MULTISCALE MODELLING OF CONGENITAL HEART DISEASE Introduction A Cardiac looping takes place in week 4 of development. Normally, the conotruncus rotates about 150°. As it does so, the aortopulmonary septum grows within it, dividing it into the Aorta and Pulmonary Artery . Thus different degrees of rotation correspond to different pathologies (Fig. 2). P Ron Summers, Tariq Abdulla, Ryan Imms, Lucile Houyel and Jean-Marc Schleich Dept. Electronic and Electrical Engineering, SEIC, Loughborough University, LEICS, UK, LE11 3TU E-mail: [email protected]Web: Marie-Lannelongue Hospital, Paris, F-92350, France LTSI, University of Rennes 1, Rennes, F-35000, France 1 1 1 2 3 1 2 3 Remodelling http://www-staff.lboro.ac.uk/~lsrs1 Conus Truncus Conotruncus Pulmonary valve Aortic valve Mitral valve Tricuspid valve Conal septum Atrioventricular septum Conotruncus P A P P P P A A A A Normal Situs Inversus DORV TOF PTA d-TGA l-TGA ANT POST R L Multiscale Modelling Our modelling framework encompasses spatial scales from 10 -9 m (protein interaction) to 10 -3 m (the primitive heart tube) and temporal scales from 10 -6 s (molecular events) to 10 6 s (weeks of development). This is illustrated schematically below. The approach adopted owes much to other methods, including those from systems engineering (e.g. integration technologies and information modelling); the world-wide Physiome consortium and the Virtual Physiological Human Network of Excellence. Modelling approaches suitable for different levels of scale are illustrated, as well as markup language specifications that enable model interchange between different tools. Along the bottom of Fig. 4, we illustrate reference ontologies applicable to different levels of scale. Annotating models, model components and parameters using well defined ontologies enables reuse and integration. But multiscale modelling presents a challenge in that no single ontology can include terms to the required specificity. A post- coordinated annotation strategy allows the combination of terms from multiple ontologies, and is a partial solution to this problem. Ontologies GO-BP GO-MF PATO, Mammalian Phenotype PRO, ChEBI CL, FMA, GO-CC FMA, EHDA Independent Continuant (Proteins, Cells, Structures) Dependent Continuant (Functions, Roles, Qualities) Occurent (Processes) High VEGF High VEGF Low VEGF Notch Delta4 Snail VE Cadherin TGF-beta BMP2 NFAT VEGF VEGF CA 2+ Calcineurin NFAT p TGF-beta Snail Wnt / BetaCat BMP4 BMP Notch VE-Cadherin VEGF High VEGF Low VEGF Heart Tube Morphogenesis Tissue Transformation Cell Behaviour Protein Interaction NFAT VEGF CA 2+ Calcineurin NFAT p Wnt / BetaCat BMP4 Pathway Models Stochastic Models ODEs Petri Nets Boolean Networks Reaction Diffusion PDEs Systems of ODEs Stochastic Petri Nets Agent Based Models Reactive Animation Cellular Automata Cellular Potts Finite Element Image Analysis 3D Reconstruction Multiphysics Simulation 10 m -9 10 m -6 10 m -3 10 s -6 Molecular Events 10 s -3 Cell Signalling 10 s 3 Mitosis 10 s 6 Heart Development Spatial Scale Temporal Scale SBML CellML FieldML CBML Markup Language Modelling Approach Cell Behaviour 10 s 0 Motility Fig. 4 Spatial and temporal scales of the multiscale modelling initiative Cardiac Development Muscular Septum Membranous Septum Fig. 3 Illustration of human cardiac morphogenesis and the redistribution of tissues. Note that tissue from the endocardial cushions in the Atrioventricular Canal (AVV, blue) becomes the mitral and tricuspid valves, while endocardial cushion tissue in the Conotruncus (CT, yellow) becomes the semilunar valves and the membranous portion of the interventricular septum [4]. . (a) (b) Fig. 2 (a) Cardiac looping during 4th week of development [2]. (b) Modifed Van Praagh diagram after showing the approximate rotation of the conotruncus corresponding to different types of CHD [after 3]. In Persistent Truncus Arteriosus (PTA), there is no septation into the aorta and pulmonary artery. Double Outlet Right Ventricle (DORV) and Tetralogy of Fallot (TOF) correspond to about 90 degrees rotation. Situs inversus is a condition where organs develop on the opposite side of the body, and hence the conotruncus rotates counterclockwise rather than clockwise. This also occurs in levo-Transposition of the Great Arteries (l-TGA). Between week 3 and 6 of embryonic development, the human heart morphs from a linear tube to a four chambered organ. It is one of the few organs that becomes functional as it is formed. Heart defects are the most common type of congenital disorder, severely affecting 6/1000 live births. A number of genes have been identified as playing a crucial role in heart morphogenesis. However the mechanisms by which altered gene transcription affects cell signalling, cell behaviour, and tissue-tissue interactions that lead to altered development are not well understood. Congenital Heart Defects (CHD) constitute a spectrum in which one gene acts through many mechanisms and can cause one of several pathologies. Multiscale modelling provides a means to study heart development as a system, and simulate how complex diseases arise from interactions at different levels of spatial and temporal scale. Development of tissues in early heart development results in altered structures in quite different places, due to the complex remodelling (Fig. 3). The endocardial cushions, which grow by an Epithelial to Mesenchymal Transformation (EMT) process, contribute to some of the most vital structures of a fully-formed heart. These are also the structures that underpin the most common and types of CHD, such as Ventricular Septal Defects (VSD), and abnormal or missing heart valves. References [1] F. Bajolle, S. Zaffran, and D. Bonnet, "Genetics and embryological mechanisms of congenital heart diseases.", Archives of Cardiovascular Diseases, vol. 102, 2009, pp. 59-63. [2] M. L. Kirby, Cardiac Development, Oxford: OUP, 2007. [3] L. F. Donnelly and C. B Higgins MR, "Imaging of Conotruncal Abnormalities.", AJR, 166, 1996, pp. 925-8. [4] D. Srivastava and E. N. Olson, "A genetic blueprint for cardiac development.", Nature, vol. 407, 2000, pp. 221-6. Several mechanisms are involved in heart development, each of which are controlled by several genes. CHD commonly involves abnormal remodelling of the conotruncus. As the conotruncus loops behind the atria, it septates into the aorta and pulmonary artery, and wedges aligned with the atrioventricular septum. A range of CHDs can be traced to abnormal degrees of rotation, which affects the positioning of the great arteries. This can be caused by a combination of mechanisms (Fig. 1). Fig. 1 Several genes control several mechanisms, which lead to one of several CHDs [1] Complexity of CHD Remodelling of the conotruncus (outflow tract)
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:
[email protected] 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.