Biomechanics and Modeling in Mechanobiology

, Volume 18, Issue 4, pp 1123–1137 | Cite as

Fluid dynamics and forces in the HH25 avian embryonic outflow tract

  • Sheldon Ho
  • Wei Xuan Chan
  • Shreyas Rajesh
  • Nhan Phan-Thien
  • Choon Hwai YapEmail author
Original Paper


The embryonic outflow tract (OFT) eventually undergoes aorticopulmonary septation to form the aorta and pulmonary artery, and it is hypothesized that blood flow mechanical forces guide this process. We performed detailed studies of the geometry, wall motions, and fluid dynamics of the HH25 chick embryonic OFT just before septation, using noninvasive 4D high-frequency ultrasound and computational flow simulations. The OFT exhibited expansion and contraction waves propagating from proximal to distal end, with periods of luminal collapse at locations of the two endocardial cushions. This, combined with periods of reversed flow, resulted in the OFT cushions experiencing wall shear stresses (WSS or flow drag forces) with elevated oscillatory characteristics, which could be important to signal for further development of cushions into valves and septum. Furthermore, the OFT exhibits interesting double-helical flow during systole, where a pair of helical flow structures twisted about each other from the proximal to distal end. This coincided with the location of the future aorticopulmonary septum, which also twisted from the proximal to distal end, suggesting that this flow pattern may be guiding OFT septation.


Embryonic outflow tract Computational fluid dynamics Oscillatory wall shear stresses Embryonic ultrasound imaging Double-helical flow Outflow tract septation 



This study was supported by the National University of Singapore 2015 Young Investigator Award (PI: Yap), entitled “Fluid Mechanics and Mechanobiology of Congenital Cardiac Outflow Tract Malformations.”

Compliance with ethical standards

Conflict of interest

All authors have no conflict of interest to declare.

Supplementary material

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Supplementary material 4 (AVI 4688 kb)


