Special Issue "Functional Morphology of the Developing and Mature Cardiovascular System"

A special issue of Journal of Cardiovascular Development and Disease (ISSN 2308-3425).

Deadline for manuscript submissions: closed (31 December 2018).

Special Issue Editor

Prof. Dr. Jörg Männer
E-Mail Website
Guest Editor
Group Cardio-Embryology, Institute of Anatomy and Embryology, UMG, Georg-August-University Goettingen, Goettingen, Germany
Interests: cardiovascular development; cardiac looping; visceral left-right asymmetry; biomechanics; pumping mechanism of valveless heart tubes; form–function relationships; in vivo imaging; proepicardial development; congenital heart defects

Special Issue Information

Dear Colleagues,

Journal of Cardiovascular Development and Disease (JCDD) launches a Special Issue on functional morphology of the developing and mature cardiovascular system. During the past two decades, remarkable advances were made in our understanding of the genetic, molecular and cellular backgrounds of normal and defective cardiovascular functions during prenatal and postnatal life. Such knowledge has, for example, led to a replacement of some of the traditional, morphology-based classifications of human diseases by molecular-based classifications. Due to the remarkable achievements of “molecular medicine”, morphology-based sciences may appear as old-fashioned disciplines, which nowadays may have only a very limited potential to provide new and clinically important insight into cardiovascular functions. During the past two decades, however, remarkable advances were made in the field of morphology-based research, which possibly may have escaped public attention. For example, new imaging techniques and simulation models were used to unravel the mystery of the three-dimensional structure of the ventricular myocardium and its functional significance in the normal and failing human heart. New in vivo imaging techniques and model simulations were also used to study the solid- (morphological) and fluid-dynamic of the embryonic cardiovascular system in diverse model organisms. Data from such studies, disclosed form-function relationships that were important for proper patterning of blood vessels as well as proper development of the myocardium, the cardiac conduction system and the heart valves. New imaging data, additionally, have stimulated new studies on the nature and role of valveless pumping phenomena in the developing and mature cardiovascular system. This special issue will provide a platform for the presentation of recent advances in knowledge on form-function relationships in the developing and mature cardiovascular system coming from diverse scientific disciplines.

Prof. Dr. Jörg Männer
Guest Editor

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1000 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Formfunction relationships
  • Solid dynamics of cardiovascular functions
  • In vivo imaging
  • Pumping mechanisms
  • Cardiovascular biomechanics
  • Myocardial structure
  • Blood vessel structure and patterning

Published Papers (9 papers)

