid advances in the development of computer models of the heart that now provide new and powerful quantitative tools for understanding the triggers and progression of heart disease. These models have delivered an important means for capturing the complex function of the heart by establishing a consistent, quantitative and multi-level framework for integrating measurements and understanding. From this work, important insights into the inter-relationships between cell contraction, heart shape and muscle structure have already been revealed.However, while the scientific importance and significant clinical potential in this approach is widely acknowledged, the promise of these computer models to increase our understanding of human heart function remains largely unfulfilled. This is because the vast majority of cardiac mathematical models are currently developed and validated using data collected from measurements in animal, rather than human, experiments. Furthermore these experiments are often performed under conditions that are very different from the environment of either a normal or diseased heart in the body. In particular, individual cells are held at constant length and are studied in the cold, whereas in the intact heart the cell length changes during the heartbeat and the cells are at body temperature; these differences alter profoundly the amount of force muscle cells can produce.This situation means that there are inherent limitations to using animal-based model frameworks and experimental data for understanding human heart function and for answering clinical questions. Thus an important challenge to address is the development of a model for the human heart that can be applied directly in clinical contexts. Recently we have developed the capacity to collect unique data on isolated cells from human hearts. Importantly these measurements can be performed at body temperature and the cell length can be changed to mimic the full range of conditions the cells experience as the heart beats. This information enables, for the first time, the ability to construct a model that will be able to directly capture human heart function. To achieve this goal, mathematical equations representing these human heart cells will be developed and combined using high-performance computers to construct a computational model - a 'virtual' heart. The heart's pumping capacity will then be computed under different conditions and linked back to the human heart experiments. Using this virtual heart we will be able to isolate the important mechanisms that govern how the human heart responds to meet the wide range of requirements placed on it. Specific examples include understanding the cellular changes that enable the heart to pump larger volumes of blood, such as in exercise, or produce more force in conditions of high blood pressure. Finally, by publishing the experimental data and model, and by making all of our computer code freely available, we will enable other heart modellers to use our model to perform their own human-based simulations. Through this work this study will provide a new way to investigate and understand human heart function and ultimately the progression of heart disease, together with ways to improve its diagnosis and prevention.

拟议中的项目将提供来自人类心脏的新实验数据，这些数据将被用来制作一个逼真的人类心脏计算机模型。心脏病是发达国家死亡的主要原因。这种疾病的特点是心脏泵血的能力下降，这是由于心脏细胞的机械和电气特性发生变化。然而，尽管进行了广泛的实验研究，但从细胞水平的功能改变到危及生命的泵故障的复杂事件序列仍然知之甚少。这种情况推动了心脏计算机模型的快速发展，这些计算机模型现在为理解心脏病的触发因素和进展提供了新的强大的量化工具。这些模型通过建立统一的、定量的和多层次的框架来整合测量和理解，为捕捉心脏的复杂功能提供了重要手段。从这项工作中，已经揭示了细胞收缩、心脏形状和肌肉结构之间的相互关系的重要见解。然而，尽管这种方法的科学重要性和巨大的临床潜力得到了广泛的认可，但这些计算机模型增加我们对人类心脏功能的理解的承诺在很大程度上仍然没有实现。这是因为目前绝大多数心脏数学模型都是使用从动物实验而不是人体实验中收集的测量数据来开发和验证的。此外，这些实验通常是在与身体内正常或患病心脏的环境截然不同的条件下进行的。特别是，单个细胞保持恒定的长度并在寒冷中进行研究，而在完整的心脏中，细胞长度在心跳期间变化，细胞处于体温；这些差异深刻地改变了肌肉细胞可以产生的力的大小。这种情况意味着，使用基于动物的模型框架和实验数据来了解人类心脏功能和回答临床问题存在固有的局限性。因此，一个需要解决的重要挑战是开发一种可以直接应用于临床的人类心脏模型。最近，我们开发了收集人体心脏分离细胞的独特数据的能力。重要的是，这些测量可以在体温下进行，细胞长度可以改变，以模拟细胞在心脏跳动时所经历的各种条件。这些信息首次使构建能够直接捕捉人类心脏功能的模型成为可能。为了实现这一目标，将开发出代表这些人类心脏细胞的数学方程，并使用高性能计算机将其组合起来，以构建一个计算模型--“虚拟”心脏。然后将计算出不同条件下心脏的泵血能力，并将其与人体心脏实验联系起来。使用这种虚拟心脏，我们将能够分离出控制人类心脏如何响应的重要机制，以满足对其提出的广泛要求。具体的例子包括了解细胞的变化，这些变化使心脏能够泵送更多的血液，比如在运动中，或者在高血压条件下产生更多的力量。最后，通过公布实验数据和模型，并通过免费提供我们所有的计算机代码，我们将使其他心脏建模人员能够使用我们的模型来执行他们自己的基于人类的模拟。通过这项工作，这项研究将为研究和了解人类心脏功能以及最终心脏病的进展提供一种新的方法，以及改进其诊断和预防的方法。

项目成果

A Spatially Detailed Model of Isometric Contraction Based on Competitive Binding of Troponin I Explains Cooperative Interactions between Tropomyosin and Crossbridges.

• DOI: 10.1371/journal.pcbi.1004376
• 发表时间: 2015-08
• 期刊: PLoS computational biology
• 影响因子: 4.3
• 作者: Land S;Niederer SA
• 通讯作者: Niederer SA

Improving the stability of cardiac mechanical simulations.

• DOI: 10.1109/tbme.2014.2373399
• 发表时间: 2015-03
• 期刊: IEEE transactions on bio-medical engineering
• 作者: Land S;Niederer SA;Lamata P;Smith NP
• 通讯作者: Smith NP

Quantifying inter-species differences in contractile function through biophysical modelling.

通过生物物理建模量化收缩功能的物种间差异。

• DOI: 10.1113/jphysiol.2014.279232
• 发表时间: 2015
• 期刊: The Journal of physiology
• 作者: Tøndel K

Insight into model mechanisms through automatic parameter fitting: a new methodological framework for model development.

• DOI: 10.1186/1752-0509-8-59
• 发表时间: 2014-05-20
• 期刊: BMC systems biology
• 作者: Tøndel K;Niederer SA;Land S;Smith NP
• 通讯作者: Smith NP

Verification of cardiac mechanics software: benchmark problems and solutions for testing active and passive material behaviour.

心脏力学软件的验证：测试主动和被动物质行为的基准测试问题和解决方案。

• DOI: 10.1098/rspa.2015.0641
• 发表时间: 2015-12-08
• 期刊: Proceedings. Mathematical, physical, and engineering sciences
• 作者: Land S;Gurev V;Arens S;Augustin CM;Baron L;Blake R;Bradley C;Castro S;Crozier A;Favino M;Fastl TE;Fritz T;Gao H;Gizzi A;Griffith BE;Hurtado DE;Krause R;Luo X;Nash MP;Pezzuto S;Plank G;Rossi S;Ruprecht D;Seemann G;Smith NP;Sundnes J;Rice JJ;Trayanova N;Wang D;Jenny Wang Z;Niederer SA
• 通讯作者: Niederer SA