An interactive in vivo and molecular investigation of the arrhythmogenic mechanisms of sudden cardiac death

Lead Research Organisation: University College London
Department Name: Medicine

Abstract

Sudden cardiac arrest (SCA) claims over 300,000 lives per year in the U.S. alone. Prior to cardiac arrest alternating changes on the surface heart tracing (ECG) occur which are thought to arise from fluctuations in the electrical activity on the outside of the heart. These fluctuations are initially in synch with one another (concordant alternans) and then become out of synch (discordant alternans) before degenerating into ventricular fibrillation (VF). Although animal studies have demonstrated this, it has not been possible to study these events in man. We have developed a unique strategy to investigate these changes in patients undergoing open heart surgery. Using data from these measurements we will be able to better understand how and why dangerous rhythms develop. This will lead to improvements in identifying people at the greatest risk of sudden death and allow us to create computer models of electrical activity in the heart. This will aid the development of new treatments in these patients.

Technical Summary

Sudden cardiac arrest (SCA) due to ventricular arrhythmias claims over 300,000 lives per year in the U.S and 50,000 lives per year in the UK). Prior to cardiac arrest alternating changes on the surface ECG frequently occur which are thought to arise from fluctuations in the electrical currents on the surface of the heart. These fluctuations are initially in phase with one another (concordant alternans) and then become out of phase (discordant alternans) before degenerating into ventricular fibrillation (VF). Although animal studies have demonstrated this, it has not been possible to study these events in man. We have developed a unique strategy to investigate these phenomena in patients undergoing cardiac surgery. This involves multielectrode mapping of the whole heart in combination with cellular electrophysiology & gene expression studies of tissue biopsied from sites susceptible to and resistant to alternans identified by our new on line analysis algorithms of alternans. We will use these data to (1) improve risk stratification of patients for implantable defibrillators based on ECG microvolt T wave alternans (2) improve our understanding of mechanisms underlying discordant alternans in patients with cardiac disease, (3) attempt to identify targets for pharmacological therapy, (4) identify novel pacing strategies to be implemented on implantable devices to prevent ventricular fibrillation, (5) provide unique human whole-heart and molecular data as a first stage in informing a computer model for future on-site, on-line interaction with combined whole-heart / cellular electrophysiology patient studies. This ?virtual heart? model could be employed to predict beat by beat events in the evolution of ventricular arrhythmia and test pacing strategies to abort the transition of alternans to VF. It could also be used to develop & evaluate the effects of new anti-dysrhythmic drugs and minimise the use of testing in animals.

Publications


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Bueno-Orovio A (2014) Slow adaptation of ventricular repolarization as a cause of arrhythmia? in Methods of information in medicine
 
Description BHF Clinical Research Fellowship
Amount £196,000 (GBP)
Organisation British Heart Foundation (BHF) 
Sector Charity/Non Profit
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 11/2013 
End 11/2016
 
Description BHF Programme Grant
Amount £1,043,000 (GBP)
Funding ID RG/13/19/30568 
Organisation British Heart Foundation (BHF) 
Sector Charity/Non Profit
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 01/2013 
End 01/2018
 
Description BRC CARDIOMETABOLIC PROGRAMME FUNDING, PUMP PRIMING PROJECT GRANT
Amount £60,000 (GBP)
Organisation National Institute for Health Research (NIHR) 
Department NIHR Biomedical Research Centre at University College London Hospitals NHS Foundation Trust and University College London
Sector Public
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 03/2014 
End 03/2015
 
Description IBME Doctoral Training Programme in Medical Device Innovation
Amount £100,000 (GBP)
Organisation University College London (UCL) 
Department UCL Biochemical Engineering
Sector Academic/University
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 10/2014 
End 10/2018
 
Description International Exchanges Scheme
Amount £12,000 (GBP)
Organisation The Royal Society 
Sector Academic/University
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 03/2015 
End 03/2017
 
Description MRC CASE Studentship
Amount £98,740 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 10/2014 
End 10/2018
 
Description Marie Curie Intra-European Fellowships for Career Development (IEF)
Amount € 230,000 (EUR)
Organisation Marie Curie Actions 
Sector Academic/University
Country Global
Start 03/2015 
End 03/2017
 
Title Signals processing algorthms 
Description We have new developed algorithms to identify sites of repolarisation alternans in vivo during cardiac surgery. These algorithms process data from 256 sites in under 3 mins to taget biopsies of important electrophysiological regions. 
Type Of Material Physiological assessment or outcome measure 
Year Produced 2011 
Provided To Others? Yes  
Impact Thanks to a user-friendly interface, data analysis can be performed easily, even by non expert user. The software is being using by many collaborators. We have published 1 methodological paper (IEEE Trans Biomed Eng) and several conference papers using this software. 
 
Title ARVC data base (ECGI) 
Description Data include: 12-lead ECG + body-surface electrical mapping (256 channels) + Cardiac MRI + epicardial unipolar electrograms reconstructed using ECG-Imaging technology Type of patients: 20 ARVC patients (cardiomyopathy) 
Type Of Material Database/Collection of data 
Year Produced 2014 
Provided To Others? Yes  
Impact This is the first data-base of this king recorded in ARVC patients 
 
Title Multielectrode Sock electrophysiological data 
Description Recordings include multielectrode (240-channels) unipolar elecrograms recorded over the epicardium during open-chest surgery 
Type Of Material Database/Collection of data 
Provided To Others? No  
Impact Spatial distribution of repolarization alternans is heterogeneous, and driven by specific ion channels that we have identified. An article will be submitted soon 
 
