Modelling Cardiac Energy Supply during Heart Failure

心力衰竭是一种致命的综合征，代表了许多心脏和呼吸系统疾病患者常见的“最后途径”。五分之一的人一生中会患心力衰竭，一旦确诊，约40%的患者在一年内死亡。心力衰竭是由于心脏无法向身体各器官输送血液而引起的。能量饥饿假说是一种新的心力衰竭模型，提出能量供应减少是心力衰竭的根本原因。能量饥饿假说是遗传研究和新的实验方法的结果，为解释心脏收缩性衰竭的发展提供了统一的机制，但能量供应受损的意义仍存在争议。该项目将通过分析心力衰竭期间能量供应减少对心功能损害的程度来研究能量饥饿假说的重要性。心脏能量供应链（CESC）横跨从器官到亚细胞尺度。心力衰竭时能量供应减少，是由于器官、组织和细胞尺度上的CESC的独立复合链路受损。在器官层面上，供血给心脏的动脉的血流量减少。在组织尺度上，从毛细血管到细胞的氧和代谢物通量减少。在细胞尺度上，氧和代谢物向高能分子的转化以及向利用点的运输受到抑制。我建议通过开发一系列耦合模型来研究衰竭心脏细胞的能量供应，这些模型代表CESC的细胞规模（代谢、电活动、生化、收缩）、组织规模（氧气和代谢物的运动、毛细血管循环）和器官规模（心脏血液供应、力学、电激活）组成部分。改变模型参数和几何形状将允许模拟心力衰竭期间的CESC。在模型开发的每个阶段，将根据实验结果系统地验证模型。最终的综合多尺度模型将通过量化心力衰竭期间个体和整体CESC的变化如何影响整个心脏功能来检验能量饥饿假说。为了建立这些模型，我们将使用复杂的图像处理技术，从高分辨率数据集建立心脏、向心脏供血的动脉和毛细血管网络的精确3D几何表示。先进的数值方法将用于制定心脏内能量转导的数学方程。尖端的实验程序将提供心脏衰竭期间细胞、组织和器官结构和功能变化的关键信息。这种数学建模技术和实验研究的结合对于阐明心力衰竭的原因和进展的机制至关重要，并可能最终导致改善治疗和预防。

Heart failure is a lethal syndrome representing a common 'final pathway' for sufferers of a multitude of cardiac and respiratory diseases. 1 in 5 people will suffer from heart failure during their life time and once diagnosed ~40% of patients die within one year. Heart failure is caused by the heart's inability to perfuse the organs of the body with blood. The energy starvation hypothesis is a new model of heart failure and proposes that the reduced supply of energy is a fundamental cause of heart failure. The energy starvation hypothesis is the result of genetic studies and new experimental methodologies and provides a unifying mechanism to explain the development of cardiac contractile failure, yet the significance of compromised energy supply is debated. This project will investigate the importance of the energy starvation hypothesis by analysing the extent to which decreases in energy supply during heart failure compromise heart function. The cardiac energy supply chain (CESC) spans from the organ to the sub cellular scale. Energy supply decreases during heart failure due to the compromise of independent compounding links of the CESC at the organ, tissue and cellular scale. At the organ scale, blood flow through the arteries supplying blood to the heart decreases. At the tissue scale, oxygen and metabolite flux from the capillaries to the cells is reduced. At the cellular scale, the conversion of oxygen and metabolites to high energy molecules and the transport of these to the points of utilization are inhibited. I propose to investigate the energy supply to heart cells in the failing heart by developing a series of coupled models representing the cellular scale (metabolism, electrical activity, biochemical, contraction), tissue scale (movement of oxygen and metabolites, capillary circulation) and organ scale (blood supply to the heart, mechanics, electrical activation) components of the CESC. Changing model parameters and geometries will then allow the CESC during heart failure to be simulated. The model will be systematically validated against experimental results at each stage in model development. The final integrated multi-scale model will be used to test the energy starvation hypothesis by quantifying how the individual and integrated changes to the CESC during heart failure affect whole heart function.In order to build these models, we will use sophisticated image processing techniques to build an accurate 3D geometrical representation of the heart, arteries supplying blood to the heart and capillary network from high resolution datasets. Advanced numerical methods will be used to formulate mathematical equations for the transduction of energy within the heart. Cutting edge experimental procedures will provide key information on changes in cellular, tissue and organ structure and function during heart failure. Such combinations of mathematical modelling techniques and experimental investigations are vital for elucidating the mechanisms underlying the causes and progression of heart failure and may ultimately lead to improved treatment and prevention.