Accurate knowledge of normal cardiac development is essential for properly understanding the morphogenesis of congenital cardiac malformations that represent the most common congenital anomaly in newborns. The heart is the first organ to function during embryonic development and is fully formed at 8 weeks of gestation. Recent studies stemming from molecular genetics have allowed specification of the role of cellular precursors in the field of heart development. In this article we review the different steps of heart development, focusing on the processes of alignment and septation. We also show, as often as possible, the links between abnormalities of cardiac development and the main congenital heart defects. The development of animal models has permitted the unraveling of many mechanisms that potentially lead to cardiac malformations. A next step towards a better knowledge of cardiac development could be multiscale cardiac modelling.

Physiologically‐based pharmacokinetic models combine knowledge about physiology, drug product properties, such as physicochemical parameters, absorption, distribution, metabolism, excretion characteristics, formulation attributes, and trial design or dosing regimen to mechanistically simulate drug pharmacokinetics (PK). The current work describes the development of a multiphase, multilayer mechanistic dermal absorption (MPML MechDermA) model within the Simcyp Simulator capable of simulating uptake and permeation of drugs through human skin following application of drug products to the skin. The model was designed to account for formulation characteristics as well as body site‐ and sex‐ population variability to predict local and systemic bioavailability. The present report outlines the structure and assumptions of the MPML MechDermA model and includes results from simulations comparing absorption at multiple body sites for two compounds, caffeine and benzoic acid, formulated as solutions. Finally, a model of the Feldene (piroxicam) topical gel, 0.5% was developed and assessed for its ability to predict both plasma and local skin concentrations when compared to in vivo PK data.

Epithelial to mesenchymal transition (EMT) is a fundamental process during development and disease, including development of the heart valves and tumour metastases. An extended cellular Potts model was implemented to represent the behaviour emerging from autonomous cell morphology, labile adhesion, junctional coupling and cell motility. Computer simulations normally focus on these functional changes independently whereas this model facilitates exploration of the interplay between cell shape changes, adhesion and migration. The simulation model is fitted to an in vitro model of endocardial EMT, and agrees with the finding that Notch signalling increases cell-matrix adhesion in addition to modulating cell-cell adhesion.

International audienceCell behaviour during epithelial to mesenchymal transition (EMT) was simulated using the cellular Potts formalism in Compucell3D. A recent in vitro study revealed that the mechanism of endocardial scattering can be induced independently of invasion into the extracellular matrix (ECM). This suggests that loss of endocardial cohesion alone is not sufficient for full EMT. The 3D simulations, which take account of changes in adhesion, match this conclusion. The principle by which the rate of mitosis regulates the endocardial monolayer was demonstrated; suggesting a route by which VEGF might regulate EMT

This paper provides a first description of a multiscale systems modeling approach applied to the congenital birth defect known as the tetralogy of Fallot. The multiscale approach adopted owes a lot to the effort of the world-wide physiome consortium and the work of research groups within the European Union on the Virtual Physiological Human. Both a spatial scale and time scale are used to establish the systems boundaries of the application. The tetralogy of Fallot includes up to four simultaneously occurring anatomic abnormalities that underpin the defect. The use of finite state machines and cellular automata pave the way to understand the processes in time and space that contribute to the defect.