Description Analysis of interactions between repolarisation and depolarisation variabilities 
Organisation University of Essex
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution Collaboration with Dr L Citi on the assessment of dynamic causal relationship between epicardial repolarisation and depolarisation temporal chanegs
Collaborator Contribution Development of methodologies
Impact Methodology and algorithms to analyse data from epicardial mapping. Two conference papers
Start Year 2012
 
Description ECG-I mapping of Cardiomyopathies 
Organisation Washington University at St Louis
Country United States of America 
Sector Academic/University 
PI Contribution We underook a study to map inherited cardiomyopathies to improve early diagnosis-we undertook MRI and mapping studies in genotyped patients
Collaborator Contribution Our partners brought the equipment to acquire the data
Impact Submitted abstract to Heart Rhythm USA and manuscripts in preparation
Start Year 2014
 
Description ECG-Imaging for studying complex cardiomyopathies 
Organisation Washington University at St Louis
Country United States of America 
Sector Academic/University 
PI Contribution We have provided expertise in cardiomyopathies, select a group of patients suitable for the study, record the data
Collaborator Contribution They have brought the technology (ECG-Imaging) and are performing the analysis of data
Impact This collaboration is multi-disciplinary. It involves cardiac electrophysiology and engineering. This is a new collaboration. We have recorded a unique database including ECG, body-surface mapping during stress test, and cardiac MRI in 20 Arrhythmogenic Right Ventricular Cardiomyopathy patients.
Start Year 2014
 
Description Modelling Electrophysiological effects of SERCA 2a expression 
Organisation Oxford Radcliffe Hospitals NHS Trust
Department NIHR Comprehensive Biomedical Research Centre
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Public 
PI Contribution I have established a collaboration with Dr Blanca Rodriguez (Wellcome Trust Senior Fellow) in the Oxford Univeristy Computational Biology Dept-we areproviding mRNA ion channel expression data and siganls information to create in silico models predictive of alternans based on the human data we have recorded and analyzed. This is also integrated with data from the John Radcliffe examining the effects of ischemia
Collaborator Contribution My partners are providing the mRNA data (Professor Boyett)
Impact Wellcome Senior Lectureship Award for Dr Rodriguez
Start Year 2012
 
Description UCLA LeDuq Consortium application 
Organisation University of California, Los Angeles (UCLA)
Department School of Medicine UCLA
Country United States of America 
Sector Academic/University 
PI Contribution Development of new research protocols to conduct at UCLA
Collaborator Contribution Exptal design and signals processing analysis-formulation of grant application to LeDuq
Impact Grant application to Leduq
Start Year 2014
 
Title User-friendly software for analysis of cardiac restitution analysis 
Description This software allows to analyse cardiac extracellular potentials to provide a quantification of important electrophysiological properties, such as cardiac restitution. 
Type Of Technology Software 
Year Produced 2015 
Impact This software has been used by us and collaborators to analyse data presented in our scientific publications and reports. 
 
Description 3 Lectures at Oxford University Computational Modelling Group 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Initiated a review and collaborations with Professor Ruy's lab on surface ECG mapping projects

Review article
Year(s) Of Engagement Activity 2013,2014
 
Description 6th form work experience placement 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact 6th former spent a week on work experience in the UCL engineering dept

School has developed links to UCL for further schemes to encourge young scientists
Year(s) Of Engagement Activity 2011
 
Description Lecture to Charterhouse School 6th Form 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach Regional
Primary Audience Schools
Results and Impact 100 pupils attedned the career talk and invited a lively discussion

Some students ahve already enquired regarding obtaining experience in the engineering dept.
Year(s) Of Engagement Activity 2011
 
Description Lecture to Cradiomyopathy Association 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach National
Primary Audience Participants in your research and patient groups
Results and Impact 130 patients & nurses attended the meeting and asked a number of questions regarding heart rhythm disorders

The meeting sparked a workshop in this area for nurses and clinicians
Year(s) Of Engagement Activity 2013
 
Description Lecture to Heart Rhythm UK 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Disucssion sparked questions afterwards

Attracted inquiries to undertake PhD's in my group
Year(s) Of Engagement Activity 2014
 
Description Lecture to charity organisation SADS UK 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact The talk was attended by over 100 people with relatives and friends who has suffered sudden cardiac death-the talk sparked questions and discussion afterwards

Was asked to return to present later results of the research
Year(s) Of Engagement Activity 2011
 
Description Presentation at UCL-Barts Heart Centre Translational E;ectrophysiology Symposium 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact This meeting was organised by Professor Lambiase to develop international collaborations in the field of arrhythmia research-it involved international speakers and had a national reach for the field.
Year(s) Of Engagement Activity 2016
URL https://www.eventbrite.co.uk/e/ucl-barts-heart-centre-translational-electrophysiology-symposium-tues...
 
Description School Visit (Ealing, London) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Inspired students to consider careers in medicine and science

After the talk a number of A level students asked to visit my department and was asked to return for a prize giving day
Year(s) Of Engagement Activity 2013,2014
 
Description Sixth form social engagement educational programme 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Schools
Results and Impact Talk inspired questions regarding cardiology and careers in hospital medicine

Increased applications to UCL medical school from socially deprived areas
Year(s) Of Engagement Activity 2011,2012,2013
 
Description Television interview 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Increased awareness of causes of cardiac arrest to general public and importance of learning CPR-Boradcast on CNN International, Sky Sports and BBC

Increased national awareness of CPR to save lives and enhanced BHF campaign
Year(s) Of Engagement Activity 2012
 
Description UCLA seminar 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Discussion about possible collaborations and joint projects

After the meeting, possible collaborations were discussed
Year(s) Of Engagement Activity 2014