Fetal Tricuspid Valve Agenesis/Atresia: Testing Predictions of the Embryonic Etiology.

Tricuspid valve agenesis/atresia (TVA) is a congenital cardiac malformation where the tricuspid valve is not formed. It is hypothesized that TVA results from a failure of the normal rightward expansion of the atrioventricular canal (AVC). We tested predictions of this hypothesis by morphometric analyses of the AVC in fetal hearts. We used high-resolution MRI and ultrasonography on a post-mortem fetal heart with TVA and with tricuspid valve stenosis (TVS) to validate the position of measurement landmarks that were to be applied to clinical echocardiograms. This revealed a much deeper right atrioventricular sulcus in TVA than in TVS. Subsequently, serial echocardiograms of in utero fetuses between 12 and 38 weeks of gestation were included (n = 23 TVA, n = 16 TVS, and n = 74 controls) to establish changes in AVC width and ventricular dimensions over time. Ventricular length and width and estimated fetal weight all increased significantly with age, irrespective of diagnosis. Heart rate did not differ between groups. However, in the second trimester, in TVA, the ratio of AVC to ventricular width was significantly lower compared to TVS and controls. This finding supports the hypothesis that TVA is due to a failed rightward expansion of the AVC. Notably, we found in the third trimester that the AVC to ventricular width normalized in TVA fetuses as their mitral valve area was greater than in controls. Hence, TVA associates with a quantifiable under-development of the AVC. This under-development is obscured in the third trimester, likely because of adaptational growth that allows for increased stroke volume of the left ventricle.

Sinus venosus incorporation: contentious issues and operational criteria for developmental and evolutionary studies.

The sinus venosus is a cardiac chamber upstream of the right atrium that harbours the dominant cardiac pacemaker. During human heart development, the sinus venosus becomes incorporated into the right atrium. However, from the literature it is not possible to deduce the characteristics and importance of this process of incorporation, due to inconsistent terminology and definitions in the description of multiple lines of evidence. We reviewed the literature regarding the incorporation of the sinus venosus and included novel electrophysiological data. Most mammals that have an incorporated sinus venosus show a loss of a functional valve guard of the superior caval vein together with a loss of the electrical sinuatrial delay between the sinus venosus and the right atrium. However, these processes are not necessarily intertwined and in a few species only the sinuatrial delay may be lost. Sinus venosus incorporation can be characterised as the loss of the sinuatrial delay of which the anatomical and molecular underpinnings are not yet understood.

Equal force generation potential of trabecular and compact wall ventricular cardiomyocytes.

Trabecular myocardium makes up most of the ventricular wall of the human embryo. A process of compaction in the fetal period presumably changes ventricular wall morphology by converting ostensibly weaker trabecular myocardium into stronger compact myocardium. Using developmental series of embryonic and fetal humans, mice and chickens, we show ventricular morphogenesis is driven by differential rates of growth of trabecular and compact layers rather than a process of compaction. In mouse, fetal cardiomyocytes are relatively weak but adult cardiomyocytes from the trabecular and compact layer show an equally large force generating capacity. In fetal and adult humans, trabecular and compact myocardium are not different in abundance of immunohistochemically detected vascular, mitochondrial and sarcomeric proteins. Similar findings are made in human excessive trabeculation, a congenital malformation. In conclusion, trabecular and compact myocardium is equally equipped for force production and their proportions are determined by differential growth rates rather than by compaction.

Lack of morphometric evidence for ventricular compaction in humans.

The remodeling of the compact wall by incorporation of trabecular myocardium, referred to as compaction, receives much attention because it is thought that its failure causes left ventricular non-compaction cardiomyopathy (LVNC). Although the notion of compaction is broadly accepted, the nature and strength of the evidence supporting this process is underexposed. Here, we review the literature that quantitatively investigated the development of the ventricular wall to understand the extent of compaction in humans, mice, and chickens. We queried PubMed using several search terms, screened 1127 records, and selected 56 publications containing quantitative data on ventricular growth. For humans, only 34 studies quantified wall development. The key premise of compaction, namely a reduction of the trabecular layer, was never documented. Instead, the trabecular layer grows slower than the compact wall in later development and this changes wall architecture. There were no reports of a sudden enlargement of the compact layer (from incorporated trabeculae), be it in thickness, area, or volume. Therefore, no evidence for compaction was found. Only in chickens, a sudden increase in compact myocardial thickness layer was reported coinciding with a decrease in trabecular thickness. In mice, morphometric and lineage tracing investigations have yielded conflicting results that allow for limited compaction to occur. In conclusion, compaction in human development is not supported while rapid intrinsic growth of the compact wall is supported in all species. If compaction takes place, it likely plays a much smaller role in determining wall architecture than intrinsic growth of the compact wall.