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Research

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Open AccessArticle
4-D Computational Modeling of Cardiac Outflow Tract Hemodynamics over Looping Developmental Stages in Chicken Embryos
J. Cardiovasc. Dev. Dis. 2019, 6(1), 11; https://doi.org/10.3390/jcdd6010011 - 27 Feb 2019
Abstract
Cardiogenesis is interdependent with blood flow within the embryonic system. Recently, a number of studies have begun to elucidate the effects of hemodynamic forces acting upon and within cells as the cardiovascular system begins to develop. Changes in flow are picked up by [...] Read more.
Cardiogenesis is interdependent with blood flow within the embryonic system. Recently, a number of studies have begun to elucidate the effects of hemodynamic forces acting upon and within cells as the cardiovascular system begins to develop. Changes in flow are picked up by mechanosensors in endocardial cells exposed to wall shear stress (the tangential force exerted by blood flow) and by myocardial and mesenchymal cells exposed to cyclic strain (deformation). Mechanosensors stimulate a variety of mechanotransduction pathways which elicit functional cellular responses in order to coordinate the structural development of the heart and cardiovascular system. The looping stages of heart development are critical to normal cardiac morphogenesis and have previously been shown to be extremely sensitive to experimental perturbations in flow, with transient exposure to altered flow dynamics causing severe late stage cardiac defects in animal models. This paper seeks to expand on past research and to begin establishing a detailed baseline for normal hemodynamic conditions in the chick outflow tract during these critical looping stages. Specifically, we will use 4-D (3-D over time) optical coherence tomography to create in vivo geometries for computational fluid dynamics simulations of the cardiac cycle, enabling us to study in great detail 4-D velocity patterns and heterogeneous wall shear stress distributions on the outflow tract endocardium. This information will be useful in determining the normal variation of hemodynamic patterns as well as in mapping hemodynamics to developmental processes such as morphological changes and signaling events during and after the looping stages examined here. Full article
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Open AccessArticle
Vortex Dynamics in Trabeculated Embryonic Ventricles
J. Cardiovasc. Dev. Dis. 2019, 6(1), 6; https://doi.org/10.3390/jcdd6010006 - 22 Jan 2019
Abstract
Proper heart morphogenesis requires a delicate balance between hemodynamic forces, myocardial activity, morphogen gradients, and epigenetic signaling, all of which are coupled with genetic regulatory networks. Recently both in vivo and in silico studies have tried to better understand hemodynamics at varying stages [...] Read more.
Proper heart morphogenesis requires a delicate balance between hemodynamic forces, myocardial activity, morphogen gradients, and epigenetic signaling, all of which are coupled with genetic regulatory networks. Recently both in vivo and in silico studies have tried to better understand hemodynamics at varying stages of veretebrate cardiogenesis. In particular, the intracardial hemodynamics during the onset of trabeculation is notably complex—the inertial and viscous fluid forces are approximately equal at this stage and small perturbations in morphology, scale, and steadiness of the flow can lead to significant changes in bulk flow structures, shear stress distributions, and chemical morphogen gradients. The immersed boundary method was used to numerically simulate fluid flow through simplified two-dimensional and stationary trabeculated ventricles of 72, 80, and 120 h post fertilization wild type zebrafish embryos and ErbB2-inhibited embryos at seven days post fertilization. A 2D idealized trabeculated ventricular model was also used to map the bifurcations in flow structure that occur as a result of the unsteadiness of flow, trabeculae height, and fluid scale ( R e ). Vortex formation occurred in intertrabecular regions for biologically relevant parameter spaces, wherein flow velocities increased. This indicates that trabecular morphology may alter intracardial flow patterns and hence ventricular shear stresses and morphogen gradients. A potential implication of this work is that the onset of vortical (disturbed) flows can upregulate Notch1 expression in endothelial cells in vivo and hence impacts chamber morphogenesis, valvulogenesis, and the formation of the trabeculae themselves. Our results also highlight the sensitivity of cardiac flow patterns to changes in morphology and blood rheology, motivating efforts to obtain spatially and temporally resolved chamber geometries and kinematics as well as the careful measurement of the embryonic blood rheology. The results also suggest that there may be significant changes in shear signalling due to morphological and mechanical variation across individuals and species. Full article
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Open AccessArticle
Hemodynamics in Cardiac Development
J. Cardiovasc. Dev. Dis. 2018, 5(4), 54; https://doi.org/10.3390/jcdd5040054 - 06 Nov 2018
Cited by 2
Abstract
The beating heart is subject to intrinsic mechanical factors, exerted by contraction of the myocardium (stretch and strain) and fluid forces of the enclosed blood (wall shear stress). The earliest contractions of the heart occur already in the 10-somite stage in the tubular [...] Read more.
The beating heart is subject to intrinsic mechanical factors, exerted by contraction of the myocardium (stretch and strain) and fluid forces of the enclosed blood (wall shear stress). The earliest contractions of the heart occur already in the 10-somite stage in the tubular as yet unsegmented heart. With development, the looping heart becomes asymmetric providing varying diameters and curvatures resulting in unequal flow profiles. These flow profiles exert various wall shear stresses and as a consequence different expression patterns of shear responsive genes. In this paper we investigate the morphological alterations of the heart after changing the blood flow by ligation of the right vitelline vein in a model chicken embryo and analyze the extended expression in the endocardial cushions of the shear responsive gene Tgfbeta receptor III. A major phenomenon is the diminished endocardial-mesenchymal transition resulting in hypoplastic (even absence of) atrioventricular and outflow tract endocardial cushions, which might be lethal in early phases. The surviving embryos exhibit several cardiac malformations including ventricular septal defects and malformed semilunar valves related to abnormal development of the aortopulmonary septal complex and the enclosed neural crest cells. We discuss the results in the light of the interactions between several shear stress responsive signaling pathways including an extended review of the involved Vegf, Notch, Pdgf, Klf2, eNos, Endothelin and Tgfβ/Bmp/Smad networks. Full article
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Review