  1. Al Naieb S, Happel CM, Yelbuz TM (2013) A detailed atlas of chick heart development in vivo. Ann Anat 195:324–341. CrossRefGoogle Scholar
  2. Al-Roubaie S, Jahnsen ED, Mohammed M, Henderson-Toth C, Jones EA (2011) Rheology of embryonic avian blood. Am J Physiol Heart Circ Physiol 301:H2473–H2481. CrossRefGoogle Scholar
  3. Antiga L, Piccinelli M, Botti L, Ene-Iordache B, Remuzzi A, Steinman DA (2008) An image-based modeling framework for patient-specific computational hemodynamics. Med Biol Eng Compu 46:1097–1112CrossRefGoogle Scholar
  4. Bajolle F, Zaffran S, Kelly RG, Hadchouel J, Bonnet D, Brown NA, Buckingham ME (2006) Rotation of the myocardial wall of the outflow tract is implicated in the normal positioning of the great arteries. Circ Res 98:421CrossRefGoogle Scholar
  5. Barakat AI, Lieu DK (2003) Differential responsiveness of vascular endothelial cells to different types of fluid mechanical shear stress. Cell Biochem Biophys 38:323–343. CrossRefGoogle Scholar
  6. Bartman T et al (2004) Early myocardial function affects endocardial cushion development in zebrafish. PLoS Biol 2:e129. CrossRefGoogle Scholar
  7. Bernal M, Nenadic I, Urban MW, Greenleaf JF (2011) Material property estimation for tubes and arteries using ultrasound radiation force and analysis of propagating modes. J Acoust Soc Am 129:1344–1354. CrossRefGoogle Scholar
  8. Bharadwaj KN, Spitz C, Shekhar A, Yalcin HC, Butcher JT (2012) Computational fluid dynamics of developing avian outflow tract heart valves. Ann Biomed Eng 40:2212–2227. CrossRefGoogle Scholar
  9. Biechler SV et al (2014) The impact of flow-induced forces on the morphogenesis of the outflow tract. Front Physiol 5:225. CrossRefGoogle Scholar
  10. Butcher JT, McQuinn TC, Sedmera D, Turner D, Markwald RR (2007) Transitions in early embryonic atrioventricular valvular function correspond with changes in cushion biomechanics that are predictable by tissue composition. Circ Res 100:1503–1511CrossRefGoogle Scholar
  11. Carmo MPd (1976) Differential geometry of curves and surfaces. Prentice Hall, Englewood CliffszbMATHGoogle Scholar
  12. Craelius W, Chen V, El-Sherif N (1988) Stretch activated ion channels in ventricular myocytes. Biosci Rep 8:407CrossRefGoogle Scholar
  13. Dewey JCF, Bussolari SR, Gimbrone JMA, Davies PF (1981) The dynamic response of vascular endothelial cells to fluid shear stress. J Biomech Eng 103:177–185. CrossRefGoogle Scholar
  14. Goenezen S, Chivukula VK, Midgett M, Phan L, Rugonyi S (2016) 4D subject-specific inverse modeling of the chick embryonic heart outflow tract hemodynamics. Biomech Model Mechanobiol 15:723–743CrossRefGoogle Scholar
  15. Groenendijk BC, Hierck BP, Gittenberger-De Groot AC, Poelmann RE (2004) Development-related changes in the expression of shear stress responsive genes KLF-2, ET-1, and NOS-3 in the developing cardiovascular system of chicken embryos. Dev Dyn 230:57–68. CrossRefGoogle Scholar
  16. Heckel E, Boselli F, Roth S, Krudewig A, Belting H-G, Charvin G, Vermot J (2015) Oscillatory flow modulates mechanosensitive klf2a expression through trpv4 and trpp2 during heart valve development. Curr Biol 25:1354–1361CrossRefGoogle Scholar
  17. Ho S, Tan GXY, Foo TJ, Phan-Thien N, Yap CH (2017) Organ dynamics and fluid dynamics of the HH25 chick embryonic cardiac ventricle as revealed by a novel 4D high-frequency ultrasound imaging technique and computational flow simulations. Ann Biomed Eng. Google Scholar
  18. Hoffman JIE, Kaplan S (2002) The incidence of congenital heart disease. J Am Coll Cardiol 39:1890–1900. CrossRefGoogle Scholar
  19. Hogers B, DeRuiter MC, Baasten AM, Gittenberger-de Groot AC, Poelmann RE (1995) Intracardiac blood flow patterns related to the yolk sac circulation of the chick embryo. Circ Res 76:871–877CrossRefGoogle Scholar
  20. Hove JR, Koster RW, Forouhar AS, Acevedo-Bolton G, Fraser SE, Gharib M (2003) Intracardiac fluid forces are an essential epigenetic factor for embryonic cardiogenesis. Nature 421:172–177. CrossRefGoogle Scholar
