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

Lead Research Organisation: University of Oxford
Department Name: Computer Science

Abstract

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.

Technical Summary

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 from ischaemic heart disease and the resulting expansion of the elderly population, HF is rapidly becoming an epidemic accounting for a significant mortality and morbidity burden in both the industrialised and developing world. Recently, the combined strength of novel experimental techniques and genetically modified animal models 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. It is generally accepted that abnormal intracellular Ca2+ handling and reduced myocyte contractility account for the depressed LV systolic and diastolic function in failing hearts. However, it has become apparent that impaired LV performance can also occur in the absence of obvious abnormalities at the single myocyte level. This illustrates the importance of integrating single cell data to their three-dimensional structural and mechanical environment.

Computational modelling approaches, which have arguably been most successfully applied to the heart, provide the ability to perform exactly this type of multi-scale integration. Specifically, existing models now enable the linking of intracellular Ca2+ handling mechanisms to cardiomyocyte characteristics and whole heart pump function. However, these models are currently of limited use for the direct interpretation of myocardial function and electrophysiology in the mouse (the most widely used experimental model of human cardiomyopathy and heart failure) due to model parameters being based on inhomogeneous data.

Our aim in this proposal is to integrate in-vitro cell measurements with in-vivo invasive measurement and imaging techniques (MR and confocal) to parameterize and fit the cellular and organ models, respectively, using consistent data sets collected from a well-established and widely used murine model of HF following a 30-40% infarction of the LV wall (obtained by proximal ligation of the left anterior descendent coronary artery). Using this model we will focus on addressing the specific question: does the altered spatial distribution of myocyte size, contractility and orientation within the remodelled myocardium contribute to reduced pump function in heart failure, in the absence of significant changes in myocyte contractility and Ca2+ handling? By developing a specific mouse model of excitation-contraction dynamics, we hope to accelerate the development of new treatment strategies and customized clinical care.

Publications

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Title Mouse Serca KO Model 4 week 
Description A mathematical model of the control, 4 and 7 week serca KO mouse has been developed 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Year Produced 2011 
Provided To Others? Yes  
Impact Is currently applied by other groups to look at genetic links and ageing. 
 
Description linking mouse ca handling models to serca KO Mice 
Organisation University of Oslo
Department Institute for Experimental Medical Research
Country Norway 
Sector Academic/University 
PI Contribution Developing the model fromm data
Collaborator Contribution Providing unique data for the models
Impact Two papers from Li at al reported in the previous section, another paper by Land et al is current about to be submitted.
Start Year 2009
 
Description School Visit - Tiffin School for Girls 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Primary Audience Schools
Results and Impact 70 students attended a talk on modelling the heart

School invited us back next year
Year(s) Of Engagement Activity 2011
 
Description interviewed on BBC horizon 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Primary Audience Media (as a channel to the public)
Results and Impact Interviewed on BBC horzon documentary "How to mend a Broken Heart" shown Feb 14 2011

Requests for other information about the project
Year(s) Of Engagement Activity 2010