Journal of Cardiovascular Development and Disease

Editorial

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Open AccessEditorial

Special Issue: Left-Right Asymmetry and Cardiac Morphogenesis

by Marina Campione and Thomas Brand

J. Cardiovasc. Dev. Dis. 2018, 5(3), 40; https://doi.org/10.3390/jcdd5030040 - 26 Jul 2018

Cited by 1 | Viewed by 3462

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(This article belongs to the Special Issue Left–Right Asymmetry and Cardiac Morphogenesis)

Research

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Open AccessFeature PaperArticle

Kinking and Torsion Can Significantly Improve the Efficiency of Valveless Pumping in Periodically Compressed Tubular Conduits. Implications for Understanding of the Form-Function Relationship of Embryonic Heart Tubes

by Florian Hiermeier and Jörg Männer

J. Cardiovasc. Dev. Dis. 2017, 4(4), 19; https://doi.org/10.3390/jcdd4040019 - 19 Nov 2017

Cited by 18 | Viewed by 15683

Abstract

Valveless pumping phenomena (peristalsis, Liebau-effect) can generate unidirectional fluid flow in periodically compressed tubular conduits. Early embryonic hearts are tubular conduits acting as valveless pumps. It is unclear whether such hearts work as peristaltic or Liebau-effect pumps. During the initial phase of its [...] Read more.

Valveless pumping phenomena (peristalsis, Liebau-effect) can generate unidirectional fluid flow in periodically compressed tubular conduits. Early embryonic hearts are tubular conduits acting as valveless pumps. It is unclear whether such hearts work as peristaltic or Liebau-effect pumps. During the initial phase of its pumping activity, the originally straight embryonic heart is subjected to deforming forces that produce bending, twisting, kinking, and coiling. This deformation process is called cardiac looping. Its function is traditionally seen as generating a configuration needed for establishment of correct alignments of pulmonary and systemic flow pathways in the mature heart of lung-breathing vertebrates. This idea conflicts with the fact that cardiac looping occurs in all vertebrates, including gill-breathing fishes. We speculate that looping morphogenesis may improve the efficiency of valveless pumping. To test the physical plausibility of this hypothesis, we analyzed the pumping performance of a Liebau-effect pump in straight and looped (kinked) configurations. Compared to the straight configuration, the looped configuration significantly improved the pumping performance of our pump. This shows that looping can improve the efficiency of valveless pumping driven by the Liebau-effect. Further studies are needed to clarify whether this finding may have implications for understanding of the form-function relationship of embryonic hearts. Full article

(This article belongs to the Special Issue Left–Right Asymmetry and Cardiac Morphogenesis)

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Review

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24 pages, 1102 KiB

Open AccessFeature PaperReview

Some Isolated Cardiac Malformations Can Be Related to Laterality Defects

by Paolo Versacci, Flaminia Pugnaloni, Maria Cristina Digilio, Carolina Putotto, Marta Unolt, Giulio Calcagni, Anwar Baban and Bruno Marino

J. Cardiovasc. Dev. Dis. 2018, 5(2), 24; https://doi.org/10.3390/jcdd5020024 - 2 May 2018

Cited by 27 | Viewed by 6259

Abstract

Human beings are characterized by a left–right asymmetric arrangement of their internal organs, and the heart is the first organ to break symmetry in the developing embryo. Aberrations in normal left–right axis determination during embryogenesis lead to a wide spectrum of abnormal internal [...] Read more.

Human beings are characterized by a left–right asymmetric arrangement of their internal organs, and the heart is the first organ to break symmetry in the developing embryo. Aberrations in normal left–right axis determination during embryogenesis lead to a wide spectrum of abnormal internal laterality phenotypes, including situs inversus and heterotaxy. In more than 90% of instances, the latter condition is accompanied by complex and severe cardiovascular malformations. Atrioventricular canal defect and transposition of the great arteries—which are particularly frequent in the setting of heterotaxy—are commonly found in situs solitus with or without genetic syndromes. Here, we review current data on morphogenesis of the heart in human beings and animal models, familial recurrence, and upstream genetic pathways of left–right determination in order to highlight how some isolated congenital heart diseases, very common in heterotaxy, even in the setting of situs solitus, may actually be considered in the pathogenetic field of laterality defects. Full article

(This article belongs to the Special Issue Left–Right Asymmetry and Cardiac Morphogenesis)

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11 pages, 9655 KiB

Open AccessFeature PaperReview

Is an Appreciation of Isomerism the Key to Unlocking the Mysteries of the Cardiac Findings in Heterotaxy?

by Robert H. Anderson, Diane E. Spicer and Rohit Loomba

J. Cardiovasc. Dev. Dis. 2018, 5(1), 11; https://doi.org/10.3390/jcdd5010011 - 6 Feb 2018

Cited by 26 | Viewed by 10766

Abstract

Pediatric cardiologists treating patients with severe congenital cardiac defects define “visceral heterotaxy” on the basis of isomerism of the atrial appendages. The isomeric features represent an obvious manifestation of disruption of left-right asymmetry during embryonic development. Thus, there are two subsets of individuals [...] Read more.