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Open AccessReview
Functional Morphology of the Cardiac Jelly in the Tubular Heart of Vertebrate Embryos
J. Cardiovasc. Dev. Dis. 2019, 6(1), 12; https://doi.org/10.3390/jcdd6010012 - 27 Feb 2019
Cited by 1
Abstract
The early embryonic heart is a multi-layered tube consisting of (1) an outer myocardial tube; (2) an inner endocardial tube; and (3) an extracellular matrix layer interposed between the myocardium and endocardium, called “cardiac jelly” (CJ). During the past decades, research on CJ [...] Read more.
The early embryonic heart is a multi-layered tube consisting of (1) an outer myocardial tube; (2) an inner endocardial tube; and (3) an extracellular matrix layer interposed between the myocardium and endocardium, called “cardiac jelly” (CJ). During the past decades, research on CJ has mainly focused on its molecular and cellular biological aspects. This review focuses on the morphological and biomechanical aspects of CJ. Special attention is given to (1) the spatial distribution and fiber architecture of CJ; (2) the morphological dynamics of CJ during the cardiac cycle; and (3) the removal/remodeling of CJ during advanced heart looping stages, which leads to the formation of ventricular trabeculations and endocardial cushions. CJ acts as a hydraulic skeleton, displaying striking structural and functional similarities with the mesoglea of jellyfish. CJ not only represents a filler substance, facilitating end-systolic occlusion of the embryonic heart lumen. Its elastic components antagonize the systolic deformations of the heart wall and thereby power the refilling phase of the ventricular tube. Non-uniform spatial distribution of CJ generates non-circular cross sections of the opened endocardial tube (initially elliptic, later deltoid), which seem to be advantageous for valveless pumping. Endocardial cushions/ridges are cellularized remnants of non-removed CJ. Full article
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Open AccessReview
Visualising the Cardiovascular System of Embryos of Biomedical Model Organisms with High Resolution Episcopic Microscopy (HREM)
J. Cardiovasc. Dev. Dis. 2018, 5(4), 58; https://doi.org/10.3390/jcdd5040058 - 15 Dec 2018
Cited by 1
Abstract
The article will briefly introduce the high-resolution episcopic microscopy (HREM) technique and will focus on its potential for researching cardiovascular development and remodelling in embryos of biomedical model organisms. It will demonstrate the capacity of HREM for analysing the cardiovascular system of normally [...] Read more.
The article will briefly introduce the high-resolution episcopic microscopy (HREM) technique and will focus on its potential for researching cardiovascular development and remodelling in embryos of biomedical model organisms. It will demonstrate the capacity of HREM for analysing the cardiovascular system of normally developed and genetically or experimentally malformed zebrafish, frog, chick and mouse embryos in the context of the whole specimen and will exemplarily show the possibilities HREM offers for comprehensive visualisation of the vasculature of adult human skin. Finally, it will provide examples of the successful application of HREM for identifying cardiovascular malformations in genetically altered mouse embryos produced in the deciphering the mechanisms of developmental disorders (DMDD) program. Full article
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Open AccessReview
The Memory of the Heart
J. Cardiovasc. Dev. Dis. 2018, 5(4), 55; https://doi.org/10.3390/jcdd5040055 - 11 Nov 2018
Cited by 1
Abstract
The embryological development of the heart is one of the most fascinating phenomena in nature and so is its final structure and function. The various ontogenetic passages form the evolutive basis of the final configuration of the heart. Each key step can be [...] Read more.
The embryological development of the heart is one of the most fascinating phenomena in nature and so is its final structure and function. The various ontogenetic passages form the evolutive basis of the final configuration of the heart. Each key step can be recognized in the final features, as the heart maintains a kind of “memory” of these passages. We can identify the major lines of development of the heart and trace these lines up to the mature organ. The aim of this review is to identify these key parameters of cardiac structure and function as essential elements of the heart’s proper functioning and bases for its treatment. We aim to track key steps of heart development to identify what it “remembers” and maintains in its final form as positively selected. A new vision based on the whole acquired knowledge must guide an in-depth scientific approach in future papers and guidelines on the topic and a complete, farsighted therapeutic conduct able to ensure the physiological correction of cardiac pathologies. The application of this modern, functional vision of the heart could improve the clinical treatment of heart disease, filling the gaps still present. Full article
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Open AccessFeature PaperReview
Examples of Weak, If Not Absent, Form-Function Relations in the Vertebrate Heart
J. Cardiovasc. Dev. Dis. 2018, 5(3), 46; https://doi.org/10.3390/jcdd5030046 - 08 Sep 2018
Abstract
That form and function are related is a maxim of anatomy and physiology. Yet, form-function relations can be difficult to prove. Human subjects with excessive trabeculated myocardium in the left ventricle, for example, are diagnosed with non-compaction cardiomyopathy, but the extent of trabeculations [...] Read more.