Quantified growth of the human embryonic heart.

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.

High heart rate associated early repolarization causes J-waves in both zebra finch and mouse.

High heart rates are a feature of small endothermic-or warm-blooded-mammals and birds. In small mammals, the QT interval is short, and local ventricular recordings reveal early repolarization that coincides with the J-wave on the ECG, a positive deflection following the QRS complex. Early repolarization contributes to short QT-intervals thereby enabling brief cardiac cycles and high heart rates. We therefore hypothesized high hearts rates associate with early repolarization and J-waves on the ECG of endothermic birds. We tested this hypothesis by comparing isolated hearts of zebra finches and mice and recorded pseudo-ECGs and optical action potentials (zebra finch, n = 8; mouse, n = 8). In both species, heart rate exceeded 300 beats per min, and total ventricular activation was fast (QRS < 10 ms). Ventricular activation progressed from the left to the right ventricle in zebra finch, whereas it progressed from apex-to-base in mouse. In both species, the early repolarization front followed the activation front, causing a positive J-wave in the pseudo-ECG. Inhibition of early repolarization by 4-aminopyridine reduced J-wave amplitude in both species. Action potential duration was similar between ventricles in zebra finch, whereas in mouse the left ventricular action potential was longer. Accordingly, late repolarization had opposite directions in zebra finch (left-right) and mouse (right-left). This caused a similar direction for the zebra finch J-wave and T-wave, whereas in the mouse they were discordant. Our findings demonstrate that early repolarization and the associated J-wave may have evolved by convergence in association with high heart rates.

Comparative analysis of avian hearts provides little evidence for variation among species with acquired endothermy.

Mammals and birds acquired high performance hearts and endothermy during their independent evolution from amniotes with many sauropsid features. A literature review shows that the variation in atrial morphology is greater in mammals than in ectothermic sauropsids. We therefore hypothesized that the transition from ectothermy to endothermy was associated with greater variation in cardiac structure. We tested the hypothesis in 14 orders of birds by assessing the variation in 15 cardiac structures by macroscopic inspection and histology, with an emphasis on the atria as they have multiple features that lend themselves to quantification. We found bird hearts to have multiple features in common with ectothermic sauropsids (synapomorphies), such as the presence of three sinus horns. Convergent features were shared with crocodylians and mammals, such as the cranial offset of the left atrioventricular junction. Other convergent features, like the compact organization of the atrial walls, were shared with mammals only. Pacemaker myocardium, identified by Isl1 expression, was anatomically node-like (Mallard), thickened (Chicken), or indistinct (Lesser redpoll, Jackdaw). Some features were distinctly avian, (autapomorphies) including the presence of a left atrial antechamber and the ventral merger of the left and right atrial auricles, which was found in some species of parrots and passerines. Most features, however, exhibited little variation. For instance, there were always three systemic veins and two pulmonary veins, whereas among mammals there are 2-3 and 1-7, respectively. Our findings suggest that the transition to high cardiac performance does not necessarily lead to a greater variation in cardiac structure.

Melanosome diversity and convergence in the evolution of iridescent avian feathers-Implications for paleocolor reconstruction.

Some of the most varied colors in the natural world are created by iridescent nanostructures in bird feathers, formed by layers of melanin-containing melanosomes. The morphology of melanosomes in iridescent feathers is known to vary, but the extent of this diversity, and when it evolved, is unknown. We use scanning electron microscopy to quantify the diversity of melanosome morphology in iridescent feathers from 97 extant bird species, covering 11 orders. In addition, we assess melanosome morphology in two Eocene birds, which are the stem lineages of groups that respectively exhibit hollow and flat melanosomes today. We find that iridescent feathers contain the most varied melanosome morphologies of all types of bird coloration sampled to date. Using our extended dataset, we predict iridescence in an early Eocene trogon (cf. Primotrogon) but not in the early Eocene swift Scaniacypselus, and neither exhibit the derived melanosome morphologies seen in their modern relatives. Our findings confirm that iridescence is a labile trait that has evolved convergently in several lineages extending down to paravian theropods. The dataset provides a framework to detect iridescence with more confidence in fossil taxa based on melanosome morphology.