Talk:Cardiovascular System Development

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Cite this page: Hill, M.A. (2021, June 21) Embryology Cardiovascular System Development. Retrieved from

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Cardiovascular System Development

<pubmed limit=5>Cardiovascular System Development</pubmed>

Heart Embryology

<pubmed limit=5>Heart Embryology</pubmed>


New pages - Arterial System | Cardiovascular - Venous Development | Cardiovascular - Detailed Cardiac Development

Bob Anderson Topics

1. Formation and subsequent remodelling of the tributaries of the systemic venous sinus Cardiovascular - Venous Sinus Development 2. Formation of the pulmonary vein, and its subsequent incorporation into the left atrium Cardiovascular - Pulmonary Vein Development 3. Formation of the superior interatrial fold and the inferior buttress of the atrial septum Cardiovascular - Atrial Septum Development 4. Fusion and remodelling of the atrioventricular cushions Cardiovascular - Atrioventricular Cushion Development 5. Expansion of the atrioventricular canal Cardiovascular - Atrioventricular Canal Development 6. Appearance and subsequent remodelling of the embryonic interventricular communication 7. Formation of the sub pulmonary infundibulum [[Cardiovascular - 8. Development of the arterial roots, with emphasis on formation of the leaflets and sinuses 9. Formation of the intrapericardial arterial trunks 10. Remodelling of the extrapericardial arterial channels 11. Appearance and remodelling of the sinus node 12. Formation of the atrioventricular conduction axis.


Development and Morphology of the Ventricular Outflow Tracts

World J Pediatr Congenit Heart Surg. 2016 Sep;7(5):561-77. doi: 10.1177/2150135116651114.

Anderson RH1, Mori S2, Spicer DE3, Brown NA4, Mohun TJ5.


It is customary, at the current time, to consider many, if not most, of the lesions involving the ventricular outflow tract in terms of conotruncal malformations. This reflects the introduction, in the early 1940s, of the terms conus and truncus to describe the components of the developing outflow tract. The definitive outflow tracts in the postnatal heart, however, possess three, rather than two, components. These are the intrapericardial arterial trunks, the arterial roots, and the subvalvar ventricular outflow tracts. Congenital lesions afflicting the arterial roots, however, are not currently considered to be conotruncal malformations. This suggests a lack of logic in the description of cardiac development and its use as a means of categorizing congenital malformations. It is our belief that the developing outflow tract, like the postnatal outflow tracts, can readily be described in tripartite fashion, with its distal, intermediate, and proximal components forming the primordiums of the postnatal parts. In this review, we present evidence obtained from developing mice and human hearts to substantiate this notion. We show that the outflow tract, initially with a common lumen, is divided into its aortic and pulmonary components by a combination of an aortopulmonary septum derived from the dorsal wall of the aortic sac and outflow tract cushions that spiral through its intermediate and proximal components. These embryonic septal structures, however, subsequently lose their septal functions as the outflow tracts develop their own discrete walls. We then compare the developmental findings with the anatomic arrangements seen postnatally in the normal human heart. We show how correlations with the embryologic findings permit logical analysis of the congenital lesions involving the outflow tracts. © The Author(s) 2016.

KEYWORDS: conotruncal anomalies; conus; episcopic microscopy; multidetector computer tomography; normal anatomy; truncus

PMID 27587491

Infrahepatic inferior caval and azygos vein formation in mammals with different degrees of mesonephric development

J Anat. 2016 Mar;228(3):495-510. doi: 10.1111/joa.12423. Epub 2015 Dec 11.

Hikspoors JP1, Mekonen HK1, Mommen GM1, Cornillie P2, Köhler SE1, Lamers WH1,3.


Controversies regarding the development of the mammalian infrahepatic inferior caval and azygos veins arise from using topography rather than developmental origin as criteria to define venous systems and centre on veins that surround the mesonephros. We compared caudal-vein development in man with that in rodents and pigs (rudimentary and extensive mesonephric development, respectively), and used Amira 3D reconstruction and Cinema 4D-remodelling software for visualisation. The caudal cardinal veins (CCVs) were the only contributors to the inferior caval (IVC) and azygos veins. Development was comparable if temporary vessels that drain the large porcine mesonephros were taken into account. The topography of the CCVs changed concomitant with expansion of adjacent organs (lungs, meso- and metanephroi). The iliac veins arose by gradual extension of the CCVs into the caudal body region. Irrespective of the degree of mesonephric development, the infrarenal part of the IVC developed from the right CCV and the renal part from vascular sprouts of the CCVs in the mesonephros that formed 'subcardinal' veins. The azygos venous system developed from the cranial remnants of the CCVs. Temporary venous collaterals in and around the thoracic sympathetic trunk were interpreted as 'footprints' of the dorsolateral-to-ventromedial change in the local course of the intersegmental and caudal cardinal veins relative to the sympathetic trunk. Interspecies differences in timing of the same events in IVC and azygos-vein development appear to allow for proper joining of conduits for caudal venous return, whereas local changes in topography appear to accommodate efficient venous perfusion. These findings demonstrate that new systems, such as the 'supracardinal' veins, are not necessary to account for changes in the course of the main venous conduits of the embryo. © 2015 Anatomical Society. KEYWORDS: azygos vein; caudal cardinal veins; human; inferior caval vein; mesonephros; mouse; pig PMID 26659476


Development of the atrial septum in relation to postnatal anatomy and interatrial communications

Heart. 2016 Dec 21. pii: heartjnl-2016-310660. doi: 10.1136/heartjnl-2016-310660. [Epub ahead of print]

Jensen B1, Spicer DE2, Sheppard MN3, Anderson RH3,4.


