MULTISCALE MODELLING OF CONGENITAL HEART DISEASE

Introduction

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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).

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Ron Summers, Tariq Abdulla, Ryan Imms, Lucile Houyel and Jean-Marc SchleichDept. Electronic and Electrical Engineering, SEIC, Loughborough University, LEICS, UK, LE11 3TUE-mail: R.Summers@lboro.ac.uk Web: Marie-Lannelongue Hospital, Paris, F-92350, France LTSI, University of Rennes 1, Rennes, F-35000, France

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Remodelling

http://www-staff.lboro.ac.uk/~lsrs1

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Multiscale ModellingOur modelling framework encompasses spatial scales from 10-9m (protein interaction) to 10-3m (the primitive heart tube) and temporal scales from 10-6s (molecular events) to 106s (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)

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Heart TubeMorphogenesis

Tissue Transformation

Cell Behaviour

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Pathway Models Stochastic Models ODEsPetri NetsBoolean Networks

Reaction Diffusion PDEsSystems of ODEsStochastic Petri Nets

Agent Based Models Reactive AnimationCellular AutomataCellular Potts

Finite Element Image Analysis3D ReconstructionMultiphysics Simulation

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Molecular Events10 s

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Cell Signalling10 s

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Fig. 4 Spatial and temporal scales of the multiscale modelling initiative

Cardiac Development

MuscularSeptum

MembranousSeptum

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].

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(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 theconotruncus (outflow tract)