Modelling the human heart: an integrated experimental and computational study

拟议中的项目将提供人类心脏的新实验数据，这些数据将用于制作人类心脏的真实计算机模型。在发达国家，心脏病是导致死亡的主要原因。这种疾病的特点是由于心脏细胞的机械和电学特性发生变化，心脏泵血能力下降。然而，尽管有大量的实验研究，从细胞水平的功能改变到危及生命的泵衰竭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，现在为了解心脏病的触发和进展提供了新的强大的定量工具。这些模型通过建立一个一致的、定量的、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的手段。从这项工作中，已经揭示了对细胞收缩、心脏形状和肌肉结构之间相互关系的重要见解。然而，尽管这种方法的科学重要性和重要的临床潜力得到了广泛认可，但这些计算机模型增加我们对人类心脏功能理解的承诺在很大程度上仍未实现。这是因为目前绝大多数心脏数学模型的开发和验证使用的是动物实验而不是人体实验中收集的测量数据。此外，这些实验通常是在与正常或患病心脏的环境大不相同的条件下进行的。特别是，单个细胞保持恒定长度，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所能产生的力量。这种情况意味着使用基于动物的模型框架和实验数据来理解人类心脏功能和回答临床问题存在固有的局限性。因此，需要解决的一个重要挑战是开发一种可以直接应用于临床环境的人类心脏模型。最近，我们已经开发了从人类心脏分离细胞中收集独特数据的能力。重要的是，这些测量可以在体温下进行，细胞长度可以改变，以模拟心脏跳动时细胞经历的所有条件。这一信息使我们第一次有能力构建一个能够直接捕捉人类心脏功能的模型。为了实现这一目标，代表这些人类心脏细胞的数学方程将被开发出来，并使用高性能计算机组合起来构建一个计算模型——一个“虚拟”心脏。然后，在不同条件下计算心脏的泵送能力，并将其与人类心脏实验联系起来。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以满足对其施加的广泛要求的重要机制。具体的例子包括了解细胞的变化，使心脏能够泵出更多的血液，比如在运动中，或者在高血压的情况下产生更多的力量。最后，通过发布实验数据和模型，并使我们所有的计算机代码免费提供，我们将使其他心脏建模者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，最终了解心脏病的进展，以及改善其诊断和预防的方法提供新的途径。

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.