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Science enabled

Science enabled. Blanca Rodriguez Computational Biology Group. Cardiac electrophysiology Arrhythmias, treatments and diagnosis. Sinus Rhythm. Ventricular Fibrillation. Courtesy: Dr Richard Gray. Ischaemia Drug cardiotoxicity. Plunge electrodes. Low spatial resolution

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Science enabled

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  1. Science enabled Blanca Rodriguez Computational Biology Group

  2. Cardiac electrophysiologyArrhythmias, treatments and diagnosis Sinus Rhythm Ventricular Fibrillation Courtesy: Dr Richard Gray Ischaemia Drug cardiotoxicity

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

  4. Computational Cardiac Electrophysiology Single cell action potential Propagation in tissue Bidomain equations • (ii)=Im+Istim,i • (ee)=-Im-Istim,e http://cor.physiol.ox.ac.uk/ www.cellml.org http://web.comlab.ox.ac.uk /chaste/

  5. The preDiCT project AIM To identify new biomarkers of drug-induced cardiotoxicity using computational techniques PARTNERS Academic:University of Oxford, Universidad Politecnica de Valencia, CRS4 in Sardinia, University of Szeged Industrial: Fujitsu, Aureus, GSK, Novartis, Roche, Pfizer, Astrazeneca http://www.vph-predict.eu

  6. Torsades de Pointes {Sims et al., 2008} The Problem £200 million, 13 years Drug market approval (DiMasi et al., 2003). Cardiotoxicity: unwanted side effects that can result in arrhythmia

  7. 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…

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

  9. IKs variability varies with location in the ventricles (midmyocardial cellslong 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 stochastic behavior Human ventricular model ICaL IKr IKs Stochastic differential equation How does noise in IKskinetics due to ion channel stochastic behaviour affect repolarization reserve? {Pueyo, Corrias, Gavaghan, Burrage, Rodriguez. HRS meeting, 2009}

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

  11. IKs stochastic behaviour might contribute to arrhythmogenesis in LQT2 due to: • EADs generation (probability=0.2) • Increased dispersion of APD IKr Block and IKs stochastic properties LQT2 (IKr block) Control {Pueyo, Corrias, Gavaghan, Burrage, Rodriguez. HRS meeting, 2009}

  12. EAD/APD dispersion Cellular AP model Ventricular model Torsades de Pointes Multiscale modelling Drug/Ion Channel model

  13. Modelling whole ventricular electrophysiology Detailed geometry and structure Electrophysiological heterogeneities Purkinje system More on Tuesday…

  14. MR Data Acquisition 11.7 T magnet 1024 x 1024 x 2048 voxels 26.4 x 26.4 x 24.4 mm resolution Jurgen Schneider, Peter Kohl, Rebecca Burton (Physiology, Cardiovascular Medicine, University of Oxford)

  15. Segmentation Result Image Segmentation Discrimination of tissue from background volume Application of three separate level-set segmentation filters ITK, www.itk.org MR Image sagittal coronal Views: transversal Martin Bishop, Vicente Grau (Computing Lab, Engineering/OeRC, University of Oxford)

  16. Blood vessels Valves Papillary muscles Generation of Finite Element Mesh Finite Element Statistics: ~ 4 million node points ~ 20 million tetrahedral elements ~ 1 million bounding triangles Tarantula (www.meshing.at) Martin Bishop, Vicente Grau (Computing Lab, Engineering/OeRC, University of Oxford)

  17. Endocardial surfaces Mesh Detail: Paracellular Resolution Martin Bishop, Vicente Grau (Computing Lab, Engineering/OeRC, University of Oxford)

  18. Computational Simulations Miguel Bernabeu, Joe Pitt-Francis, David Gavaghan, Blanca Rodriguez (Computing Lab, University of Oxford)

  19. Role of MEF in ischaemia NZ ?? TRIGGER ARRHYTHMIA STRETCH BZ CIZ {Rodriguez et al. IEEE, 2006} Experiments by Christian Bollensdorff and Peter Kohl, Oxford Physiology

  20. Role of MEF in ischaemia ?? TRIGGER ARRHYTHMIA STRETCH ISCHAEMIA + Understand whether and how stretch can trigger arrhythmias in ischaemic cells Incorporate the effects of stretch on the ventricular model of ischaemia Experiments by Christian Bollensdorff and Peter Kohl, Oxford Physiology Investigate the role of stretch in arrhythmogenesis in ischaemia

  21. Chaste: Science enabled Heart Rhythm Mechanisms? Numerical algorithms Computational techniques Mathematical models

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