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Despite the widespread use of mouse lines to study cardiogenesis, quantitative parameters of normal mouse heart development remain largely undocumented. As a result, there is no systematic or comprehensive yardstick for assessing the phenotype of individual mutant mice beyond qualitative comparisons.

The development of high resolution imaging methods for studying heart structure and the ability to model them precisely in 3D make quantitative studies with large numbers of samples a realistic possibility.

The aim of this project is to investigate the changes in structure of the ventricular wall of the mouse heart during embryogenesis using quantitative methods. Until the completion of chamber formation, trabecular myocardium fills a large proportion of the ventricular chambers, but this is reduced during subsequent growth and maturation of the heart, with concomitant expansion of the compact layer.

3D modelling of the mouse heart

Figure 1: 3D modelling of the mouse heart shows the extensive trabecular network at E13.5 (left). By E18.5, this is much reduced, and the compact layer of the ventricular wall is more prominent (right).

The precise nature of ventricular wall remodelling in the embryonic heart is poorly understood, although it coincides with vascularisation of the myocardium and development of the peripheral cardiac conduction system.

These developmental changes are of clinical significance since their failure may well result in non-compaction cardiomyopathy. This genetically heterogeneous disease, recognised as a result of improved cardiac imaging methods, is characterised by abnormally prominent and extensive trabeculae, (finger-like projections from the muscular wall), and a relative thinning ("non-compaction") of the wall itself.

Current diagnosis (based on the ratio of trabecular and compact layer thicknesses) is known to be problematic, but without a better understanding of non-compaction aetiology from tractable animal models, there is currently little prospect of pre-symptomatic diagnosis. Since formation of trabeculae and compaction of the ventricular wall normally occur during embryonic development, it is possible that the disease is either developmental in origin, or results from inappropriate activation of a normally embryonic genetic programme.

This project has two goals. Firstly by studying trabeculation in the mouse embryo using 3D modelling and morphometric analysis, we aim to establish an accurate and quantitative description of normal development that can be used as a baseline to assess abnormalities in ventricular wall remodelling. We are using a variety of known mouse mutants in which trabeculation is altered to validate this approach. Secondly, we are constructing mouse models of non-compaction based on mutations identified in studies familial isolated ventricular non-compaction (IVNC). These will be used to investigate the mechanistic origins of non-compaction and provide models to study its progression.

Collaborators - Perry Elliott MBBS MD MRCP, UCL; Nigel Brown, St George's, University of London