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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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

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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