1. MULTISCALE MODELLING OF CONGENITAL HEART DISEASE1 1 3Ron Summers, Tariq Abdulla, Ryan Imms, Lucile Houyel and Jean-Marc Schleich 1 21Dept. Electronic and Electrical Engineering, SEIC, Loughborough University, LEICS, UK, LE11 3TUE-mail: R.Summers@lboro.ac.uk Web: http://www-staff.lboro.ac.uk/~lsrs12Marie-Lannelongue Hospital, Paris, F-92350, France3LTSI, University of Rennes 1, Rennes, F-35000, FranceIntroductionCardiac Development Multiscale ModellingBetween week 3 and 6 of embryonic development, the humanCardiac looping takes place in week 4 of development. Our modelling framework encompasses spatial scales fromheart morphs from a linear tube to a four chambered organ. It Normally, the conotruncus rotates about 150. As it does so,10 m (protein interaction) to 10 m (the primitive heart tube) and-9 -3is one of the few organs that becomes functional as it is the aortopulmonary septum grows within it, dividing it into the temporal scales from 10 s (molecular events) to 10 s (weeks of -66formed. Heart defects are the most common type of Aorta A and Pulmonary Artery P . Thus different degrees ofdevelopment). This is illustrated schematically below. Thecongenital disorder, severely affecting 6/1000 live births. A rotation correspond to different pathologies (Fig. 2).approach adopted owes much to other methods, including thosenumber of genes have been identified as playing a crucial roleFig. 2 (a) Cardiac looping during 4th week of (b)Conotruncusfrom systems engineering (e.g. integration technologies andin heart morphogenesis. However the mechanisms by which development [2]. l-TGAd-TGAinformation modelling); the world-wide Physiome consortium and(b) Modifed Van Praagh diagram after showingaltered gene transcription affects cell signalling, cellAAthe Virtual Physiological Human Network of Excellence.the approximate rotation of the conotruncus P Pbehaviour, and tissue-tissue interactions that lead to alteredcorresponding to different types of CHD [after 3]. . ANT DORVModelling approaches suitable for different levels of scale aredevelopment are not well understood. Congenital Heart (a) PA ConotruncusConalseptumPulmonary Aorticvalve valveL R TOFillustrated, as well as markup language specifications that TruncusDefects (CHD) constitute a spectrum in which one gene actsConus POST PTAenable model interchange between different tools. Along theP Pthrough many mechanisms and can cause one of severalbottom of Fig. 4, we illustrate reference ontologies applicable toMitralTricuspid A Apathologies. Multiscale modelling provides a means to studyAtrioventricular septumvalve valveSitus InversusNormaldifferent levels of scale.heart development as a system, and simulate how complex In Persistent Truncus Arteriosus (PTA), there is no septation-9 -6-3 10 m10 m10 mdiseases arise from interactions at different levels of spatial into the aorta and pulmonary artery. Double Outlet RightSpatial Scale ProteinCell Tissue Heart Tubeand temporal scale. Ventricle (DORV) and Tetralogy of Fallot (TOF) correspond to InteractionBehaviourTransformationMorphogenesisComplexity of CHD about 90 degrees rotation. Situs inversus is a condition whereCA 2+ High VEGFVEGFHigh VEGFSnail VE Cadherinorgans develop on the opposite side of the body, and henceBMP2CalcineurinNotch pVEGF NFATNFAT Delta4Low VEGFthe conotruncus rotates counterclockwise rather than VEGFVE-Cadherin 2+CA TGF-betaCalcineurin TGF-beta pWnt /LowNFAT NFATSnail BetaCat VEGFVEGFclockwise. This also occurs in levo-Transposition of the GreatHigh VEGFWnt /BMP BetaCat Notch BMP4Markup BMP4Arteries (l-TGA). Language SBML CellML CBMLFieldMLModelling Pathway Models Stochastic Models Agent Based ModelsFinite ElementDevelopment of tissues in early heart development results inApproach ODEsPetri Nets Reaction Diffusion PDEs Systems of ODEsReactive AnimationCellular AutomataImage Analysis3D Reconstructionaltered structures in quite different places, due to the complexBoolean Networks Stochastic Petri NetsCellular PottsMultiphysics Simulation Independent ContinuantPRO, ChEBI CL, FMA, GO-CC FMA, EHDAremodelling (Fig. 3). The endocardial cushions, which grow by(Proteins, Cells, Structures) Remodelling PATO, Mammalian Phenotype Dependent Continuantan Epithelial to Mesenchymal Transformation (EMT) process,OntologiesGO-MFCell Behaviour (Functions, Roles, Qualities)Remodelling of theconotruncus (outflow tract)contribute to some of the most vital structures of a fully-formed GO-BPOccurent (Processes)heart. These are also the structures that underpin the mostTemporal Scalecommon and types of CHD, such as Ventricular Septal Defects -6 -30 36 10 s10 s10 s 10 s10 s Molecular EventsCell Signalling Motility Mitosis Heart Development(VSD), and abnormal or missing heart valves.Fig. 4 Spatial and temporal scales of the multiscale modelling initiativeFig. 3 Illustration of human cardiac morphogenesis and the redistribution of tissues.Note that tissue from the endocardial cushions in the Atrioventricular Canal (AVV,Annotating models, model components and parameters usingblue) becomes the mitral and tricuspid valves, while endocardial cushion tissue in thewell defined ontologies enables reuse and integration. ButConotruncus (CT, yellow) becomes the semilunar valves and the membranous portionof the interventricular septum [4]. multiscale modelling presents a challenge in that no singleFig. 1 Several genes control several mechanisms, which lead to one of several CHDs [1]ontology can include terms to the required specificity. A post-Several mechanisms are involved in heart development, each of coordinated annotation strategy allows the combination of termswhich are controlled by several genes. CHD commonly involvesfrom multiple ontologies, and is a partial solution to this problem.abnormal remodelling of the conotruncus. As the conotruncusloops behind the atria, it septates into the aorta and pulmonaryMembranousSeptumReferences[1] F. Bajolle, S. Zaffran, and D. Bonnet, "Genetics and embryological mechanisms of congenital heartMuscularartery, and wedges aligned with the atrioventricular septum. ASeptumdiseases.", Archives of Cardiovascular Diseases, vol. 102, 2009, pp. 59-63.[2] M. L. Kirby, Cardiac Development, Oxford: OUP, 2007.range of CHDs can be traced to abnormal degrees of rotation,[3] L. F. Donnelly and C. B Higgins MR, "Imaging of Conotruncal Abnormalities.", AJR, 166, 1996, pp.925-8.which affects the positioning of the great arteries. This can be[4] D. Srivastava and E. N. Olson, "A genetic blueprint for cardiac development.", Nature, vol. 407,caused by a combination of mechanisms (Fig. 1). 2000, pp. 221-6.