Integrative computational and experimental study of arrhythmogenesis and defibrillation in acute myocardial ischaemia

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

Abstract

We aim at finding the mechanisms by which myocardial ischaemia results in lethal ventricular arrhythmias and changes in defibrillation efficacy. We expect this new insight will help in optimizing defibrillation therapy in patients suffering from coronary heart disease.
Sudden cardiac death subsequent to ventricular fibrillation is the leading cause of mortality in the UK. In 80% of the victims, the arrhythmia arises in consequence of mismatch between cardiac oxygen supply and demand (myocardial ischaemia), caused by coronary heart disease.
The only effective therapy to avert sudden cardiac death is electrical defibrillation: timely application of an electric shock to the myocardium. However, although the majority of patients undergoing defibrillation suffer from ischaemia, research has mostly focused on uncovering the mechanisms of defibrillation in the normal myocardium. This is in part due to the complexity and the rapidity of ischaemia-induced alterations in myocardial electrophysiological properties, which render experimental evaluation of the underlying mechanisms very difficult.
We will develop a novel anatomically-based rabbit model of the regionally-ischaemic ventricles, validated using experimental data from the ionic to the whole organ level. We then will conduct a combination of computer simulations and experiments to investigate changes in arrhythmia and defibrillation mechanisms in acute myocardial ischaemia.

Technical Summary

Electrical defibrillation by timely application of a strong shock to the myocardium is the only effective therapy to prevent sudden cardiac death subsequent to ventricular fibrillation. However, although the majority of patients undergoing defibrillation suffer from coronary heart disease, little is known about the ischaemic tissue response to the delivery of defibrillation shocks. The main focus of the proposed research is to unravel the mechanisms underlying changes in defibrillation efficacy during the first 45 min of acute myocardial ischaemia. We hypothesize that (i) stretch of ischaemic border zone tissue plays a key role in arrhythmogenesis and defibrillation failure at 15-45min post-occlusion, when altered calcium dynamics favour occurrence of afterdepolarizations; (ii) elevated defibrillation threshold in acute regional ischaemia stems from heterogeneous tissue responses to the shock resulting from heterogeneous ischaemic electrophysiological substrate. This project is based on direct and multiple level iteration between experimental and computational research, coordinated by the Applicant. A mathematical model of the rabbit ventricles in regional ischaemia will be developed with realistic representation of ischaemia-induced effects. Experiments will provide the electrophysiological and anatomical data required to develop the model and to validate the model predictions. Computer simulations will be conducted using the ventricular model to examine changes in defibrillation threshold at several timings post-occlusion for both electrically-induced and spontaneous arrhythmias secondary to regional ischaemia. The Applicant will be directly involved in all aspects of the research, and will put special emphasis in acquiring expertise in the experimental techniques used in cardiac electrophysiology. The interdisciplinary training gained by the Applicant through the proposed studies will set the basis for an efficient and rigorous use of experimental and computational techniques in the study of cardiac arrhythmogenesis and anti-arrhythmia therapies during her Research Career. The combination of the Applicant‘s expertise, local experimental and theoretical know-how at Oxford, computational resources available through association with the UK e-science program, and established collaboration with Prof. Efimov will offer a unique opportunity to provide the mechanistic insight into arrhythmogenesis and defibrillation during acute ischaemia. This is hoped to ultimately advance the development of new or improved anti-arrhythmia interventions with increased success rates of cardiac defibrillation, which could reduce mortality /morbidity from sudden cardiac death. Finally and most importantly, patients with coronary heart disease could benefit from more efficient therapies, improved quality of life and prolonged life expectancy. Thus, the proposed research would contribute to reduce the burden of cardiovascular disease on the community.

Publications

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Abramson D (2010) High-throughput cardiac science on the Grid. in Philosophical transactions. Series A, Mathematical, physical, and engineering sciences

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Bernabeu MO (2009) CHASTE: incorporating a novel multi-scale spatial and temporal algorithm into a large-scale open source library. in Philosophical transactions. Series A, Mathematical, physical, and engineering sciences

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Bernabeu MO (2010) Shock-induced arrhythmogenesis in the human heart: A computational modelling study. in Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference

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Bordas R (2012) A Bidomain Model of the Ventricular Specialized Conduction System of the Heart in SIAM Journal on Applied Mathematics

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Brennan T (2009) Multiscale modelling of drug-induced effects on cardiac electrophysiological activity. in European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences

 
Description Doctoral Training Centres
Geographic Reach National 
Policy Influence Type Influenced training of practitioners or researchers
Impact I teach Computational Biology courses to graduate studies at Oxford and talk about my MRC-funded research to them
 
Description • Invited participant to USA Food and Drug Administration (FDA), FDA Cardiac Modelling working group (Washington DC, July 2013).
Geographic Reach North America 
Policy Influence Type Participation in advisory committee
Impact The Food and Drug Administration Office invited meet to participate in a working group to define how in silico methods (as developed through my MRC award) could replace current drug testing methodologies used in safety pharmacology by pharmaceutical companies.
 