The atrial septum is probe patent in some 30% of the population, and is prone to have overt defects. Atrial septation is the coming together of several myocardial structures and mesenchymal tissues of intracardiac and extracardiac origin that must change identity to myocardium. We propose that the propensity for malformation of the atrial septum reflects this complicated morphogenesis. The morphogenesis of the atrial septum initiates from a ridge of mesenchyme, only a few hundred micrometres long, in the roof of the undivided atrial cavity. By growth of the myocardial primary septum, the mesenchymal ridge will be approximated to, and ultimately fuse, with the mesenchyme of the atrioventricular cushions. This fusion also takes in the so-called vestibular spine, and serves to close the primary atrial foramen. Interatrial communication is maintained by the development of perforations in the myocardial septum that will coalesce to produce the secondary foramen. Late in gestation, an infolding of the right atrial roof, previously identified as the secondary septum, will come to form the roof of the secondary foramen. Muscularisation of the mesenchymal ridge and vestibular spine serves to reinforce the attachment of the primary muscular septum to the atrioventricular insulating plane, with the muscularised components, and the cranial infolding, then producing the rims of the oval fossa as seen in the postnatal heart. We show that other lesions that produce the potential for interatrial shunting are outside the confines of the atrial septum, and hence are best considered as interatrial communications, rather than 'atrial septal defects'. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to

PMID 28003417

Endocardial tip cells in the human embryo - facts and hypotheses

PLoS One. 2015 Jan 24;10(1):e0115853. doi: 10.1371/journal.pone.0115853. eCollection 2015.

Rusu MC1, Poalelungi CV2, Vrapciu AD3, Nicolescu MI4, Hostiuc S5, Mogoanta L6, Taranu T7.

Erratum in Correction: Endocardial tip cells in the human embryo--facts and hypotheses. [PLoS One. 2015]


Experimental studies regarding coronary embryogenesis suggest that the endocardium is a source of endothelial cells for the myocardial networks. As this was not previously documented in human embryos, we aimed to study whether or not endothelial tip cells could be correlated with endocardial-dependent mechanisms of sprouting angiogenesis. Six human embryos (43-56 days) were obtained and processed in accordance with ethical regulations; immunohistochemistry was performed for CD105 (endoglin), CD31, CD34, α-smooth muscle actin, desmin and vimentin antibodies. Primitive main vessels were found deriving from both the sinus venosus and aorta, and were sought to be the primordia of the venous and arterial ends of cardiac microcirculation. Subepicardial vessels were found branching into the outer ventricular myocardium, with a pattern of recruiting α-SMA+/desmin+ vascular smooth muscle cells and pericytes. Endothelial sprouts were guided by CD31+/CD34+/CD105+/vimentin+ endothelial tip cells. Within the inner myocardium, we found endothelial networks rooted from endocardium, guided by filopodia-projecting CD31+/CD34+/CD105+/ vimentin+ endocardial tip cells. The myocardial microcirculatory bed in the atria was mostly originated from endocardium, as well. Nevertheless, endocardial tip cells were also found in cardiac cushions, but they were not related to cushion endothelial networks. A general anatomical pattern of cardiac microvascular embryogenesis was thus hypothesized; the arterial and venous ends being linked, respectively, to the aorta and sinus venosus. Further elongation of the vessels may be related to the epicardium and subepicardial stroma and the intramyocardial network, depending on either endothelial and endocardial filopodia-guided tip cells in ventricles, or mostly on endocardium, in atria.

PMID 25617624

Rusu MC, Poalelungi CV, Vrapciu AD, Nicolescu MI, Hostiuc S, Mogoanta L, et al. (2015) Endocardial Tip Cells in the Human Embryo – Facts and Hypotheses. PLoS ONE 10(1): e0115853. doi:10.1371/journal.pone.0115853


Rings and Slings Revisited

Magn Reson Imaging Clin N Am. 2015 Feb;23(1):127-135. doi: 10.1016/j.mric.2014.09.011. Epub 2014 Oct 3.

Smith BM1, Lu JC2, Dorfman AL2, Ghadimi Mahani M3, Agarwal PP4.


Vascular rings and pulmonary artery slings are rare congenital anomalies that often present with symptoms of tracheal and esophageal compression. These can involve the aortic arch branches and pulmonary arteries, respectively. This review illustrates the current role of MR imaging, highlights its advantages, and provides insight into the diagnosis of these anomalies by describing the embryology and characteristic imaging features of these lesions. Copyright © 2015 Elsevier Inc. All rights reserved. KEYWORDS: MR imaging; Pediatrics; Pulmonary sling; Vascular ring

  • Vascular rings - rare (<1 %) congenital abnormalities of the aortic arch-derived vascular or ligamentous structures (aorta, arch branch vessels, pulmonary artery, ductus arteriosus or ligamentum arteriosum) that encircle the trachea and oesophagus to varying degrees.
  • Sling - an abnormality of pulmonary arterial system resulting in airway compression.

PMID 25476681

Insights into Imaging © The Author(s) 2014 10.1007/s13244-014-0343-3


Evolution and Development of Ventricular Septation in the Amniote Heart

PLoS One. 2014 Sep 5;9(9):e106569. doi: 10.1371/journal.pone.0106569. eCollection 2014.

Poelmann RE1, Groot AC2, Vicente-Steijn R3, Wisse LJ3, Bartelings MM3, Everts S3, Hoppenbrouwers T4, Kruithof BP5, Jensen B6, de Bruin PW7, Hirasawa T8, Kuratani S8, Vonk F9, van de Put JM4, de Bakker MA4, Richardson MK4.


During cardiogenesis the epicardium, covering the surface of the myocardial tube, has been ascribed several functions essential for normal heart development of vertebrates from lampreys to mammals. We investigated a novel function of the epicardium in ventricular development in species with partial and complete septation. These species include reptiles, birds and mammals. Adult turtles, lizards and snakes have a complex ventricle with three cava, partially separated by the horizontal and vertical septa. The crocodilians, birds and mammals with origins some 100 million years apart, however, have a left and right ventricle that are completely separated, being a clear example of convergent evolution. In specific embryonic stages these species show similarities in development, prompting us to investigate the mechanisms underlying epicardial involvement. The primitive ventricle of early embryos becomes septated by folding and fusion of the anterior ventricular wall, trapping epicardium in its core. This folding septum develops as the horizontal septum in reptiles and the anterior part of the interventricular septum in the other taxa. The mechanism of folding is confirmed using DiI tattoos of the ventricular surface. Trapping of epicardium-derived cells is studied by transplanting embryonic quail pro-epicardial organ into chicken hosts. The effect of decreased epicardium involvement is studied in knock-out mice, and pro-epicardium ablated chicken, resulting in diminished and even absent septum formation. Proper folding followed by diminished ventricular fusion may explain the deep interventricular cleft observed in elephants. The vertical septum, although indistinct in most reptiles except in crocodilians and pythonidsis apparently homologous to the inlet septum. Eventually the various septal components merge to form the completely septated heart. In our attempt to discover homologies between the various septum components we aim to elucidate the evolution and development of this part of the vertebrate heart as well as understand the etiology of septal defects in human congenital heart malformations.

