Cardiovascular System - Heart Valve Development

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Human embryo heart right atrio-ventricular valve (stage 22)
Human embryo heart valve (stage 22)

The heart valves form between the atria and ventricles (mitral valve, tricuspid valve) and between the atria and blood vessels (aortic valve, pulmonary valve). The cardiac cushions in the atrioventricular (AV) canal contain cells that are the primordia of the cardiac valves. The atrioventricular valves are attached to papillary muscles by chordae tendineae.

Scleraxis (SCX) is a transcription factor involved in tendon and ligament development and has been identified as also expressed in early heart valve development.[1]

Mitral valve also called the "bicuspid valve".

Cardiac Tutorial: Intermediate - Heart Valves | Advanced - Valve Development

Cardiovascular Links: cardiovascular | Heart Tutorial | Lecture - Early Vascular | Lecture - Heart | Movies | 2016 Cardiac Review | heart | coronary circulation | heart valve | heart rate | Circulation | blood | blood vessel | blood vessel histology | heart histology | Lymphatic | ductus venosus | spleen | Stage 22 | cardiovascular abnormalities | OMIM | 2012 ECHO Meeting | Category:Cardiovascular
Historic Embryology - Cardiovascular 
1902 Vena cava inferior | 1905 Brain Blood Vessels | 1909 Cervical Veins | 1909 Dorsal aorta and umbilical veins | 1912 Heart | 1912 Human Heart | 1914 Earliest Blood-Vessels | 1915 Congenital Cardiac Disease | 1915 Dura Venous Sinuses | 1916 Blood cell origin | 1916 Pars Membranacea Septi | 1919 Lower Limb Arteries | 1921 Human Brain Vascular | 1921 Spleen | 1922 Aortic-Arch System | 1922 Pig Forelimb Arteries | 1922 Chicken Pulmonary | 1923 Head Subcutaneous Plexus | 1923 Ductus Venosus | 1925 Venous Development | 1927 Stage 11 Heart | 1928 Heart Blood Flow | 1935 Aorta | 1935 Venous valves | 1938 Pars Membranacea Septi | 1938 Foramen Ovale | 1939 Atrio-Ventricular Valves | 1940 Vena cava inferior | 1940 Early Hematopoiesis | 1941 Blood Formation | 1942 Truncus and Conus Partitioning | Ziegler Heart Models | 1951 Heart Movie | 1954 Week 9 Heart | 1957 Cranial venous system | 1959 Brain Arterial Anastomoses | Historic Embryology Papers | 2012 ECHO Meeting | 2016 Cardiac Review | Historic Disclaimer

