Science enabled Blanca Rodriguez Computational Biology Group

Cardiac electrophysiology Arrhythmias, treatments and diagnosis Sinus RhythmVentricular Fibrillation Courtesy: Dr Richard Gray Ischaemia Drug cardiotoxicity

Why Computational Modelling? Plunge electrodes Low spatial resolution During shocks - saturated Optical mapping {Rodriguez et al. Circ Res 2005, Bishop et al, Biophys J 2007} Only the surface Photon scattering Experimental techniquesLimitations Computer Simulations in Cardiac Electrophysiology 3D activity in the whole ventricular volume High spatio-temporal resolution 3Rs: reduce, refine, replace animal experiments

Computational Cardiac Electrophysiology Propagation in tissue  (  i  i )=I m +I stim,i  (  e  e )=-I m -I stim,e Bidomain equations Single cell action potential /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 AIM To identify new biomarkers of drug-induced cardiotoxicity using computational techniques

£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 (I Kr ) Action potential duration (at 1Hz) In vivo QT interval Something is not working…

Modelling Drug-induced Effects Drug/Ion Channel model EAD/APD dispersion Cellular AP model Torsades de Pointes Ventricular model

I CaL I Ks I Kr IKs stochastic behavior How does noise in I Ks kinetics due to ion channel stochastic behaviour affect repolarization reserve? varies with location in the ventricles (  midmyocardial cells  long APD) increases during 24h exposure to I Kr blocker {Xiao et al., 2008} Small number of channels  ion channel stochastic behaviour manifests itself at macroscopic ionic current level {Krogh-Madsen, 2004}. I Ks variability Stochastic differential equation Human ventricular model {Pueyo, Corrias, Gavaghan, Burrage, Rodriguez. HRS meeting, 2009}

I Kr Block and I Ks stochastic properties Deterministic Control  IKr block APD prolongation Increased dispersion in APD I Kr block Stochastic IKs {Pueyo, Corrias, Gavaghan, Burrage, Rodriguez. HRS meeting, 2009}

Control LQT2 (I Kr block) I Kr Block and I Ks 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 modelling Drug/Ion Channel model EAD/APD dispersion Cellular AP model Torsades de Pointes Ventricular model

Modelling whole ventricular electrophysiology Detailed geometry and structure Purkinje 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 volume Application of three separate level-set segmentation filters ITK, Martin Bishop, Vicente Grau (Computing Lab, Engineering/OeRC, University of Oxford)

Generation of Finite Element Mesh Finite Element Statistics: ~ 4 million node points ~ 20 million tetrahedral elements ~ 1 million bounding triangles Tarantula ( 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 NZ STRETCH TRIGGER ARRHYTHMIA ?? Experiments by Christian Bollensdorff and Peter Kohl, Oxford Physiology {Rodriguez et al. IEEE, 2006} Role of MEF in ischaemia

STRETCH TRIGGER 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 algorithms Computational techniques Chaste: Science enabled