Description EPSRC postdoctoral fellowship (to Dr Alex Quinn)
Amount £279,930 (GBP)
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Public
Country United Kingdom
Start 10/2008 
End 09/2011
 
Description International Joint project
Amount £12,000 (GBP)
Organisation The Royal Society 
Sector Charity/Non Profit
Country United Kingdom
Start 12/2009 
End 11/2011
 
Description Marie Curie Intra-European Fellowship
Amount € 200,371 (EUR)
Organisation European Commission 
Department Seventh Framework Programme (FP7)
Sector Public
Country European Union (EU)
Start 09/2012 
End 08/2014
 
Description NC3Rs Maths in Toxicology
Amount € 512,253 (EUR)
Funding ID NC/P001076/1 
Organisation National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2016 
End 09/2021
 
Description Research Grant
Amount € 25,000 (EUR)
Organisation Johnson & Johnson 
Department Janssen Pharmaceuticals
Sector Private
Country United States
Start 06/2012 
End 11/2012
 
Description Wellcome Trust Senior Research Fellowship in Basic Biomedical Sciences
Amount £1,238,564 (GBP)
Funding ID 100246/Z/12/Z 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2013 
End 09/2018
 
Description euHeart project (ICT Virtual Physiological Human call )
Amount £13,900,000 (GBP)
Funding ID 224495 
Organisation European Commission 
Sector Public
Country European Union (EU)
Start 06/2008 
End 05/2012
 
Description preDiCT project (ICT Virtual Physiological Human call )
Amount £4,100,000 (GBP)
Organisation European Commission 
Sector Public
Country European Union (EU)
Start 06/2008 
End 05/2011
 
Title Chaste 
Description Chaste is an open source software to simulate the electromechanical activity of the heart. The software is used for research into heart rhythm mechanisms (cardiac arrhythmias, defibrillation, drug-induced effects) 
Type Of Material Technology assay or reagent 
Year Produced 2009 
Provided To Others? Yes  
Impact The software is used for research into heart rhythm mechanisms (cardiac arrhythmias, defibrillation, drug-induced effects). Chaste and the research outputs from using Chaste are described in our publications. The software was released in March 2009 and a workshop was organised to teach research groups around the world how to use it. The FDA participated in the event and is using our software. 
URL http://www.sciencedirect.com/science/article/pii/S0010465509002604
 
Title Rabbit Purkinje Action Potential model 
Description A mathematical model of the rabbit action potential has been developed for investigations of drug induced effects and pro-arrhythmic mechanisms. 
Type Of Material Model of mechanisms or symptoms - in vitro 
Year Produced 2011 
Provided To Others? Yes  
Impact The rabbit purkinje action potential model was published in a journal publication and the model made publicly available to the research community. Further work is being conducted to validate the model using experimental recordings from industrial collaborators with the aim of producing a tool that could be used for the preclinical assessment of drug safety. This could contribute to the 3Rs. 
URL http://ajpheart.physiology.org/content/300/5/H1806.short
 
Title Rabbit whole ventricular model with specialised conduction system 
Description A biophysically detailed electrophysiological model of the rabbit ventricles including the specialised conduction system was constructed, described in a journal paper and made available to the scientific community. 
Type Of Material Model of mechanisms or symptoms - in vitro 
Year Produced 2011 
Provided To Others? Yes  
Impact The model can be used to investigate multiscale mechanisms of ventricular electrophysiology and for drug and device testing. 
URL http://www.sciencedirect.com/science/article/pii/S0079610711000472
 
Description Astrazeneca 
Organisation AstraZeneca
Department Modelling and simulation team based in Manchester Astra Zeneca
Country United Kingdom 
Sector Private 
PI Contribution We have conducted modelling and simulations studies designed in collaboration with the industrial partner.
Collaborator Contribution We have an active collaboration funded by the EU project preDICT on "Computational prediction of drug cardiotoxicity". The industrial partner has provided input in the definition of scientific projects with the aim of using modelling and simulation to investigate drug-induced effects in the heart under normal and diseased conditions.
Impact Several conference proceedings publications and a journal paper have been accepted. A joint grant application is in preparation.
Start Year 2009
 