Pediatric cardiologists treating patients with severe congenital cardiac defects define “visceral heterotaxy” on the basis of isomerism of the atrial appendages. The isomeric features represent an obvious manifestation of disruption of left-right asymmetry during embryonic development. Thus, there are two subsets of individuals within the overall syndrome, with features of either right or left isomerism. Within the heart, it is only the atrial appendages that are truly isomeric. The remainder of the cardiac components shows variable morphology, as does the arrangement of the remaining body organs. Order is provided in this potentially chaotic arrangement simply by describing the specific features of each of the systems. These features as defined by clinicians, however, seem less well recognized by those investigating the developmental origins of the disruption of symmetry. Developmental biologists place much greater emphasis on ventricular looping. Although the direction of the loop can certainly be interpreted as representing an example of asymmetry, it is not comparable to the isomeric features that underscore the clinical syndromes. This is because, thus far, there is no evidence of ventricular isomerism, with the ventricles distinguished one from the other on the basis of their disparate anatomical features. In similar fashion, some consider transposition to represent abnormal lateralization, but again, clinical diagnosis depends on recognition of the lateralized features. In this review, therefore, we discuss the key questions that currently underscore the mismatch in the approaches to “lateralization” as taken by clinicians and developmental biologists. Full article

(This article belongs to the Special Issue Left–Right Asymmetry and Cardiac Morphogenesis)

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Open AccessFeature PaperReview

Vertebrate Left-Right Asymmetry: What Can Nodal Cascade Gene Expression Patterns Tell Us?

by Axel Schweickert, Tim Ott, Sabrina Kurz, Melanie Tingler, Markus Maerker, Franziska Fuhl and Martin Blum

J. Cardiovasc. Dev. Dis. 2018, 5(1), 1; https://doi.org/10.3390/jcdd5010001 - 29 Dec 2017

Cited by 13 | Viewed by 6074

Abstract

Laterality of inner organs is a wide-spread characteristic of vertebrates and beyond. It is ultimately controlled by the left-asymmetric activation of the Nodal signaling cascade in the lateral plate mesoderm of the neurula stage embryo, which results from a cilia-driven leftward flow of [...] Read more.

Laterality of inner organs is a wide-spread characteristic of vertebrates and beyond. It is ultimately controlled by the left-asymmetric activation of the Nodal signaling cascade in the lateral plate mesoderm of the neurula stage embryo, which results from a cilia-driven leftward flow of extracellular fluids at the left-right organizer. This scenario is widely accepted for laterality determination in wildtype specimens. Deviations from this norm come in different flavors. At the level of organ morphogenesis, laterality may be inverted (situs inversus) or non-concordant with respect to the main body axis (situs ambiguus or heterotaxia). At the level of Nodal cascade gene activation, expression may be inverted, bilaterally induced, or absent. In a given genetic situation, patterns may be randomized or predominantly lacking laterality (absence or bilateral activation). We propose that the distributions of patterns observed may be indicative of the underlying molecular defects, with randomizations being primarily caused by defects in the flow-generating ciliary set-up, and symmetrical patterns being the result of impaired flow sensing, on the left, the right, or both sides. This prediction, the reasoning of which is detailed in this review, pinpoints functions of genes whose role in laterality determination have remained obscure. Full article

(This article belongs to the Special Issue Left–Right Asymmetry and Cardiac Morphogenesis)

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Open AccessReview

The Role of Cerl2 in the Establishment of Left-Right Asymmetries during Axis Formation and Heart Development

by José A. Belo, Sara Marques and José M. Inácio

J. Cardiovasc. Dev. Dis. 2017, 4(4), 23; https://doi.org/10.3390/jcdd4040023 - 10 Dec 2017

Cited by 12 | Viewed by 5194

Abstract

The formation of the asymmetric left-right (LR) body axis is one of the fundamental aspects of vertebrate embryonic development, and one still raising passionate discussions among scientists. Although the conserved role of nodal is unquestionable in this process, several of the details around [...] Read more.

