Modelling the human heart: an integrated experimental and computational study

点击翻译按钮获取中文摘要

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.