PMID 25192012

Assembly of the Cardiac Intercalated Disk during Pre- and Postnatal Development of the Human Heart

PLoS One. 2014 Apr 14;9(4):e94722. doi: 10.1371/journal.pone.0094722. eCollection 2014.

Vreeker A1, van Stuijvenberg L1, Hund TJ2, Mohler PJ3, Nikkels PG4, van Veen TA1. Author information


BACKGROUND: In cardiac muscle, the intercalated disk (ID) at the longitudinal cell-edges of cardiomyocytes provides as a macromolecular infrastructure that integrates mechanical and electrical coupling within the heart. Pathophysiological disturbance in composition of this complex is well known to trigger cardiac arrhythmias and pump failure. The mechanisms underlying assembly of this important cellular domain in human heart is currently unknown. METHODS: We collected 18 specimens from individuals that died from non-cardiovascular causes. Age of the specimens ranged from a gestational age of 15 weeks through 11 years postnatal. Immunohistochemical labeling was performed against proteins comprising desmosomes, adherens junctions, the cardiac sodium channel and gap junctions to visualize spatiotemporal alterations in subcellular location of the proteins. RESULTS: Changes in spatiotemporal localization of the adherens junction proteins (N-cadherin and ZO-1) and desmosomal proteins (plakoglobin, desmoplakin and plakophilin-2) were identical in all subsequent ages studied. After an initial period of diffuse and lateral labelling, all proteins were fully localized in the ID at approximately 1 year after birth. Nav1.5 that composes the cardiac sodium channel and the gap junction protein Cx43 follow a similar pattern but their arrival in the ID is detected at (much) later stages (two years for Nav1.5 and seven years for Cx43, respectively). CONCLUSION: Our data on developmental maturation of the ID in human heart indicate that generation of the mechanical junctions at the ID precedes that of the electrical junctions with a significant difference in time. In addition arrival of the electrical junctions (Nav1.5 and Cx43) is not uniform since sodium channels localize much earlier than gap junction channels.

PMID 24733085

Comparative and developmental anatomy of cardiac lymphatics

ScientificWorldJournal. 2014 Jan 27;2014:183170. doi: 10.1155/2014/183170. eCollection 2014.

Ratajska A1, Gula G2, Flaht-Zabost A1, Czarnowska E3, Ciszek B4, Jankowska-Steifer E5, Niderla-Bielinska J5, Radomska-Lesniewska D5. Author information


The role of the cardiac lymphatic system has been recently appreciated since lymphatic disturbances take part in various heart pathologies. This review presents the current knowledge about normal anatomy and structure of lymphatics and their prenatal development for a better understanding of the proper functioning of this system in relation to coronary circulation. Lymphatics of the heart consist of terminal capillaries of various diameters, capillary plexuses that drain continuously subendocardial, myocardial, and subepicardial areas, and draining (collecting) vessels that lead the lymph out of the heart. There are interspecies differences in the distribution of lymphatic capillaries, especially near the valves, as well as differences in the routes and number of draining vessels. In some species, subendocardial areas contain fewer lymphatic capillaries as compared to subepicardial parts of the heart. In all species there is at least one collector vessel draining lymph from the subepicardial plexuses and running along the anterior interventricular septum under the left auricle and further along the pulmonary trunk outside the heart and terminating in the right venous angle. The second collector assumes a different route in various species. In most mammalian species the collectors run along major branches of coronary arteries, have valves and a discontinuous layer of smooth muscle cells. PMID 24592145


Velocity profiles in the human ductus venosus: a numerical fluid structure interaction study

Biomech Model Mechanobiol. 2013 Jan 1. [Epub ahead of print]

Leinan PR, Degroote J, Kiserud T, Skallerud B, Vierendeels J, Hellevik LR. Source Biomechanics Division, Department of Structural Engineering, The Norwegian University of Science and Technology, 7491, Trondheim, Norway,


The veins distributing oxygenated blood from the placenta to the fetal body have been given much attention in clinical Doppler velocimetry studies, in particular the ductus venosus. The ductus venosus is embedded in the left liver lobe and connects the intra-abdominal portion of the umbilical vein (IUV) directly to the inferior vena cava, such that oxygenated blood can bypass the liver and flow directly to the fetal heart. In the current work, we have developed a mathematical model to assist the clinical assessment of volumetric flow rate at the inlet of the ductus venosus. With a robust estimate of the velocity profile shape coefficient (VC), the volumetric flow rate may be estimated as the product of the time-averaged cross-sectional area, the time-averaged cross-sectional maximum velocity and the VC. The time average quantities may be obtained from Doppler ultrasound measurements, whereas the VC may be estimated from numerical simulations. The mathematical model employs a 3D fluid structure interaction model of the bifurcation formed by the IUV, the ductus venosus and the left portal vein. Furthermore, the amniotic portion of the umbilical vein, the right liver lobe and the inferior vena cava were incorporated as lumped model boundary conditions for the fluid structure interaction model. A hyperelastic material is used to model the structural response of the vessel walls, based on recently available experimental data for the human IUV and ductus venous. A parametric study was constructed to investigate the VC at the ductus venosus inlet, based on a reference case for a human fetus at 36 weeks of gestation. The VC was found to be [Formula: see text] (Mean [Formula: see text] SD of parametric case study), which confirms previous studies in the literature on the VC at the ductus venosus inlet. Additionally, CFD simulations with rigid walls were performed on a subsection of the parametric case study, and only minor changes in the predicted VCs were observed compared to the FSI cases. In conclusion, the presented mathematical model is a promising tool for the assessment of ductus venosus Doppler velocimetry.

