Talk:Cardiovascular System - Heart Valve Development

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Cite this page: Hill, M.A. (2019, December 7) Embryology Cardiovascular System - Heart Valve Development. Retrieved from


The Trileaflet Mitral Valve

Am J Cardiol. 2018 Feb 15;121(4):513-519. doi: 10.1016/j.amjcard.2017.11.018. Epub 2017 Nov 28.

Chui J1, Anderson RH2, Lang RM3, Tsang W4.


With the advent of 3-dimensional echocardiography, visualization of the mitral valve has greatly improved. Recently, there has been an increase in reporting of a distinct entity called the "trileaflet mitral valve" using 3-dimensional echocardiography. It is controversial whether this is a new entity or an improved visualization of isolated mitral valve clefts or trifoliate left atrioventricular valve in the setting of an atrioventricular septal defect (AVSD) with intact septum. We present a case of a trifoliate valve, interpreting our findings based on a systematic review of previous publication on trileaflet mitral valves, isolated clefts in the mural (posterior) leaflet of the mitral valve, and trifoliate left atrioventricular valves with AVSD and intact septal structures. 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. PMID: 29304994 DOI: 10.1016/j.amjcard.2017.11.018

GATA4 Loss-of-Function Mutation and the Congenitally Bicuspid Aortic Valve

Am J Cardiol. 2018 Feb 15;121(4):469-474. doi: 10.1016/j.amjcard.2017.11.012. Epub 2017 Nov 23.

Li RG1, Xu YJ2, Wang J3, Liu XY4, Yuan F5, Huang RT6, Xue S6, Li L7, Liu H1, Li YJ1, Qu XK1, Shi HY1, Zhang M1, Qiu XB1, Yang YQ8.


Aggregating evidence suggests that genetic determinants play a pivotal role in the pathogenesis of the congenitally bicuspid aortic valve (BAV). BAV is of pronounced genetic heterogeneity, and the genetic components underlying BAV in an overwhelming majority of patients remain elusive. In the current study, the whole coding exons and adjacent introns, as well as 5' and 3' untranslated regions of the GATA4 gene, which codes for a zinc-finger transcription factor crucial for the normal development of the aortic valve, were screened by direct sequencing in 150 index patients with congenital BAV. The available family members of an identified mutation carrier and 300 unrelated, ethnically matched healthy individuals used as controls were also genotyped for GATA4. The functional effect of the mutation was characterized using a dual-luciferase reporter assay system. As a result, 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. Functional deciphers revealed that the mutant GATA4 protein lost transcriptional activity compared with its wild-type counterpart. Furthermore, the mutation disrupted the synergistic transcriptional activation between GATA4 and NKX2.5, another transcription factor responsible for BAV. In conclusion, this study associates the GATA4 loss-of-function mutation with enhanced susceptibility to a BAV, thus providing novel insight into the molecular mechanism underpinning the BAV. PMID: 29325903 DOI: 10.1016/j.amjcard.2017.11.012

Development and maturation of the fibrous components of the arterial roots in the mouse heart

J Anat. 2018 Apr;232(4):554-567. doi: 10.1111/joa.12713. Epub 2017 Oct 15.

Richardson R1, Eley L1, Donald-Wilson C1, Davis J1, Curley N1, Alqahtani A1, Murphy L1, Anderson RH1, Henderson DJ1, Chaudhry B1.


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. Despite the mouse being the animal model of choice for studying cardiac development, few studies have examined the structure of their arterial roots. As a consequence, our understanding of their formation and maturation is incomplete. We set out to clarify the anatomical and histological features of the mouse arterial roots, particularly focusing on their walls and the points of attachment of the valve leaflets. We then sought to determine the embryonic lineage relationships between these tissues, as a forerunner to understanding how they form and mature over time. Using histological stains and immunohistochemistry, we show that the walls of the mouse arterial roots show a gradual transition, with smooth muscle cells (SMC) forming the bulk of wall at the most distal points of attachments of the valve leaflets, while being entirely fibrous at their base. Although the interleaflet triangles lie within the ventricular chambers, we show that they are histologically indistinguishable from the arterial sinus walls until the end of gestation. Differences become apparent after birth, and are only completed by postnatal day 21. 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. KEYWORDS: aortic root; arterial wall; bicuspid aortic valve; fibrous tissue; hypoplastic left heart syndrome; interleaflet triangles; neural crest cells; second heart field; sinus; smooth muscle cells; valves

PMID: 29034473 PMCID: PMC5835783 DOI: 10.1111/joa.12713

Calcific Aortic Valve Disease: a Developmental Biology Perspective

Curr Cardiol Rep. 2018 Mar 8;20(4):21. doi: 10.1007/s11886-018-0968-9.