  21. Hu N, Christensen DA, Agrawal AK, Beaumont C, Clark EB, Hawkins JA (2009) Dependence of aortic arch morphogenesis on intracardiac blood flow in the left atrial ligated chick embryo. Anat Rec (Hoboken) 292:652–660. CrossRefGoogle Scholar
  22. Keller BB, Hu N, Serrino PJ, Clark EB (1991) Ventricular pressure-area loop characteristics in the stage 16 to 24 chick embryo. Circ Res 68:226CrossRefGoogle Scholar
  23. Kowalski WJ, Teslovich NC, Menon PG, Tinney JP, Keller BB, Pekkan K (2014) Left atrial ligation alters intracardiac flow patterns and the biomechanical landscape in the chick embryo. Dev Dyn 243:652–662. CrossRefGoogle Scholar
  24. Ku DN, Giddens DP, Zarins CK, Glagov S (1985) Pulsatile flow and atherosclerosis in the human carotid bifurcation. Positive correlation between plaque location and low oscillating shear stress. Arterioscler Thromb Vasc Biol 5:293–302Google Scholar
  25. Lai CQ, Lim GL, Jamil M, Mattar CNZ, Biswas A, Yap CH (2016) Fluid mechanics of blood flow in human fetal left ventricles based on patient-specific 4D ultrasound scans. Biomech Model Mechanobiol 15:1159. CrossRefGoogle Scholar
  26. Li Y-SJ, Haga JH, Chien S (2005) Molecular basis of the effects of shear stress on vascular endothelial cells. J Biomech 38:1949–1971. CrossRefGoogle Scholar
  27. Liu A et al (2011a) Quantifying blood flow and wall shear stresses in the outflow tract of chick embryonic hearts. Comput Struct 89:855–867. CrossRefGoogle Scholar
  28. Liu A et al (2011b) Quantifying blood flow and wall shear stresses in the outflow tract of chick embryonic hearts. Comput Struct 89:855–867CrossRefGoogle Scholar
  29. Liu A, Yin X, Shi L, Li P, Thornburg KL, Wang R, Rugonyi S (2012) Biomechanics of the chick embryonic heart outflow tract at HH18 using 4D optical coherence tomography imaging and computational modeling. PLoS ONE 7:e40869. CrossRefGoogle Scholar
  30. Lucitti JL, Tobita K, Keller BB (2005) Arterial hemodynamics and mechanical properties after circulatory intervention in the chick embryo. J Exp Biol 208:1877–1885. CrossRefGoogle Scholar
  31. Menon V, Eberth JF, Goodwin RL, Potts JD (2015) Altered hemodynamics in the embryonic heart affects outflow valve development. J Cardiovasc Dev Dis 2:108–124. CrossRefGoogle Scholar
  32. Midgett M, Rugonyi S (2014) Congenital heart malformations induced by hemodynamic altering surgical interventions. Front Physiol 5:287. CrossRefGoogle Scholar
  33. Midgett M, Goenezen S, Rugonyi S (2014) Blood flow dynamics reflect degree of outflow tract banding in Hamburger-Hamilton stage 18 chicken embryos. J R Soc Interface 11:20140643CrossRefGoogle Scholar
  34. Midgett M, Chivukula VK, Dorn C, Wallace S, Rugonyi S (2015) Blood flow through the embryonic heart outflow tract during cardiac looping in HH13–HH18 chicken embryos. J R Soc Interface 12:20150652CrossRefGoogle Scholar
  35. Midgett M, López CS, David L, Maloyan A, Rugonyi S (2017) Increased hemodynamic load in early embryonic stages alters endocardial to mesenchymal transition. Front Physiol 8:56. Google Scholar
  36. Nakajima Y, Hiruma T, Nakazawa M, Morishima M (1998) Hypoplasia of cushion ridges in the proximal outflow tract elicits formation of a right ventricle-to-aortic route in retinoic acid-induced complete transposition of the great arteries in the mouse: scanning electron microscopic observations of corrosion cast models. Anat Rec 245:76–82.;2-6 CrossRefGoogle Scholar
  37. Nomura-Kitabayashi A et al (2009) Outflow tract cushions perform a critical valve-like function in the early embryonic heart requiring BMPRIA-mediated signaling in cardiac neural crest. Am J Physiol Heart Circ Physiol 297:H1617–H1628CrossRefGoogle Scholar
  38. Olesen S-P, Claphamt D, Davies P (1988) Haemodynamic shear stress activates a K + current in vascular endothelial cells. Nature 331:168–170CrossRefGoogle Scholar
  39. Pasipoularides A, Murgo JP, Miller JW, Craig WE (1987) Nonobstructive left ventricular ejection pressure gradients in man. Circ Res 61:220–227CrossRefGoogle Scholar
  40. Peiffer V, Sherwin SJ, Weinberg PD (2013) Does low and oscillatory wall shear stress correlate spatially with early atherosclerosis? A systematic review. Cardiovasc Res 99:242–250CrossRefGoogle Scholar