PMID 23277410


Identifying the evolutionary building blocks of the cardiac conduction system

PLoS One. 2012;7(9):e44231. doi: 10.1371/journal.pone.0044231. Epub 2012 Sep 11.

Jensen B, Boukens BJ, Postma AV, Gunst QD, van den Hoff MJ, Moorman AF, Wang T, Christoffels VM. Source Department of Anatomy, Embryology & Physiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.


The endothermic state of mammals and birds requires high heart rates to accommodate the high rates of oxygen consumption. These high heart rates are driven by very similar conduction systems consisting of an atrioventricular node that slows the electrical impulse and a His-Purkinje system that efficiently activates the ventricular chambers. While ectothermic vertebrates have similar contraction patterns, they do not possess anatomical evidence for a conduction system. This lack amongst extant ectotherms is surprising because mammals and birds evolved independently from reptile-like ancestors. Using conserved genetic markers, we found that the conduction system design of lizard (Anolis carolinensis and A. sagrei), frog (Xenopus laevis) and zebrafish (Danio rerio) adults is strikingly similar to that of embryos of mammals (mouse Mus musculus, and man) and chicken (Gallus gallus). Thus, in ectothermic adults, the slow conducting atrioventricular canal muscle is present, no fibrous insulating plane is formed, and the spongy ventricle serves the dual purpose of conduction and contraction. Optical mapping showed base-to-apex activation of the ventricles of the ectothermic animals, similar to the activation pattern of mammalian and avian embryonic ventricles and to the His-Purkinje systems of the formed hearts. Mammalian and avian ventricles uniquely develop thick compact walls and septum and, hence, form a discrete ventricular conduction system from the embryonic spongy ventricle. Our study uncovers the evolutionary building plan of heart and indicates that the building blocks of the conduction system of adult ectothermic vertebrates and embryos of endotherms are similar.

PMID 22984480

The second heart field

Curr Top Dev Biol. 2012;100:33-65. doi: 10.1016/B978-0-12-387786-4.00002-6.

Kelly RG. Source Developmental Biology Institute of Marseilles-Luminy, Aix-Marseille Université, CNRS UMR 7288, Marseilles, France.


Ten years ago, a population of cardiac progenitor cells was identified in pharyngeal mesoderm that gives rise to a major part of the amniote heart. These multipotent progenitor cells, termed the second heart field (SHF), contribute progressively to the poles of the elongating heart tube during looping morphogenesis, giving rise to myocardium, smooth muscle, and endothelial cells. Research into the mechanisms of SHF development has contributed significantly to our understanding of the properties of cardiac progenitor cells and the origins of congenital heart defects. Here recent data concerning the regulation, clinically relevant subpopulations, evolution and lineage relationships of the SHF are reviewed. Proliferation and differentiation of SHF cells are controlled by multiple intercellular signaling pathways and a transcriptional regulatory network that is beginning to be elucidated. Perturbation of SHF development results in common forms of congenital heart defects and particular progenitor cell subpopulations are highly relevant clinically, including cells giving rise to myocardium at the base of the pulmonary trunk and the interatrial septum. A SHF has recently been identified in amphibian, fish, and agnathan embryos, highlighting the important contribution of these cells to the evolution of the vertebrate heart. Finally, SHF-derived parts of the heart share a lineage relationship with craniofacial skeletal muscles revealing that these progenitor cells belong to a broad cardiocraniofacial field of pharyngeal mesoderm. Investigation of the mechanisms underlying the dynamic process of SHF deployment is likely to yield further insights into cardiac development and pathology. Copyright © 2012 Elsevier Inc. All rights reserved.

PMID 22449840

The human brain intracerebral microvascular system: development and structure

Front Neuroanat. 2012 Sep 13;6:38. eCollection 2012.

Marín-Padilla M1.


The capillary from the meningeal inner pial lamella play a crucial role in the development and structural organization of the cerebral cortex extrinsic and intrinsic microvascular compartments. Only pial capillaries are capable of perforating through the cortex external glial limiting membrane (EGLM) to enter into the nervous tissue, although incapable of perforating the membrane to exit the brain. Circulatory dynamics and functional demands determine which capillaries become arterial and which capillaries become venous. The perforation of the cortex EGLM by pial capillaries is a complex process characterized by three fundamental stages: (1) pial capillary contact with the EGLM with fusion of vascular and glial basal laminae at the contact site, (2) endothelial cell filopodium penetration through the fussed laminae with the formation of a funnel between them that accompanies it into the nervous tissue while remaining open to the meningeal interstitium and, (3) penetration of the whole capillary carrying the open funnel with it and establishing an extravascular Virchow-Robin Compartment (V-RC) that maintains the perforating vessel extrinsic (outside) the nervous tissue through its entire length. The V-RC is walled internally by the vascular basal lamina and externally by the basal lamina of joined glial cells endfeet. The VRC outer glial wall appear as an extension of the cortex superficial EGLM. All the perforating vessels within the V-RCs constitute the cerebral cortex extrinsic microvascular compartment. These perforating vessels are the only one capable of responding to inflammatory insults. The V-RC remains open (for life) to the meningeal interstitium permitting the exchanges of fluid and of cells between brain and meninges. The V-RC function as the brain sole drainage (prelymphatic) system in both physiological as well as pathological situations. During cortical development, capillaries emerge from the perforating vessels, by endothelial cells growing sprouts analogous to their angiogenesis, entering into their corresponding V-RCs. These new capillaries to enter into the nervous tissue must perforate through the V-RC outer glial wall, a process analogous to the original perforation of the cortex EGLM by pial capillaries. These emerging capillaries are incapable of reentering the V-RCs and/or perforating vessels. As the new capillary enters into the nervous tissue, it becomes surrounded by glial endfeet and carries a single basal lamina (possibly glial). Capillaries emerging from contiguous perforators establish an anastomotic plexus between them, by mechanisms still poorly understood. The capillaries of this anastomotic plexus constitute the cerebral cortex intrinsic microvascular compartment and together constitute the so-called blood-brain-barrier. The intrinsic capillaries are changing and readapting continuously, by both active angiogenesis and reabsorption, to the gray matter neurons developmental and functional needs. The brain intrinsic capillaries are among the most active microvessels of the human body. Unresolved developmental and functional aspects concerning the cerebral cortex intrinsic capillary plexus need to be further investigated. KEYWORDS: EGLM; endothelial cell filopodium; human brain; intracerebral microvascular system; meningeal inner pial lamella

PMID 22993505


Development of the Pulmonary Vein and the Systemic Venous Sinus: An Interactive 3D Overview

PLoS One. 2011;6(7):e22055. Epub 2011 Jul 11.

van den Berg G, Moorman AF. Source Department of Anatomy, Embryology and Physiology, Academic Medical Center, Heart Failure Research Center, Amsterdam, The Netherlands.