That form and function are related is a maxim of anatomy and physiology. Yet, form-function relations can be difficult to prove. Human subjects with excessive trabeculated myocardium in the left ventricle, for example, are diagnosed with non-compaction cardiomyopathy, but the extent of trabeculations may be without relation to ejection fraction. Rather than rejecting a relation between form and function, we may ask whether the salient function is assessed. Is there a relation to electrical propagation, mean arterial blood pressure, or propensity to form blood clots? In addition, how should the extent of trabeculated muscle be assessed? While reviewing literature on trabeculated muscle, we applied Tinbergen’s four types of causation—how does it work, why does it work, how is it made, and why did it evolve—to better parse what is meant by form and function. The paper is structured around cases that highlight advantages and pitfalls of applying Tinbergen’s questions. It further uses the evolution of lunglessness in amphibians to argue that lung reduction impacts on chamber septation and it considers the evolution of an arterial outflow in fishes to argue that reductions in energy consumption may drive structural changes with little consequences to function. Concerning trabeculations, we argue they relate to pumping function in the embryo in the few weeks before the onset of coronary circulation. In human fetal and postnatal stages, a spectrum of trabeculated-to-compact myocardium makes no difference to cardiac function and in this period, form and function may appear unrelated. Full article
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Open AccessFeature PaperReview
Resolving the True Ventricular Mural Architecture
J. Cardiovasc. Dev. Dis. 2018, 5(2), 34; https://doi.org/10.3390/jcdd5020034 - 20 Jun 2018
Cited by 4
Abstract
The precise nature of packing together of the cardiomyocytes within the ventricular walls has still to be determined. The spiraling nature of the chains of interconnected cardiomyocytes has long been recognized. As long ago as the end of the nineteenth century, Pettigrew had [...] Read more.
The precise nature of packing together of the cardiomyocytes within the ventricular walls has still to be determined. The spiraling nature of the chains of interconnected cardiomyocytes has long been recognized. As long ago as the end of the nineteenth century, Pettigrew had emphasized that the ventricular cone was not arranged on the basis of skeletal muscle. Despite this guidance, subsequent anatomists described entities such as “bulbo-spiral muscles”, with this notion of subunits culminating in the suggestion that the ventricular cone could be unwrapped so as to produce a “ventricular myocardial band”. Others, in contrast, had suggested that the ventricular walls were arranged on the basis of “sheets”, or more recently “sheetlets”, with investigators seeking to establishing the angulation of these entities using techniques such as magnetic resonance imaging. Our own investigations, in contrast, have shown that the cardiomyocytes are aggregated together within the supporting fibrous matrix so as to produce a three-dimensional myocardial mesh. In this review, we summarize the previous accounts, and provide the anatomical evidence we have thus far accumulated to support the model of the myocardial mesh. We show how these anatomic findings underscore the concept of the myocardial mesh functioning in antagonistic fashion. They lend evidence to support the notion that the ventricular myocardium works as a muscular hydrostat. Full article
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Open AccessFeature PaperReview
What Is the Heart? Anatomy, Function, Pathophysiology, and Misconceptions
J. Cardiovasc. Dev. Dis. 2018, 5(2), 33; https://doi.org/10.3390/jcdd5020033 - 04 Jun 2018
Cited by 5
Abstract
Cardiac dynamics are traditionally linked to a left ventricle, right ventricle, and septum morphology, a topography that differs from the heart’s five-century-old anatomic description of containing a helix and circumferential wrap architectural configuration. Torrent Guasp’s helical ventricular myocardial band (HVMB) defines this anatomy [...] Read more.
Cardiac dynamics are traditionally linked to a left ventricle, right ventricle, and septum morphology, a topography that differs from the heart’s five-century-old anatomic description of containing a helix and circumferential wrap architectural configuration. Torrent Guasp’s helical ventricular myocardial band (HVMB) defines this anatomy and its structure, and explains why the heart’s six dynamic actions of narrowing, shortening, lengthening, widening, twisting, and uncoiling happen. The described structural findings will raise questions about deductions guiding “accepted cardiac mechanics”, and their functional aspects will challenge and overturn them. These suppositions include the LV, RV, and septum description, timing of mitral valve opening, isovolumic relaxation period, reasons for torsion/twisting, untwisting, reasons for longitudinal and circumferential strain, echocardiographic sub segmentation, resynchronization, RV function dynamics, diastolic dysfunction’s cause, and unrecognized septum impairment. Torrent Guasp’s revolutionary contributions may alter future understanding of the diagnosis and treatment of cardiac disease. Full article
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