Abstract
Formation of trabeculae in the embryonic heart and the remodelling that occurs prior to birth is a conspicuous, but poorly understood, feature of vertebrate cardiogenesis. Mutations disrupting trabecular development in the mouse are frequently embryonic lethal, testifying to the importance of the trabeculae, and aberrant trabecular structure is associated with several human cardiac pathologies. Here, trabecular architecture in the developing mouse embryo has been analysed using high‐resolution episcopic microscopy (HREM) and three‐dimensional (3D) modelling. This study shows that at all stages from mid‐gestation to birth, the ventricular trabeculae comprise a complex meshwork of myocardial strands. Such an arrangement defies conventional methods of measurement, and an approach based upon fractal algorithms has been used to provide an objective measure of trabecular complexity. The extent of trabeculation as it changes along the length of left and right ventricles has been quantified, and the changes that occur from formation of the four‐chambered heart until shortly before birth have been mapped. This approach not only measures qualitative features evident from visual inspection of 3D models, but also detects subtle, consistent and regionally localised differences that distinguish each ventricle and its developmental stage. Finally, the combination of HREM imaging and fractal analysis has been applied to analyse changes in embryonic heart structure in a genetic mouse model in which trabeculation is deranged. It is shown that myocardial deletion of the Notch pathway component Mib1 (Mib1 flox/flox; cTnT‐cre) results in a complex array of abnormalities affecting trabeculae and other parts of the heart.
Highlights
In all vertebrates the muscular walls of the heart possess a complex morphology that is most pronounced in the ventricular chambers
The beginnings of trabeculation can first be seen at E9.5 as the prospective ventricular chambers balloon out from the common ventricular portion of the Developmental changes in trabecular morphology
Taking advantage of the very large number of serial section images captured by high-resolution episcopic microscopy (HREM), hearts were analysed at successive stages of development, measuring the 2D FD value along the sectioning axis and tracking how this changes from completion of ventricular septation (E14.5) to birth (E18.5)
Summary
In all vertebrates the muscular walls of the heart possess a complex morphology that is most pronounced in the ventricular chambers. The complexity of trabecular architecture has proved challenging to capture (Sedmera et al 2000), being variously described as ‘sheet-like projections’ (Liu et al 2010), ‘muscular luminar protrusions’ (Samsa et al 2013), ‘ramifications’ (King et al 2002), ‘ridge-like myocardial structures’ (Staudt et al 2014), ‘endocardial ruffles’ (Sedmera & McQuinn, 2008) and ‘finger-like projections’ (Lavine & Ornitz, 2008) that protrude into the ventricular lumen Such variability in description might be of little consequence if it reflected linguistic imprecision, or indicated the range of trabecular architecture amongst different vertebrate species (zebrafish, mouse and quail in the above examples) that have been studied. It illustrates the profound difficulty of providing an accurate and mean-
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