Knowledge of the normal formation of the heart is crucial for the understanding of cardiac pathologies and congenital malformations. The understanding of early cardiac development, however, is complicated because it is inseparably associated with other developmental processes such as embryonic folding, formation of the coelomic cavity, and vascular development. Because of this, it is necessary to integrate morphological and experimental analyses. Morphological insights, however, are limited by the difficulty in communication of complex 3D-processes. Most controversies, in consequence, result from differences in interpretation, rather than observation. An example of such a continuing debate is the development of the pulmonary vein and the systemic venous sinus, or "sinus venosus". To facilitate understanding, we present a 3D study of the developing venous pole in the chicken embryo, showing our results in a novel interactive fashion, which permits the reader to form an independent opinion. We clarify how the pulmonary vein separates from a greater vascular plexus within the splanchnic mesoderm. The systemic venous sinus, in contrast, develops at the junction between the splanchnic and somatic mesoderm. We discuss our model with respect to normal formation of the heart, congenital cardiac malformations, and the phylogeny of the venous tributaries.

PMID 21779373

Prenatal cardiovascular shunts in amniotic vertebrates

Respir Physiol Neurobiol. 2011 Apr 13. [Epub ahead of print]

Dzialowski EM, Sirsat T, van der Sterren S, Villamor E. Source Department of Biological Sciences, University of North Texas, Denton, TX 76203, USA. Abstract During amniotic vertebrate development, the embryo and fetus employ a number of cardiovascular shunts. These shunts provide a right-to-left shunt of blood and are essential components of embryonic life ensuring proper blood circulation to developing organs and fetal gas exchanger, as well as bypassing the pulmonary circuit and the unventilated, fluid filled lungs. In this review we examine and compare the embryonic shunts available for fetal mammals and embryonic reptiles, including lizards, crocodilians, and birds. These groups have either a single ductus arteriosus (mammals) or paired ductus arteriosi that provide a right-to-left shunt of right ventricular output away from the unventilated lungs. The mammalian foramen ovale and the avian atrial foramina function as a right-to-left shunt of blood between the atria. The presence of atrial shunts in non-avian reptiles is unknown. Mammals have a venous shunt, the ductus venosus that diverts umbilical venous return away from the liver and towards the inferior vena cava and foramen ovale. Reptiles do not have a ductus venosus during the latter two thirds of development. While the fetal shunts are well characterized in numerous mammalian species, much less is known about the developmental physiology of the reptilian embryonic shunts. In the last years, the reactivity and the process of closure of the ductus arteriosus have been characterized in the chicken and the emu. In contrast, much less is known about embryonic shunts in the non-avian reptiles. It is possible that the single ventricle found in lizards, snakes, and turtles and the origin of the left aorta in the crocodilians play a significant role in the right-to-left embryonic shunt in these species.

Copyright © 2011. Published by Elsevier B.V.

PMID 21513818

Fetal cardiac dimensions at 14-40 weeks' gestation obtained using cardio-STIC-M

Ultrasound Obstet Gynecol. 2011 Feb 8. doi: 10.1002/uog.8961. [Epub ahead of print]

Luewan S, Yanase Y, Tongprasert F, Srisupundit K, Tongsong T. Source Faculty of Medicine, Department of Obstetrics and Gynecology, Chiang Mai University, Chiang Mai, Thailand. Abstract OBJECTIVES: To establish normative reference ranges of fetal cardiac dimensions derived from volume datasets acquired using spatiotemporal image correlation with M-mode display (cardio-STIC-M).

METHODS: A cross-sectional study was undertaken on singleton pregnancies with normal fetuses and accurate gestational ages. Cardio-STIC volume datasets were acquired by experienced operators using a high-resolution ultrasound machine; these were maneuvered to obtain a four chamber-view with exactly horizontal interventricular septum (IVS). Cardiac dimensions were measured in STIC-M-mode using 4D View software.

RESULTS: A total of 657 measurements, at a rate of between 15 and 37 per week, were obtained. Normal reference ranges for biventricular outer diameter, left and right ventricular inner diameter, left and right ventricular wall thickness, IVS thickness, left to right ventricular diameter ratio and left and right ventricular shortening fractions were constructed based on best-fit equations as a function of gestational age, fetal head circumference and biparietal diameter. Thirty-four volume datasets of abnormal fetal hearts were also separately assessed, many of which showed abnormal cardiac dimensions.

CONCLUSIONS: This is the first report on normal ranges of fetal cardiac dimensions constructed using the new cardio-STIC-M technology. Preliminary evaluation suggests that these reference ranges may be a useful tool in the assessment of fetal cardiac abnormalities. Copyright © 2011 ISUOG. Published by John Wiley & Sons, Ltd.

Copyright © 2011 ISUOG. Published by John Wiley & Sons, Ltd.

PMID 21305637

Notch signaling regulates remodeling and vessel diameter in the extraembryonic yolk sac

BMC Dev Biol. 2011 Feb 25;11:12.

Copeland JN, Feng Y, Neradugomma NK, Fields PE, Vivian JL. Source Department of Pathology and Laboratory Medicine and Institute for Reproductive Health and Regenerative Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA.