The formation of the asymmetric left-right (LR) body axis is one of the fundamental aspects of vertebrate embryonic development, and one still raising passionate discussions among scientists. Although the conserved role of nodal is unquestionable in this process, several of the details around this signaling cascade are still unanswered. To further understand this mechanism, we have been studying Cerberus-like 2 (Cerl2), an inhibitor of Nodal, and its role in the generation of asymmetries in the early vertebrate embryo. The absence of Cerl2 results in a wide spectrum of malformations commonly known as heterotaxia, which comprises defects in either global organ position (e.g., situs inversus totalis), reversed orientation of at least one organ (e.g., situs ambiguus), and mirror images of usually asymmetric paired organs (e.g., left or right isomerisms of the lungs). Moreover, these laterality defects are frequently associated with congenital heart diseases (e.g., transposition of the great arteries, or atrioventricular septal defects). Here, reviewing the knowledge on the establishment of LR asymmetry in mouse embryos, the emerging conclusion is that as necessary as is the activation of the Nodal signaling cascade, the tight control that Cerl2-mediates on Nodal signaling is equally important, and that generates a further regionalized LR genetic program in the proper time and space. Full article

(This article belongs to the Special Issue Left–Right Asymmetry and Cardiac Morphogenesis)

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Open AccessFeature PaperReview

Multiple Roles of Pitx2 in Cardiac Development and Disease

by Diego Franco, David Sedmera and Estefanía Lozano-Velasco

J. Cardiovasc. Dev. Dis. 2017, 4(4), 16; https://doi.org/10.3390/jcdd4040016 - 11 Oct 2017

Cited by 40 | Viewed by 9041

Abstract

Cardiac development is a complex morphogenetic process initiated as bilateral cardiogenic mesoderm is specified at both sides of the gastrulating embryo. Soon thereafter, these cardiogenic cells fuse at the embryonic midline configuring a symmetrical linear cardiac tube. Left/right bilateral asymmetry is first detected [...] Read more.

Cardiac development is a complex morphogenetic process initiated as bilateral cardiogenic mesoderm is specified at both sides of the gastrulating embryo. Soon thereafter, these cardiogenic cells fuse at the embryonic midline configuring a symmetrical linear cardiac tube. Left/right bilateral asymmetry is first detected in the forming heart as the cardiac tube bends to the right, and subsequently, atrial and ventricular chambers develop. Molecular signals emanating from the node confer distinct left/right signalling pathways that ultimately lead to activation of the homeobox transcription factor Pitx2 in the left side of distinct embryonic organ anlagen, including the developing heart. Asymmetric expression of Pitx2 has therefore been reported during different cardiac developmental stages, and genetic deletion of Pitx2 provided evidence of key regulatory roles of this transcription factor during cardiogenesis and thus congenital heart diseases. More recently, impaired Pitx2 function has also been linked to arrhythmogenic processes, providing novel roles in the adult heart. In this manuscript, we provide a state-of-the-art review of the fundamental roles of Pitx2 during cardiogenesis, arrhythmogenesis and its contribution to congenital heart diseases. Full article

(This article belongs to the Special Issue Left–Right Asymmetry and Cardiac Morphogenesis)

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335 KiB

Open AccessReview

Establishing the Embryonic Axes: Prime Time for Teratogenic Insults

by Thomas W. Sadler

J. Cardiovasc. Dev. Dis. 2017, 4(3), 15; https://doi.org/10.3390/jcdd4030015 - 11 Sep 2017

Cited by 14 | Viewed by 5691

Abstract

A long standing axiom in the field of teratology states that the teratogenic period, when most birth defects are produced, occurs during the third to eighth weeks of development post-fertilization. Any insults prior to this time are thought to result in a slowing [...] Read more.

A long standing axiom in the field of teratology states that the teratogenic period, when most birth defects are produced, occurs during the third to eighth weeks of development post-fertilization. Any insults prior to this time are thought to result in a slowing of embryonic growth from which the conceptus recovers or death of the embryo followed by spontaneous abortion. However, new insights into embryonic development during the first two weeks, including formation of the anterior-posterior, dorsal-ventral, and left-right axes, suggests that signaling pathways regulating these processes are prime targets for genetic and toxic insults. Establishment of the left-right (laterality) axis is particularly sensitive to disruption at very early stages of development and these perturbations result in a wide variety of congenital malformations, especially heart defects. Thus, the time for teratogenic insults resulting in birth defects should be reset to include the first two weeks of development. Full article

(This article belongs to the Special Issue Left–Right Asymmetry and Cardiac Morphogenesis)

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