Science enabled
Blanca RodriguezComputational Biology Group
Cardiac electrophysiologyArrhythmias, treatments and diagnosis
Sinus Rhythm Ventricular Fibrillation
Courtesy: Dr Richard Gray
IschaemiaDrug cardiotoxicity
Why Computational Modelling?
Plunge electrodes
http://www.cvrti.utah.edu
Low spatial resolutionDuring shocks - saturated
Optical mapping
{Rodriguez et al. Circ Res 2005, Bishop et al, Biophys J 2007}
Only the surfacePhoton scattering
Experimental techniques Limitations
Computer Simulations in Cardiac Electrophysiology • 3D activity in the whole ventricular volume
• High spatio-temporal resolution• 3Rs: reduce, refine, replace animal experiments
Computational Cardiac ElectrophysiologyPropagation in tissue
(ii)=Im+Istim,i
(ee)=-Im-Istim,e
Bidomain equations
ionm
stim IdtdVCI
KCaNaion IIII
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V (m
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Single cell action potential
http://cor.physiol.ox.ac.uk/www.cellml.org
http://web.comlab.ox.ac.uk/chaste/
The preDiCT project
Academic: University of Oxford, Universidad Politecnica de Valencia, CRS4 in Sardinia, University of Szeged
Industrial: Fujitsu, Aureus, GSK, Novartis, Roche, Pfizer, Astrazeneca
PARTNERS
AIMTo identify new biomarkers of drug-induced cardiotoxicity using computational techniques
http://www.vph-predict.eu
£200 million, 13 years Drug market approval (DiMasi et al., 2003).
The Problem
Cardiotoxicity: unwanted side effects that can result in arrhythmia
Torsades de Pointes
{Sims et al., 2008}
The Methods
Preclinical assessment of drug cardiotoxicity
Recordings of the HERG current (IKr)Action potential duration (at 1Hz)
In vivo QT interval
Something is not working…
Modelling Drug-induced EffectsDrug/Ion Channel model
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EAD/APD dispersion Cellular AP model
Torsades de PointesVentricular model
ICaL
IKsIKr
IKs stochastic behavior
How does noise in IKs kinetics due to ion channel stochastic behaviour affect repolarization reserve?
varies with location in the ventricles(midmyocardial cellslong APD)
• increases during 24h exposure to IKr blocker{Xiao et al., 2008}
•Small number of channels ion channel stochastic behaviour manifests itself at macroscopic ionic current level {Krogh-Madsen, 2004}.
IKs variability
92 93 94 95 96
0
0.2
0.4
Iks
time (s)
Iks
(pA
/pF)
Stochastic differential equation
Human ventricular model
{Pueyo, Corrias, Gavaghan, Burrage, Rodriguez. HRS meeting, 2009}
IKr Block and IKs stochastic properties
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Deterministic ControlIKr block
APD prolongation
Increased dispersion in APD
IKr block
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Stochastic IKs
{Pueyo, Corrias, Gavaghan, Burrage, Rodriguez. HRS meeting, 2009}
Control LQT2 (IKr block)
IKr Block and IKs stochastic properties
•EADs generation (probability=0.2) •Increased dispersion of APD
IKs stochastic behaviour might contribute to arrhythmogenesis in LQT2 due to:
{Pueyo, Corrias, Gavaghan, Burrage, Rodriguez. HRS meeting, 2009}
Multiscale modellingDrug/Ion Channel model
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EAD/APD dispersion Cellular AP model
Torsades de PointesVentricular model
Modelling whole ventricular electrophysiology
Detailedgeometry
and structurePurkinje system Electrophysiological
heterogeneities
More on Tuesday…
MR Data Acquisition
11.7 T magnet
1024 x 1024 x 2048 voxels
26.4 x 26.4 x 24.4 m resolution
Jurgen Schneider, Peter Kohl, Rebecca Burton
(Physiology, Cardiovascular Medicine, University of Oxford)
Image Segmentation
MR Image
transversal sagittal coronal
Segmentation Result
Views:
Discrimination of tissue from background volumeApplication of three separate level-set segmentation filters ITK, www.itk.org
Martin Bishop, Vicente Grau (Computing Lab, Engineering/OeRC, University of Oxford)
Generation of Finite Element MeshFinite Element Statistics:~ 4 million node points~ 20 million tetrahedral elements~ 1 million bounding trianglesTarantula (www.meshing.at)
Blood vessels
Papillary muscles
Valves
Martin Bishop, Vicente Grau (Computing Lab, Engineering/OeRC, University of Oxford)
Mesh Detail: Paracellular Resolution
Endocardial surfaces
Martin Bishop, Vicente Grau (Computing Lab, Engineering/OeRC, University of Oxford)
Computational Simulations
Miguel Bernabeu, Joe Pitt-Francis, David Gavaghan, Blanca Rodriguez
(Computing Lab, University of Oxford)
CIZ
BZ
NZSTRETCH
TRIGGER
ARRHYTHMIA
??
Experiments by Christian Bollensdorff and
Peter Kohl, Oxford Physiology
{Rodriguez et al. IEEE, 2006}
Role of MEF in ischaemia
Role of MEF in ischaemia
STRETCHTRIGGER
ARRHYTHMIA
??
Experiments by Christian Bollensdorff and
Peter Kohl, Oxford Physiology
ISCHAEMIA +
Understand whether and how stretch can trigger
arrhythmias in ischaemic cells
Incorporate the effects of stretch on the ventricular
model of ischaemia
Investigate the role of stretch in arrhythmogenesis
in ischaemia
Heart Rhythm Mechanisms?
Mathematical models Numerical algorithmsComputational techniques
Chaste: Science enabled
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