BACKGROUND: The signaling cascades that direct the morphological differentiation of the vascular system during early embryogenesis are not well defined. Several signaling pathways, including Notch and VEGF signaling, are critical for the formation of the vasculature in the mouse. To further understand the role of Notch signaling during endothelial differentiation and the genes regulated by this pathway, both loss-of-function and gain-of-function approaches were analyzed in vivo.

RESULTS: Conditional transgenic models were used to expand and ablate Notch signaling in the early embryonic endothelium. Embryos with activated Notch1 signaling in the vasculature displayed a variety of defects, and died soon after E10.5. Most notably, the extraembryonic vasculature of the yolk sac displayed remodeling differentiation defects, with greatly enlarged lumens. These phenotypes were distinct from endothelial loss-of-function of RBPJ, a transcriptional regulator of Notch activity. Gene expression analysis of RNA isolated from the yolk sac endothelia of transgenic embryos indicated aberrant expression in a variety of genes in these models. In particular, a variety of secreted factors, including VEGF and TGF-β family members, displayed coordinate expression defects in the loss-of-function and gain-of-function models.

CONCLUSIONS: Morphological analyses of the in vivo models confirm and expand the understanding of Notch signaling in directing endothelial development, specifically in the regulation of vessel diameter in the intra- and extraembryonic vasculature. Expression analysis of these in vivo models suggests that the vascular differentiation defects may be due to the regulation of key genes through the Notch-RBPJ signaling axis. A number of these genes regulated by Notch signaling encode secreted factors, suggesting that Notch signaling may mediate remodeling and vessel diameter in the extraembryonic yolk sac via autocrine and paracrine cell communication. We propose a role for Notch signaling in elaborating the microenvironment of the nascent arteriole, suggesting novel regulatory connections between Notch signaling and other signaling pathways during endothelial differentiation.

PMID 21352545

Maternal genome-wide DNA methylation patterns and congenital heart defects

PLoS One. 2011 Jan 24;6(1):e16506.

Chowdhury S, Erickson SW, Macleod SL, Cleves MA, Hu P, Karim MA, Hobbs CA. Department of Pediatrics, College of Medicine, University of Arkansas for Medical Sciences, Arkansas Children's Hospital Research Institute, Little Rock, Arkansas, United States of America.


The majority of congenital heart defects (CHDs) are thought to result from the interaction between multiple genetic, epigenetic, environmental, and lifestyle factors. Epigenetic mechanisms are attractive targets in the study of complex diseases because they may be altered by environmental factors and dietary interventions. We conducted a population based, case-control study of genome-wide maternal DNA methylation to determine if alterations in gene-specific methylation were associated with CHDs. Using the Illumina Infinium Human Methylation27 BeadChip, we assessed maternal gene-specific methylation in over 27,000 CpG sites from DNA isolated from peripheral blood lymphocytes. Our study sample included 180 mothers with non-syndromic CHD-affected pregnancies (cases) and 187 mothers with unaffected pregnancies (controls). Using a multi-factorial statistical model, we observed differential methylation between cases and controls at multiple CpG sites, although no CpG site reached the most stringent level of genome-wide statistical significance. The majority of differentially methylated CpG sites were hypermethylated in cases and located within CpG islands. Gene Set Enrichment Analysis (GSEA) revealed that the genes of interest were enriched in multiple biological processes involved in fetal development. Associations with canonical pathways previously shown to be involved in fetal organogenesis were also observed. We present preliminary evidence that alterations in maternal DNA methylation may be associated with CHDs. Our results suggest that further studies involving maternal epigenetic patterns and CHDs are warranted. Multiple candidate processes and pathways for future study have been identified.

PMID 21297937


Three-dimensional reconstruction imaging of the human foetal heart in the first trimester

Eur Heart J. 2010 Feb;31(4):415. Epub 2009 Dec 3.

Matsui H, Mohun T, Gardiner HM. Source Institute of Reproductive and Developmental Biology, Faculty of Medicine, Imperial College, Queen Charlotte's and Chelsea Hospital, Du Cane Road, London W12 0HS, UK. PMID 19965862

An endocardial pathway involving Tbx5, Gata4, and Nos3 required for atrial septum formation

Proc Natl Acad Sci U S A. 2010 Oct 25. [Epub ahead of print]

Nadeau M, Georges RO, Laforest B, Yamak A, Lefebvre C, Beauregard J, Paradis P, Bruneau BG, Andelfinger G, Nemer M.

Research Unit in Cardiac Growth and Differentiation and Molecular Biology Program, Université de Montréal, Montréal, QC, Canada H3C 3J7.

Abstract In humans, septal defects are among the most prevalent congenital heart diseases, but their cellular and molecular origins are not fully understood. We report that transcription factor Tbx5 is present in a subpopulation of endocardial cells and that its deletion therein results in fully penetrant, dose-dependent atrial septal defects in mice. Increased apoptosis of endocardial cells lacking Tbx5, as well as neighboring TBX5-positive myocardial cells of the atrial septum through activation of endocardial NOS (Nos3), is the underlying mechanism of disease. Compound Tbx5 and Nos3 haploinsufficiency in mice worsens the cardiac phenotype. The data identify a pathway for endocardial cell survival and unravel a cell-autonomous role for Tbx5 therein. The finding that Nos3, a gene regulated by many congenital heart disease risk factors including stress and diabetes, interacts genetically with Tbx5 provides a molecular framework to understand gene-environment interaction in the setting of human birth defects.

PMID 20974940

Heart Valve Development

Transcriptional Regulation of Heart Valve Progenitor Cells

PEDIATRIC CARDIOLOGY Volume 31, Number 3, 414-421, DOI: 10.1007/s00246-009-9616-x

"The development and normal function of the heart valves requires complex interactions among signaling molecules, transcription factors and structural proteins that are tightly regulated in time and space. Here we review the roles of critical transcription factors that are required for specific aspects of normal valve development. The early progenitors of the heart valves are localized in endocardial cushions that express transcription factors characteristic of mesenchyme, including Twist1, Tbx20, Msx1 and Msx2. As the valve leaflets mature, they are composed of complex stratified extracellular matrix proteins that are regulated by the transcriptional functions of NFATc1, Sox9, and Scleraxis. Each of these factors has analogous functions in differentiation of related connective tissue lineages. Together, the precise timing and localized functions of specific transcription factors control cell proliferation, differentiation, elongation, and remodeling processes that are necessary for normal valve structure and function. In addition, there is increasing evidence that these same transcription factors contribute to congenital, as well as degenerative, valve disease."