Dutta P1,2, Lincoln J3,4,5.


PURPOSE OF REVIEW: This review aims to highlight the past and more current literature related to the multifaceted pathogenic programs that contribute to calcific aortic valve disease (CAVD) with a focus on the contribution of developmental programs. RECENT FINDINGS: 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. This comprehensive review of the literature highlights the complex nature of CAVD but concurrently identifies key regulators that can be targeted in the development of mechanistic-based therapies beyond surgical intervention to improve patient outcome. KEYWORDS: Calcification; Cell signaling; Extracellular matrix; Heart valve; Valvulogenesis

PMID: 29520694 DOI: 10.1007/s11886-018-0968-9

Macrophage Transitions in Heart Valve Development and Myxomatous Valve Disease

Arterioscler Thromb Vasc Biol. 2018 Mar;38(3):636-644. doi: 10.1161/ATVBAHA.117.310667. Epub 2018 Jan 18.

Hulin A1, Anstine LJ1, Kim AJ1, Potter SJ1, DeFalco T1, Lincoln J1, Yutzey KE2.


OBJECTIVE: Hematopoietic-derived cells have been reported in heart valves but remain poorly characterized. Interestingly, recent studies reveal infiltration of leukocytes and increased macrophages in human myxomatous mitral valves. Nevertheless, timing and contribution of macrophages in normal valves and myxomatous valve disease are still unknown. The objective is to characterize leukocytes during postnatal heart valve maturation and identify macrophage subsets in myxomatous valve disease. APPROACH AND RESULTS: Leukocytes are detected in heart valves after birth, and their numbers increase during postnatal valve development. Flow cytometry and immunostaining analysis indicate that almost all valve leukocytes are myeloid cells, consisting of at least 2 differentially localized macrophage subsets and dendritic cells. Beginning a week after birth, increased numbers of CCR2+ (C-C chemokine receptor type 2) macrophages are present, consistent with infiltrating populations of monocytes, and macrophages are localized in regions of biomechanical stress in the valve leaflets. Valve leukocytes maintain expression of CD (cluster of differentiation) 45 and do not contribute to significant numbers of endothelial or interstitial cells. Macrophage lineages were examined in aortic and mitral valves of Axin2 KO (knockout) mice that exhibit myxomatous features. Infiltrating CCR2+ monocytes and expansion of CD206-expressing macrophages are localized in regions where modified heavy chain hyaluronan is observed in myxomatous valve leaflets. Similar colocalization of modified hyaluronan and increased numbers of macrophages were observed in human myxomatous valve disease. CONCLUSIONS: Our study demonstrates the heterogeneity of myeloid cells in heart valves and highlights an alteration of macrophage subpopulations, notably an increased presence of infiltrating CCR2+ monocytes and CD206+ macrophages, in myxomatous valve disease. © 2018 American Heart Association, Inc. KEYWORDS: animals; heart valve diseases; heart valves; leukocytes; macrophages PMID: 29348122 PMCID: PMC5823761 [Available on 2019-03-01] DOI: 10.1161/ATVBAHA.117.310667


Twist1 directly regulates genes that promote cell proliferation and migration in developing heart valves

PLoS One. 2011;6(12):e29758. Epub 2011 Dec 29.

Lee MP, Yutzey KE. Source Division of Molecular Cardiovascular Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America. Abstract 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. However, the Twist1 downstream target genes that mediate increased cell proliferation and migration during early heart valve development remain largely unknown. Candidate gene and global gene profiling approaches were used to identify transcriptional targets of Twist1 during heart valve development. Candidate target genes were analyzed for evolutionarily conserved regions (ECRs) containing E-box consensus sequences that are potential Twist1 binding sites. ECRs containing conserved E-box sequences were identified for Twist1 responsive genes Tbx20, Cdh11, Sema3C, Rab39b, and Gadd45a. Twist1 binding to these sequences in vivo was determined by chromatin immunoprecipitation (ChIP) assays, and binding was detected in ECCs but not late stage remodeling valves. In addition identified Twist1 target genes are highly expressed in ECCs and have reduced expression during heart valve remodeling in vivo, which is consistent with the expression pattern of Twist1. Together these analyses identify multiple new genes involved in cell proliferation and migration that are differentially expressed in the developing heart valves, are responsive to Twist1 transcriptional function, and contain Twist1-responsive regulatory sequences.

