Quantified growth of the human embryonic heart

ABSTRACT The size and growth patterns of the components of the human embryonic heart have remained largely undefined. To provide these data, three-dimensional heart models were generated from immunohistochemically stained sections of ten human embryonic hearts ranging from Carnegie stage 10 to 23. Fifty-eight key structures were annotated and volumetrically assessed. Sizes of the septal foramina and atrioventricular canal opening were also measured. The heart grows exponentially throughout embryonic development. There was consistently less left than right atrial myocardium, and less right than left ventricular myocardium. We observed a later onset of trabeculation in the left atrium compared to the right. Morphometry showed that the rightward expansion of the atrioventricular canal starts in week 5. The septal foramina are less than 0.1 mm2 and are, therefore, much smaller than postnatal septal defects. This chronological, graphical atlas of the growth patterns of cardiac components in the human embryo provides quantified references for normal heart development. Thereby, this atlas may support early detection of cardiac malformations in the foetus. This article has an associated First Person interview with the first author of the paper.

 Myocardialised_AV_cushion: Parts of the atrioventricular cushions that have become myocardialised.
 Ventricular_myocardium: The outer compact ventricular myocardium downstream of the atrioventricular canal before ventricular septation occurs. Before trabeculation, it can be separated from the atrioventricular canal myocardium and the outflow tract myocardium by its bulging appearance.
 Ventricular_trabecular_myocardium: The inner trabecular myocardium of the single ventricle before ventricular septation occurs.
 LV_compact_myocardium: The outer compact myocardium caudal to the atrioventricular canal and located to the left of the interventricular septum. Only segmented after the anterior interventricular sulcus can be recognised.
 LV_trabecular_myocardium: Myocardium within the left ventricular cavity.
 RV_compact_myocardium: The outer compact myocardium caudal to the atrioventricular canal and located to the right of the interventricular septum. Only segmented after the anterior interventricular sulcus can be recognised.
 RV_trabecular_myocardium: Myocardium within the right ventricular cavity.
 Interventricular_septum_myocardium: More densely trabeculated myocardium found adjacent to the interventricular sulcus. Because it was not possible to distinguish where the interventricular septum ends and the compact ventricular myocardium begins, an artificial cut-off at a 45 degree angle is made towards the apex of the ventricle (see Figure 1B). Cranially, the interventricular septum approaches, and ultimately connects with, the atrioventricular cushions.
 OFT_myocardium: Permanently untrabeculated myocardium located cranial to the ventricles and ventral to the atrioventricular canal.
 AV_cushions: Cellularised mesenchyme located at the level of the atrioventricular canal. By indentation it can be segmented separately from the other cushions.
 OFT_cushions: Cellularised mesenchyme in the outflow tract of the heart. A sharp border between it and the mesenchyme of the aorta and pulmonary artery is drawn where the semilunal valve primordia are located and the myocardium connects with the arterial wall.
 DMP_cushion: Cellularised mesenchyme protruding into the atria from the mesenchyme located dorsal to the heart towards the atrioventricular canal cushions.  Epicardium: Mesenchyme located on the outside of the heart. It has been reported that the epicardium covers the entire heart around CS15 (Risebro et al., 2015). On the basis of the Biology Open (2021): doi:10.1242/bio.057059 Supplementary information myocardial stained sections this one cell-layer could not be robustly differentiated from the myocardium. This is the reason that the Epicardium label only includes the thicker mesenchyme in the atrioventricular and interventricular groove. Similarly, we chose not to label the endocardium.
 Veins: Non-myocardial wall of the veins connecting to the heart before the caval veins are formed.
 R_systemic_vein_non-myocardium: Non-myocardial wall of the right superior caval vein.
 L_systemic_vein_non-myocardium: Non-myocardial wall of the left superior caval vein.
 Pulmonary_vein_non-myocardium: Non-myocardial wall of the pulmonary veins.
 Truncus arteriosus: Non-myocardial wall, up to the pericardial reflection, of the artery connecting to the heart before outflow tract septation occurs.
 Pulmonary_artery: Non-myocardial wall of the pulmonary artery.
 Aorta: Non-myocardial wall of the aorta.   Clicking on the model (1) activates it. When the left mouse button is clicked and held the model will turn when the mouse is moved. Clicking on one of the pre-set views (2) opens this view. Here, the 'Specimen' view is used. The button panel (3) allows for a pre-set selection of labels to be made visible (left button), made transparent (middle button) or invisible (right button). Clicking on a structure in the model (4) allows for an individual label to be made transparent or invisible (5). All labels can be viewed in the Model Tree option of Acrobat (6). Here all labels can be switched on or off individually.