Regulation of heart valve morphogenesis by Eph receptor ligand, ephrin-A1

Wnt signaling in heart valve development and osteogenic gene induction

Alfieri CM, Cheek J, Chakraborty S, Yutzey KE. Dev Biol. 2010 Feb 15;338(2):127-35. Epub 2009 Dec 1. PMID: 19961844

Heart valve development: regulatory networks in development and disease. Combs MD, Yutzey KE. Circ Res. 2009 Aug 28;105(5):408-21. Review. PMID 19713546

A new role for the human placenta as a hematopoietic site throughout gestation.

PMID 19208786

We investigated whether the human placenta contributes to embryonic and fetal hematopoietic development. Two cell populations--CD34(++)CD45(low) and CD34( +)CD45(low)--were found in chorionic villi. CD34(++) CD45(low) cells display many markers that are characteristic of multipotent primitive hematopoietic progenitors and hematopoietic stem cells. Clonogenic in vitro assays showed that CD34(++)CD45( low) cells contained colony-forming units-culture with myeloid and erythroid potential and differentiated into CD56(+) natural killer cells and CD19(+) B cells in culture. CD34(+)CD45(low) cells were mostly enriched in erythroid- and myeloid-committed progenitors. While the number of CD34(++)CD45(low) cells increased throughout gestation in parallel with placental mass. However, their density (cells per gram of tissue) reached its peak at 5 to 8 weeks, decreasing more than 7-fold from the ninth week onward. In addition to multipotent progenitors, the placenta contained intermediate progenitors, indicative of active hematopoiesis. Together, these data suggest that the human placenta is potentially an important hematopoietic organ, opening the possibility of banking placental hematopoietic stem cells along with cord blood for transplantation.


Human cardiac development in the first trimester: a high-resolution magnetic resonance imaging and episcopic fluorescence image capture atlas

Circulation. 2009 Jul 28;120(4):343-51. doi: 10.1161/CIRCULATIONAHA.108.796698.

Dhanantwari P1, Lee E, Krishnan A, Samtani R, Yamada S, Anderson S, Lockett E, Donofrio M, Shiota K, Leatherbury L, Lo CW.

Based on analysis of histological sections and scaled reproductions of human embryos, Grant showed a large cushion in the developing heart at 6 6/7 weeks (CS 14) and separate AV valves at 9 1/7 weeks (CS 22)2. At the end of the 8th week (CS 8), separate aortic and pulmonary outflows were observed. Orts-Llorca used three dimensional reconstructions of transverse sections of human embryos to define development of the truncus arteriosus and described completion of septation of the truncus arteriosus in 14–16mm embryos, equivalent to EGA 8 weeks (CS18)5.

cardiac development movies

PMID 19635979

Fetal aortic arch measurements at 14 to 40 weeks' gestation derived by spatiotemporal image correlation volume data sets

J Ultrasound Med. 2009 Dec;28(12):1651-6. Udomwan P, Luewan S, Tongsong T. Source Department of Obstetrics and Gynecology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand. Abstract OBJECTIVE: The purpose of this study was to establish reference ranges for the transverse aortic arch diameter (TAD) and distal aortic isthmus diameter (DAID) in normal singleton pregnancies (14-40 weeks) based on the 3-vessel/trachea (3VT) view of cardio-spatiotemporal image correlation (STIC) volume data sets.

METHODS: A prospective descriptive study was conducted on uncomplicated singleton pregnancies with healthy fetuses and an accurate gestational age (GA). Cardio-STIC examinations were performed by experienced sonographers using a high-resolution ultrasound machine, and the volume data sets were manipulated to obtain the 3VT view and measured for the TAD and DAID.

RESULTS: A total of 554 measurements were performed, ranging from 13 to 30 for each gestational week. The best regression models were as follows: TAD (in millimeters) = -1.01 + 1.69 (GA, in weeks) (r(2) = 0.93; P < .001), and DAID (in millimeters) = -0.85 + 1.54 (GA, in weeks) (r(2) = 0.92; P < .001). A table of nomograms for 5th, 50th, and 95th percentile ranges was constructed.

CONCLUSIONS: Normative data for the TAD and DAID at each gestational week from 14 to 40 weeks were constructed by a new technique of measurement based on cardio-STIC. These reference ranges may be useful tools for assessment of fetal aortic arch abnormalities.

PMID 19933478


Embryonic cardiac morphometry in Carnegie stages 15-23, from the Complutense University of Madrid Institute of Embryology Human Embryo Collection

Cells Tissues Organs. 2008;187(3):211-20. Epub 2007 Dec 5.

Arráez-Aybar LA, Turrero-Nogués A, Marantos-Gamarra DG. Source Department of Human Anatomy and Embryology II, Faculty of Medicine, University Complutense, Madrid, Spain.

Abstract AIMS: We performed a morphometric study of cardiac development on human embryos to complement the scarce data on human embryonic cardiac morphometry and to attempt to establish, from these, algorithms describing cardiac growth during the second month of gestation. METHODS: Thirty human embryos from Carnegie stages 15-23 were included in the study. Shrinkage and compression effects from fixation and inclusion in paraffin were considered in our calculations. RESULTS: Growth of the cardiac (whole heart) volume and volume of ventricular myocardium through the Carnegie stages were analysed by ANOVA. Linear correlation was used to describe the relationship between the ventricular myocardium and cardiac volumes. Comparisons of models were carried out through the R2 statistic. The relationship volume of ventricular myocardium versus cardiac volume is expressed by the equation: cardiac volume = 0.6266 + 2.4778 volume of ventricular myocardium. The relationship cardiac volume versus crown-rump length is expressed by the equation: cardiac volume = 1.3 e(0.126 CR length), where e is the base of natural logarithms. CONCLUSION: At a clinical level, these results can contribute towards the establishment of a normogram for cardiac development, useful for the design of strategies for early diagnosis of congenital heart disease. They can also help in the study of embryogenesis, for example in the discussion of ventricular trabeculation. Copyright 2007 S. Karger AG, Basel.