Some Recent Findings

  • The Trileaflet Mitral Valve[2] "With the advent of 3-dimensional echocardiography, visualization of the mitral valve has greatly improved. ... We describe the latter entity as a left atrioventricular valve because it never achieves the features of a normal mitral valve. We compare the features of isolated clefts of the mural leaflet of the mitral valve with trifoliate left atrioventricular valve found in the setting of AVSDs with intact septal structures to illustrate the current controversy regarding these conditions. In conclusion, our review suggested the reported trileaflet left atrioventricular valves is likely a misnomer because of a lack of consideration of embryologic development and nomenclature, rather than a greater appreciation and identification of a new distinct disease entity."
  • Development and maturation of the fibrous components of the arterial roots in the mouse heart[3] "The arterial roots are important transitional regions of the heart, connecting the intrapericardial components of the aortic and pulmonary trunks with their ventricular outlets. They house the arterial (semilunar) valves and, in the case of the aorta, are the points of coronary arterial attachment. Moreover, because of the semilunar attachments of the valve leaflets, the arterial roots span the anatomic ventriculo-arterial junction. By virtue of this arrangement, the interleaflet triangles, despite being fibrous, are found on the ventricular aspect of the root and located within the left ventricular cavity. Malformations and diseases of the aortic root are common and serious. ...Using Cre-lox-based lineage tracing technology to label progenitor populations, we show that the SMC and fibrous tissue within the walls of the mature arterial roots share a common origin from the second heart field (SHF) and exclude trans-differentiation of myocardium as a source for the interleaflet triangle fibrous tissues. Moreover, we show that the attachment points of the leaflets to the walls, like the leaflets themselves, are derived from the outflow cushions, having contributions from both SHF-derived endothelial cells and neural crest cells. Our data thus show that the arterial roots in the mouse heart are similar to the features described in the human heart. They provide a framework for understanding complex lesions and diseases affecting the aortic root." Mouse Development
  • Review - Calcific Aortic Valve Disease: a Developmental Biology Perspective[4] "Calcification of the aortic valve is an active process characterized by calcific nodule formation on the aortic surface leading to a less supple and more stiffened cusp, thereby limiting movement and causing clinical stenosis. The mechanisms underlying these pathogenic changes are largely unknown, but emerging studies have suggested that signaling pathways common to valvulogenesis and bone development play significant roles and include Transforming Growth Factor-β (TGF-β), bone morphogenetic protein (BMP), Wnt, Notch, and Sox9."
  • Twist1 directly regulates genes that promote cell proliferation and migration in developing heart valves[5] "Twist1, a basic helix-loop-helix transcription factor, is expressed in mesenchymal precursor populations during embryogenesis and in metastatic cancer cells. In the developing heart, Twist1 is highly expressed in endocardial cushion (ECC) valve mesenchymal cells and is down regulated during valve differentiation and remodeling. Previous studies demonstrated that Twist1 promotes cell proliferation, migration, and expression of primitive extracellular matrix (ECM) molecules in ECC mesenchymal cells. Furthermore, Twist1 expression is induced in human pediatric and adult diseased heart valves." OMIM - TWIST1
  • Hemodynamic patterning of the avian atrioventricular valve[6] "In this study, we develop an innovative approach to rigorously quantify the evolving hemodynamic environment of the atrioventricular (AV) canal of avian embryos. Ultrasound generated velocity profiles were imported into Micro-Computed Tomography generated anatomically precise cardiac geometries between Hamburger-Hamilton (HH) stages 17 and 30. Computational fluid dynamic simulations were then conducted and iterated until results mimicked in vivo observations. Blood flow in tubular hearts (HH17) was laminar with parallel streamlines, but strong vortices developed simultaneous with expansion of the cushions and septal walls. For all investigated stages, highest wall shear stresses (WSS) are localized to AV canal valve-forming regions. Peak WSS increased from 19.34 dynes/cm(2) at HH17 to 287.18 dynes/cm(2) at HH30, but spatiotemporally averaged WSS became 3.62 dynes/cm(2) for HH17 to 9.11 dynes/cm(2) for HH30. Hemodynamic changes often preceded and correlated with morphological changes." Chicken Development
More recent papers  
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Search term: Heart Valve Embryology

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


  • Human Embryology (2nd ed.) Larson Ch7 p151-188 Heart
  • The Developing Human: Clinically Oriented Embryology (6th ed.) Moore and Persaud Ch14: p304-349
  • Before we Are Born (5th ed.) Moore and Persaud Ch12; p241-254
  • Essentials of Human Embryology Larson Ch7 p97-122 Heart
  • Human Embryology Fitzgerald and Fitzgerald Ch13-17: p77-111

Tutorial Images

Cardiac Tutorial: Intermediate - Heart Valves | Advanced - Valve Development

Fetal Heart Valve Sounds

<html5media height="50" width="400">File:Week17 fetal heart rate.mp3</html5media>

Audio recording of the Second Trimester fetal heart (GA week 17).