Description Collaboration with Department of Pharmacology, University of Szeged 
Organisation Hungarian Academy of Sciences (MTA)
Country Hungary 
Sector Academic/University 
PI Contribution We have investigated the mechanisms of ventricular rate adaptation in human and in dog using computer simulations. Our results have been validated using experimental data by our collaborators.
Collaborator Contribution The collaboration has provided experimental data that are key for the development of computational models and validation of simulation results in my research.
Impact The collaboration has led to a journal publication (Pueyo E, Husti Z, Hornyik T, Baczko I, Laguna P, Varro A, Rodriguez B. Mechanisms of ventricular rate adaptation as a predictor of arrhythmic risk. Am J Physiol Heart Circ, 298:1577-1587, 2010.) and another one that is to appear in the next issue of Biophysical Journal. The collaboration is multidisciplinary: it combines multiscale modelling and simulation performed at Oxford with experimental work performed in Szeged. Joint grant applications are in preparation.
Start Year 2008
 
Description Johnson & Johnson 
Organisation Johnson & Johnson
Department Safety Pharmacology in Janssen
Country United Kingdom 
Sector Private 
PI Contribution We are constructing and validating mathematical models of the rabbit purkinje action potential based on the data provided by Johnson & Johnson.
Impact A journal paper and a joint grant application is currently in preparation. The collaboration is multi-disciplinary involving combined experimental and computational work and physiologist, pharmacologists, mathematicians, physicists and engineers. The data provided by Johnson & Johnson are used at Oxford to construct and validate rabbit purkinje action potential mathematical models. Simulation studies using the mathematical models are being conducted to investigate drug induced pro-arrhythmic effects. Following this work, the models could potentially be used to replace, refine and reduce animal experiments.
Start Year 2011
 
Description The Heart Hospital 
Organisation University College London
Country United Kingdom 
Sector Academic/University 
PI Contribution We are using computational methods to investigate clinically relevant questions in collaboration with clinicians and engineers at the Heart hospital
Collaborator Contribution They have provided us with clinical recordings and clinically-relevant questions.
Impact We have presented work at international meetings and a joint paper has been submitted. The collaboration involves cardiologists and engineers.
Start Year 2010
 
Description USA Food and Drug Administration Office 
Organisation Food and Drug Administration (FDA)
Department Centre for Biologics Evaluation and Research
Country United States 
Sector Academic/University 
PI Contribution I am an external collaborator in a project funded internally by the FDA.
Collaborator Contribution We have discussions and joint research to promote the use of computational modelling and simulation in pharmacological and device testing.
Impact An FDA scientist was awarded funded for an internal Critical Path project to construct a electromechanical model of the rabbit ventricles based on the tools developed in our team at Oxford. I am the only external collaborator in this FDA project.
Start Year 2011
 
Description Universidad Politecnica de Valencia 
Organisation Polytechnic University of Valencia
Country Spain 
Sector Academic/University 
PI Contribution Our group's contribution to this collaboration is our expertise on multiscale computational modelling. Valencia provides expertise on modelling of drug action at the ionic level.
Collaborator Contribution A researcher from Valencia visited our group and this led to a publication in Am J Physiol.
Impact A publication in American Journal of Physiology and joint participation in the European grant preDiCT. In addition several publications are in preparation.
 
Description Universidad de Zaragoza 
Organisation University of Zaragoza
Country Spain 
Sector Academic/University 
PI Contribution Our team provides expertise in computational modelling of the heart and the group lead by Prof Pablo Laguna and Esther Pueyo provides expertise in signal processing of the electrocardiogram. This is key in making the link between computational modelling studies and clinical results based on the electrocardiogram.
Collaborator Contribution Two researchers from Zaragoza have participated in our projects and the collaboration has led to at least four publications currently published, under review or in preparation.
Impact Outputs include an International Joint Project awarded by the Royal Society, a number of conference publications, three papers in American Journal of Physiology, one paper in Phil Trans Roy Society and another paper in Biophysical Journal. The collaboration is multi-disciplinary including engineers, mathematicians, physiologists and computer scientists.
Start Year 2007
 
Description AstraZeneca 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Primary Audience Public/other audiences
Results and Impact Members of the Computational Biology and Safety Pharmacology departments of AstraZeneca attended the talk.

AstraZeneca has a growing interest and has adopted computational methods for drug safety testing.
Year(s) Of Engagement Activity 2011
 
Description Regulators workshop 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Primary Audience Policymakers/politicians
Results and Impact Regulators from european and US agencies attended a workshop on the use of modelling and simulation for drug safety assessment.

Increased interest in modelling and simulation technologies for drug and device testing both in regulatory agencies and industry.
Year(s) Of Engagement Activity 2011