PMID 18057862

  • Endothelial cell lineages of the heart. Ishii Y, Langberg J, Rosborough K, Mikawa T. Cell Tissue Res. 2009 Jan;335(1):67-73. Epub 2008 Aug 6. Review. PMID: 18682987 | PMC: 2729171

Cardiac dimensions determined by cross-sectional echocardiography in the normal human fetus from 18 weeks to term

Am J Cardiol. 1992 Dec 1;70(18):1459-67.

Tan J, Silverman NH, Hoffman JI, Villegas M, Schmidt KG. Department of Pediatrics, University of California, San Francisco 94143.


Assessment of cardiac dimensions of the chambers, great arteries and veins in the human fetus is important to distinguish abnormal dimensions from normal. This study establishes normal values based on cross-sectional echocardiographic measurements over the gestational period where these measurements may be clinically useful. Ventricular and atrial dimensions were measured from the 4-chamber view, the short-axis dimension immediately below the mitral and tricuspid valve leaflets in diastole, and the long axis from the closed apposed atrioventricular valves to their respective apices. The ventricular walls and septum were measured at the level at which cavity dimensions in diastole were measured, defining both the left and right ventricular wall thickness, as well as that of the ventricular septum. Furthermore, the long axis of the right and left atria was measured from the center of the apposed atrioventricular valve leaflets to the posterior atrial wall, and the sizes of the atrial chambers were defined using their widths at the prospective broadest points through the area of foramen ovale. From a variety of views, diameters were measured at maximal expansion of the main, left and right pulmonary arteries, the ductus arteriosus, and the superior and inferior venae cavae. The data were evaluated longitudinally from 18 weeks to term, and regression analysis was performed using the best fit of a linear or polynomial equation. The data provide a means for evaluating the normal sizes and dimensions of the fetal heart chambers, as well as the thickness of the ventricular walls and septum.

PMID 1442619

The links in this next sections are to the original 2008 online notes pages for Cardiovascular System Development.

Cardiovascular Notes Introduction | Abnormalities | Stage 13/14 | Stage 22 | Stage 22 Selected Highpower | Heart | Heart Rate | BloodBlood Vessels | Molecular | Lymphatic | Text only page | WWW Links | Postnatal | History - Harvey

Cardiovascular Movies Heart Movies | Heart Looping | Atrial Septation | Realignment | Ventricular Septation | Heart Septation Models | Historic Heart Movie |

Other Cardiac and Vascular Movies Fetal Circulation (Before Birth) | Circulation (After Birth) | Aortic Branches to Glands (Kidneys only) | Aortic Branches to Glands (Gonads only)

Coronary Vessels

  • Origin, fate, and function of epicardium-derived cells (EPDCs) in normal and abnormal cardiac development.[1] Lie-Venema H, van den Akker NM, Bax NA, Winter EM, Maas S, Kekarainen T, Hoeben RC, deRuiter MC, Poelmann RE, Gittenberger-de Groot AC. ScientificWorldJournal. 2007 Nov 12;7:1777-98. Review. PMID: 18040540 | PDF full article
  • Cellular and molecular mechanisms of coronary vessel development.[2] Mu H, Ohashi R, Lin P, Yao Q, Chen C. Vasc Med. 2005 Feb;10(1):37-44. Review. PMID: 15920999

  • Development of innervation of coronary arteries in human foetus up until 230 mm. stage (mid-term). Br Heart J. 1970 Jan;32(1):108-13.

Smith RB.

PMID: 5417838

  • Innervation of the coronary vessels is initiated before the 30mm. stage of development.
  • All the main branches of the coronary arteries are formed and in their definitive positions by the 40 mm. stage.
  • Two plexuses have been shown for all the larger vessels after the 120 mm. stage.
  • There are coarse-fibre and fine-fibre plexuses, situated at different levels in the tunica adventitia.
  • Ganglion cells have been found in relation to the coronary arteries over the ventricles.
  • This confirms the part played by the vagal system in the innervation of the ventricle.
  • No nerve endings were seen in the tunica media.


  1. <pubmed>18040540</pubmed>
  2. <pubmed>15920999</pubmed>


Toxicol Pathol. 2009 Jun;37(4):395-414. Epub 2009 Apr 9. Histology atlas of the developing mouse heart with emphasis on E11.5 to E18.5. Savolainen SM, Foley JF, Elmore SA. Source NIEHS, Cellular and Molecular Pathology Branch, Research Triangle Park, North Carolina 27709, USA. Abstract In humans, congenital heart diseases are common. Since the rapid progression of transgenic technologies, the mouse has become the major animal model of defective cardiovascular development. Moreover, genetically modified mice frequently die in utero, commonly due to abnormal cardiovascular development. A variety of publications address specific developmental stages or structures of the mouse heart, but a single reference reviewing and describing the anatomy and histology of cardiac developmental events, stage by stage, has not been available. The aim of this color atlas, which demonstrates embryonic/fetal heart development, is to provide a tool for pathologists and biomedical scientists to use for detailed histological evaluation of hematoxylin and eosin (H&E)-stained sections of the developing mouse heart with emphasis on embryonic days (E) 11.5-18.5. The selected images illustrate the main structures and developmental events at each stage and serve as reference material for the confirmation of the chronological age of the embryo/early fetus and assist in the identification of any abnormalities. An extensive review of the literature covering cardiac development pre-E11.5 is summarized in the introduction. Although the focus of this atlas is on the descriptive anatomic and histological development of the normal mouse heart from E11.5 to E18.5, potential embryonic cardiac lesions are discussed with a list of the most common transgenic pre- and perinatal heart defects. Representative images of hearts at E11.5-15.5 and E18.5 are provided in Figures 2-4, 6, 8, and 9. A complete set of labeled images (Figures E11.5-18.5) is available on the CD enclosed in this issue of Toxicologic Pathology. All digital images can be viewed online at with the username "ToxPath" and the password "embryohearts."

PMID 19359541