The characteristic "lub-dup" sounds are associated with closing of heart valves.
  • First sound (lub) occurs as atrioventricular valves close and signifies beginning of systole (contraction)
  • Second sound (dup) occurs when semilunar valves close at the beginning of ventricular diastole (relaxation)
Links: Fetal Heart Sounds Audio


Scleraxis (Scx) - basic helix–loop–helix transcription factor expressed in the progenitors and cells of all tendon tissues (mouse).[7]

Periostin - regulates lineage commitment of valve precursor cells (chicken).[8]

Gata4 and Gata6


Factor Links: AMH | hCG | BMP | sonic hedgehog | bHLH | HOX | FGF | FOX | Hippo | LIM | Nanog | NGF | Nodal | Notch | PAX | retinoic acid | SIX | Slit2/Robo1 | SOX | TBX | TGF-beta | VEGF | WNT | Category:Molecular


Noonan syndrome

An autosomal dominant single-gene cause of congenital heart disease. Patients also have proportionate short stature, facial abnormalities, and an increased risk of myeloproliferative disease. About half the patients have mutations in PTPN11, encoding the protein tyrosine phosphatase SHP2. A recent study in mice has identified PTPN11 acting in endocardium to enhance endocardial-mesenchymal transformation.[9]

Bicuspid Aortic Valve

GATA4 and NKX2.5 genes have been identified associated with this disorder.

A recent genetic screening study of GATA4 in 150 patients with bicuspid aortic valve (BAV)[10] identified a novel heterozygous GATA4 mutation, p.E147X, was identified in a family with BAV transmitted in an autosomal dominant pattern. The nonsense mutation was absent in 600 control chromosomes. The mutation disrupted the synergistic transcriptional activation between GATA4 and NKX2.5, another transcription factor responsible for BAV.

  • GATA4 - (8p23.1) transcription factors that control gene expression and differentiation in a variety of cell types. Family of DNA-binding proteins recognize a consensus sequence known as the "GATA" motif, important cis-element in the promoters of many genes.
  • NKX2-5 - (5q35.1) Homeobox-containing gene expressed only in the heart.
Links: OMIM - GATA4 | OMIM - NKX2.5

Calcific Aortic Valve Disease

Calcification of the aortic valve shows calcific nodule formation on the aortic surface, leading to a less supple and more stiffened cusp, limiting movement and causing clinical stenosis.[4]

Pathogenic mechanism is unknown but may involve signaling pathways common to valvulogenesis and bone development:

  • Transforming Growth Factor-β (TGF-β)
  • bone morphogenetic protein (BMP)
  • Wnt
  • Notch
  • Sox9

Factor Links: AMH | hCG | BMP | sonic hedgehog | bHLH | HOX | FGF | FOX | Hippo | LIM | Nanog | NGF | Nodal | Notch | PAX | retinoic acid | SIX | Slit2/Robo1 | SOX | TBX | TGF-beta | VEGF | WNT | Category:Molecular



Historic Disclaimer - information about historic embryology pages 
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Pages where the terms "Historic" (textbooks, papers, people, recommendations) appear on this site, and sections within pages where this disclaimer appears, indicate that the content and scientific understanding are specific to the time of publication. This means that while some scientific descriptions are still accurate, the terminology and interpretation of the developmental mechanisms reflect the understanding at the time of original publication and those of the preceding periods, these terms, interpretations and recommendations may not reflect our current scientific understanding.     (More? Embryology History | Historic Embryology Papers)

Odgers PNB. The development of the atrio-ventricular valves in man. (1939) J Anat. 73: 643-57. PMID 17104787


