Dissecting Heart Failure mechanisms by integrating in vivo and in vitro data within customised in silico models

心力衰竭(HF)的定义是心脏-S由于左心室(LV)收缩和舒张期功能下降而降低了泵血能力。随着心脏病发作后存活率的提高和英国S老年人口的扩大，心力衰竭正迅速成为一种流行病，占很大的死亡率和发病率负担。最近，新实验技术的力量为支撑心力衰竭临床综合征的机制之谜贡献了几块新的碎片。然而，尽管做出了这些努力，我们对这一重要过程的了解仍然支离破碎，阻碍了为治疗干预确定强有力的靶点。计算心脏生理学通过使用数学和计算模型定量描述心脏的生理行为，为解决这一问题提供了一种令人兴奋的方法。这些模型的发展提供了捕捉复杂的、多因素的因果关系的能力，这些关系联系着潜在的病理生理机制。此外，心脏可以说是最先进的集成模型的例子，因此代表着令人兴奋的工具，用来专注于一种重要的疾病。将这种计算技术与最先进的体内和体外实验技术相结合，我们的目标是同化多个数据集，以测试我们对一致模型中的心力衰竭机制的理解。我们的初步实验测量表明，在HF中，单个心肌细胞可能继续正常收缩，然而，它们在心脏组织中连接方式的改变可能会对收缩产生不利影响。应用我们集成的实验和计算方法，我们将能够检验这一假设，并在这样做的过程中，为开发这种疾病的新治疗策略指明了一个潜在的全新方向。

Heart Failure (HF) is defined by the heart?s reduced ability to pump blood due to a drop in left ventricular (LV) systolic and diastolic function. With the improved survival after a heart attack and the expansion of the U.K.?s elderly population, HF is rapidly becoming an epidemic accounting for a significant mortality and morbidity burden. Recently, the strength of new experimental techniques has contributed several new pieces to the mechanistic puzzle that underpins the clinical syndrome of HF. Despite these efforts, however, our knowledge of this important process remains fragmented, hampering the identification of robust targets for therapeutic intervention. The discipline of computational cardiac physiology offers an exciting approach to address this issue by quantitatively describing the physiological behavior of the heart using mathematical and computational models. The development of such models presents the ability capture the complex and multi-factorial cause and effect relationships which link underlying patho-physiological mechanisms. Furthermore, the heart is arguable the most advanced example of an integrated model and as such represents exciting tool with which to focus, in the case of HF, on an important disease.Combining this computational technology with state of the art in-vivo and in-vitro experimental techniques we aim to assimilate multiple data sets to test our understanding of HF mechanisms within a consistent model. Our preliminary experimental measurements indicate that in HF individual cardiac cells may continue to contract normally, however, it is a change in the way they are connected in heart tissue which may be adversely affecting contraction. Applying our integrated experimental and computational approach we will be able to test this hypothesis and in doing so indicate a potentially brand new direction for the development of new treatment strategies for this disease.