1) The document discusses multiscale modeling of congenital heart disease, which can help study heart development as a complex system and how diseases arise from interactions at different spatial and temporal scales. 2) During the 4th week of embryonic development, cardiac looping transforms the linear heart tube into a four-chambered organ through rotation of the conotruncus; different degrees of rotation correspond to different pathologies. 3) The modeling framework encompasses scales from 10-9m to 10-3m and 10-6s to 106s to integrate information from protein interactions to weeks of development using techniques from systems engineering, physiology, and ontologies.

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