PMID 22242143

Reference ranges of fetal aortic and pulmonary valve diameter derived by STIC from 14 to 40 weeks of gestation

Prenat Diagn. 2011 May;31(5):439-45. doi: 10.1002/pd.2711. Epub 2011 Feb 10.

Tongprasert F, Srisupundit K, Luewan S, Sirichotiyakul S, Piyamongkol W, Wanapirak C, Tongsong T. Source Department of Obstetrics and Gynecology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.

Abstract OBJECTIVE: To develop reference ranges of fetal aortic and pulmonary valve diameter derived from volume datasets of spatio-temporal image correlation (STIC).

METHODS: A cross-sectional study was undertaken on low-risk pregnancies with well-established data from 14 to 40 weeks. Volume datasets of STIC were acquired for subsequent off-line analysis. Aortic and pulmonary valve diameters were measured in STIC multiplanar view using 4D-View version 9. Normal Z scores and centile reference ranges were constructed from these measurements against gestational age (GA) and biparietal diameter (BPD) as independent variables, using regression models for both mean and SD.

RESULTS: A total of 606 volume datasets were successfully measured. Normal reference ranges for predicting mean values and SD of aortic and pulmonary valve diameter were constructed based on best-fit equations (linear function) as follows: mean aortic diameter (mm) was modeled as a function of GA (weeks) and BPD (mm) as - 2.4838 + 0.2702× GA, (SD = 0.1482 + 0.0156× GA) and - 1.5952 + 0.0989× BPD (SD = 0.1672 + 0.00572× BPD). Mean pulmonary diameter was modeled as - 2.5924 + 0.2935× GA (SD = 0.2317 + 0.01524× GA) and - 1.6830 + 0.1083× BPD (SD = 0.1971 + 0.0059× BPD).

CONCLUSION: We have provided nomograms and Z scores of fetal aortic and pulmonary valve diameters. These reference ranges may be a useful tool in the assessment of fetal cardiac abnormalities. Copyright © 2011 John Wiley & Sons, Ltd.

Copyright © 2011 John Wiley & Sons, Ltd.

PMID 21312198

Cardiac-specific transcription factor genes Smad4 and Gata4 cooperatively regulate cardiac valve development

Proc Natl Acad Sci U S A. 2011 Mar 8;108(10):4006-11. Epub 2011 Feb 17.

Moskowitz IP, Wang J, Peterson MA, Pu WT, Mackinnon AC, Oxburgh L, Chu GC, Sarkar M, Berul C, Smoot L, Robertson EJ, Schwartz R, Seidman JG, Seidman CE.

Departments of Pediatrics and Pathology, University of Chicago, Chicago, IL 60637.

Abstract We report that the dominant human missense mutations G303E and G296S in GATA4, a cardiac-specific transcription factor gene, cause atrioventricular septal defects and valve abnormalities by disrupting a signaling cascade involved in endocardial cushion development. These GATA4 missense mutations, but not a mutation causing secundum atrial septal defects (S52F), demonstrated impaired protein interactions with SMAD4, a transcription factor required for canonical bone morphogenetic protein/transforming growth factor-β (BMP/TGF-β) signaling. Gata4 and Smad4 genetically interact in vivo: atrioventricular septal defects result from endothelial-specific Gata4 and Smad4 compound haploinsufficiency. Endothelial-specific knockout of Smad4 caused an absence of valve-forming activity: Smad4-deficient endocardium was associated with acellular endocardial cushions, absent epithelial-to-mesenchymal transformation, reduced endocardial proliferation, and loss of Id2 expression in valve-forming regions. We show that Gata4 and Smad4 cooperatively activated the Id2 promoter, that human GATA4 mutations abrogated this activity, and that Id2 deficiency in mice could cause atrioventricular septal defects. We suggest that one determinant of the phenotypic spectrum caused by human GATA4 mutations is differential effects on GATA4/SMAD4 interactions required for endocardial cushion development.

PMID 21330551

Hemodynamic patterning of the avian atrioventricular valve

Dev Dyn. 2011 Jan;240(1):23-35.

Yalcin HC, Shekhar A, McQuinn TC, Butcher JT.

Department of Biomedical Engineering, Cornell University, Ithaca, New York 14853-7501, USA.

Abstract 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. These results establish a quantitative baseline supporting future hemodynamic analyses and interpretations.

© 2010 Wiley-Liss, Inc.