  1. Barnette DN, VandeKopple M, Wu Y, Willoughby DA & Lincoln J. (2014). RNA-seq analysis to identify novel roles of scleraxis during embryonic mouse heart valve remodeling. PLoS ONE , 9, e101425. PMID: 24983472 DOI.
  2. Chui J, Anderson RH, Lang RM & Tsang W. (2018). The Trileaflet Mitral Valve. Am. J. Cardiol. , 121, 513-519. PMID: 29304994 DOI.
  3. Richardson R, Eley L, Donald-Wilson C, Davis J, Curley N, Alqahtani A, Murphy L, Anderson RH, Henderson DJ & Chaudhry B. (2018). Development and maturation of the fibrous components of the arterial roots in the mouse heart. J. Anat. , 232, 554-567. PMID: 29034473 DOI.
  4. 4.0 4.1 Dutta P & Lincoln J. (2018). Calcific Aortic Valve Disease: a Developmental Biology Perspective. Curr Cardiol Rep , 20, 21. PMID: 29520694 DOI.
  5. Lee MP & Yutzey KE. (2011). Twist1 directly regulates genes that promote cell proliferation and migration in developing heart valves. PLoS ONE , 6, e29758. PMID: 22242143 DOI.
  6. Yalcin HC, Shekhar A, McQuinn TC & Butcher JT. (2011). Hemodynamic patterning of the avian atrioventricular valve. Dev. Dyn. , 240, 23-35. PMID: 21181939 DOI.
  7. Levay AK, Peacock JD, Lu Y, Koch M, Hinton RB, Kadler KE & Lincoln J. (2008). Scleraxis is required for cell lineage differentiation and extracellular matrix remodeling during murine heart valve formation in vivo. Circ. Res. , 103, 948-56. PMID: 18802027 DOI.
  8. Norris RA, Potts JD, Yost MJ, Junor L, Brooks T, Tan H, Hoffman S, Hart MM, Kern MJ, Damon B, Markwald RR & Goodwin RL. (2009). Periostin promotes a fibroblastic lineage pathway in atrioventricular valve progenitor cells. Dev. Dyn. , 238, 1052-63. PMID: 19334280 DOI.
  9. Araki T, Chan G, Newbigging S, Morikawa L, Bronson RT & Neel BG. (2009). Noonan syndrome cardiac defects are caused by PTPN11 acting in endocardium to enhance endocardial-mesenchymal transformation. Proc. Natl. Acad. Sci. U.S.A. , 106, 4736-41. PMID: 19251646 DOI.
  10. Li RG, Xu YJ, Wang J, Liu XY, Yuan F, Huang RT, Xue S, Li L, Liu H, Li YJ, Qu XK, Shi HY, Zhang M, Qiu XB & Yang YQ. (2018). GATA4 Loss-of-Function Mutation and the Congenitally Bicuspid Aortic Valve. Am. J. Cardiol. , 121, 469-474. PMID: 29325903 DOI.


Hinton RB & Yutzey KE. (2011). Heart valve structure and function in development and disease. Annu. Rev. Physiol. , 73, 29-46. PMID: 20809794 DOI.

Markwald RR, Norris RA, Moreno-Rodriguez R & Levine RA. (2010). Developmental basis of adult cardiovascular diseases: valvular heart diseases. Ann. N. Y. Acad. Sci. , 1188, 177-83. PMID: 20201901 DOI.

Délot EC. (2003). Control of endocardial cushion and cardiac valve maturation by BMP signaling pathways. Mol. Genet. Metab. , 80, 27-35. PMID: 14567955

Barnett JV & Desgrosellier JS. (2003). Early events in valvulogenesis: a signaling perspective. Birth Defects Res. C Embryo Today , 69, 58-72. PMID: 12768658 DOI.


van den Berg G, Somi S, Buffing AA, Moorman AF & van den Hoff MJ. (2007). Patterns of expression of the Follistatin and Follistatin-like1 genes during chicken heart development: a potential role in valvulogenesis and late heart muscle cell formation. Anat Rec (Hoboken) , 290, 783-7. PMID: 17549728 DOI.

Rivera-Feliciano J, Lee KH, Kong SW, Rajagopal S, Ma Q, Springer Z, Izumo S, Tabin CJ & Pu WT. (2006). Development of heart valves requires Gata4 expression in endothelial-derived cells. Development , 133, 3607-18. PMID: 16914500 DOI.

Odgers PN. (1939). The development of the atrio-ventricular valves in man. J. Anat. , 73, 643-57. PMID: 17104787

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