PMID 21181939


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

Noonan syndrome cardiac defects are caused by PTPN11 acting in endocardium to enhance endocardial-mesenchymal transformation

Araki T, Chan G, Newbigging S, Morikawa L, Bronson RT, Neel BG. Proc Natl Acad Sci U S A. 2009 Mar 24;106(12):4736-41. Epub 2009 Feb 27. PMID: 19251646


Shared gene expression profiles in developing heart valves and osteoblast progenitor cells

Physiol Genomics. 2008 Sep 17;35(1):75-85. Epub 2008 Jul 8.

Chakraborty S, Cheek J, Sakthivel B, Aronow BJ, Yutzey KE.

Division of Molecular Cardiovascular Biology, Cincinnati Children's Medical Center, Cincinnati, Ohio 45229, USA. Abstract The atrioventricular (AV) valves of the heart develop from undifferentiated mesenchymal endocardial cushions, which later mature into stratified valves with diversified extracellular matrix (ECM). Because the mature valves express genes associated with osteogenesis and exhibit disease-associated calcification, we hypothesized the existence of shared regulatory pathways active in developing AV valves and in bone progenitor cells. To define gene regulatory programs of valvulogenesis relative to osteoblast progenitors, we undertook Affymetrix gene expression profiling analysis of murine embryonic day (E)12.5 AV endocardial cushions compared with E17.5 AV valves (mitral and tricuspid) and with preosteoblast MC3T3-E1 (subclone4) cells. Overall, MC3T3 cells were significantly more similar to E17.5 valves than to E12.5 cushions, supporting the hypothesis that valve maturation involves the expression of many genes also expressed in osteoblasts. Several transcription factors characteristic of mesenchymal and osteoblast precursor cells, including Twist1, are predominant in E12.5 cushion. Valve maturation is characterized by differential regulation of matrix metalloproteinases and their inhibitors as well as complex collagen gene expression. Among the most highly enriched genes during valvulogenesis were members of the small leucine-rich proteoglycan (SLRP) family including Asporin, a known negative regulator of osteoblast differentiation and mineralization. Together, these data support shared gene expression profiles of the developing valves and osteoblast bone precursor cells in normal valve development and homeostasis with potential functions in calcific valve disease.

PMID: 18612084


Valvulogenesis: the moving target

Philos Trans R Soc Lond B Biol Sci. 2007 Aug 29;362(1484):1489-503.

Butcher JT, Markwald RR.

Department of Biomedical Engineering, 270 Olin Hall, Cornell University, Ithaca, NY 14853, USA. Abstract Valvulogenesis is an extremely complex process by which a fragile gelatinous matrix is populated and remodelled during embryonic development into thin fibrous leaflets capable of maintaining unidirectional flow over a lifetime. This process occurs during exposure to constantly changing haemodynamic forces, with a success rate of approximately 99%. Defective valvulogenesis results in impaired cardiac function and lifelong complications. This review integrates what is known about the roles of genetics and mechanics in the development of valves and how changes in either result in impaired morphogenesis. It is hoped that appropriate developmental cues and phenotypic endpoints could help engineers and clinicians in their efforts to regenerate living valve alternatives.

PMID: 17569640

Signal transduction in early heart development (II): ventricular chamber specification, trabeculation, and heart valve formation

Exp Biol Med (Maywood). 2007 Jul;232(7):866-80.

Wagner M, Siddiqui MA.

Department of Anatomy and Cell Biology, State University of New York Downstate Medical Center, 450 Clarkson Avenue, Brooklyn, NY 11203. Abstract The formation of a four-chambered heart with ventricular chambers aligned in a left-right orientation begins with the rightward looping of the linear heart tube in accordance with the left-right embryonic axis. The functional specification of the ventricular chambers in the looped heart occurs with the formation of a trabeculated myocardium along the outer curvature of the realigned heart tube. Two major signal transduction pathways are involved in this process, the retinoic acid and neuregulin signaling pathways, with the retinoic acid pathway also participating in rightward heart tube looping. With the establishment of the atrial and ventricular chambers, maintenance of a unidirectional flow of blood between the two chambers must be ensured. To achieve this, heart valves develop at the atrioventricular juncture. This process begins with formation of endocardial cushions, the primordia of heart valves, and ends with formation of heart valve leaflets. Underlying this process is a complex network of signal transduction pathways that mediate communication between the endocardial and myocardial cell layers to form the endocardial cushions and nascent heart valve. Some of the signaling molecules involved are vascular endothelial growth factor, Wnts, bone morphogenetic proteins, epidermal growth factor, hyaluronic acid, neurofibromin, and calcium.

PMID: 17609502