  41. Qayyum SR, Webb S, Anderson RH, Verbeek FJ, Brown NA, Richardson MK (2001) Septation and valvar formation in the outflow tract of the embryonic chick heart. Anat Rec 264:273–283CrossRefGoogle Scholar
  42. Rugonyi S, Shaut C, Liu A, Thornburg K, Wang RK (2008) Changes in wall motion and blood flow in the outflow tract of chick embryonic hearts observed with optical coherence tomography after outflow tract banding and vitelline-vein ligation. Phys Med Biol 53:5077–5091. CrossRefGoogle Scholar
  43. Sadoshima J, Takahashi T, Jahn L, Izumo S (1992) Roles of mechano-sensitive ion channels, cytoskeleton, and contractile activity in stretch-induced immediate-early gene expression and hypertrophy of cardiac myocytes. Proc Natl Acad Sci 89:9905–9909CrossRefGoogle Scholar
  44. Sedmera D, Pexieder T, Rychterova V, Hu N, Clark EB (1999) Remodeling of chick embryonic ventricular myoarchitecture under experimentally changed loading conditions. Anat Rec 254:238–252CrossRefGoogle Scholar
  45. Tan GXY, Jamil M, Tee NGZ, Zhong L, Yap CH (2015) 3D reconstruction of chick embryo vascular geometries using non-invasive high-frequency ultrasound for computational fluid dynamics studies. Ann Biomed Eng 43:2780. CrossRefGoogle Scholar
  46. Tobita K, Keller BB (2000) Right and left ventricular wall deformation patterns in normal and left heart hypoplasia chick embryos. Am J Physiol Heart Circ Physiol 279:H959CrossRefGoogle Scholar
  47. Tobita K, Schroder EA, Tinney JP, Garrison JB, Keller BB (2002) Regional passive ventricular stress-strain relations during development of altered loads in chick embryo. Am J Physiol Heart Circ Physiol 282(6):H2386–H2396CrossRefGoogle Scholar
  48. Tobita K, Garrison JB, Liu LJ, Tinney JP, Keller BB (2005) Three-dimensional myofiber architecture of the embryonic left ventricle during normal development and altered mechanical loads. Anat Rec A Discov Mol Cell Evol Biol 283:193–201. CrossRefGoogle Scholar
  49. Vappou J, Luo J, Konofagou EE (2010) Pulse wave imaging for noninvasive and quantitative measurement of arterial stiffness in vivo. Am J Hypertens 23:393–398. CrossRefGoogle Scholar
  50. Vedula V, Lee J, Xu H, Kuo C-CJ, Hsiai TK, Marsden AL (2017) A method to quantify mechanobiologic forces during zebrafish cardiac development using 4-D light sheet imaging and computational modeling. PLoS Comput Biol 13:e1005828CrossRefGoogle Scholar
  51. Vermot J, Forouhar AS, Liebling M, Wu D, Plummer D, Gharib M, Fraser SE (2009) Reversing blood flows act through klf2a to ensure normal valvulogenesis in the developing heart. PLoS Biol 7:e1000246. CrossRefGoogle Scholar
  52. Wang Y, Dur O, Patrick MJ, Tinney JP, Tobita K, Keller BB, Pekkan K (2009) Aortic arch morphogenesis and flow modeling in the chick embryo. Ann Biomed Eng 37:1069–1081CrossRefGoogle Scholar
  53. Webb S, Qayyum SR, Anderson RH, Lamers WH, Richardson MK (2003) Septation and separation within the outflow tract of the developing heart. J Anat 202:327–342. CrossRefGoogle Scholar
  54. Wiputra H et al (2017) Peristaltic-like motion of the human fetal right ventricle and its effects on fluid dynamics and energy dynamics. Ann Biomed Eng 45:2335. CrossRefGoogle Scholar
  55. Wiputra H et al (2016) Fluid mechanics of human fetal right ventricles from image-based computational fluid dynamics using 4D clinical ultrasound scans. Am J Physiol Heart Circ Physiol. Google Scholar
  56. Ya J, van den Hoff MJB, de Boer PAJ, Tesink-Taekema S, Franco D, Moorman AFM, Lamers WH (1998) Normal development of the outflow tract in the rat. Circ Res 82:464CrossRefGoogle Scholar
  57. Yang Q, Chen H, Correa A, Devine O, Mathews TJ, Honein MA (2006) Racial differences in infant mortality attributable to birth defects in the United States, 1989–2002. Birth Defects Res A Clin Mol Teratol 76:706–713. CrossRefGoogle Scholar
  58. Yap CH, Liu X, Pekkan K (2014) Characterizaton of the vessel geometry, flow mechanics and wall shear stress in the great arteries of wildtype prenatal mouse. PLoS ONE 9:e86878CrossRefGoogle Scholar
  59. Yoshida H, Manasek F, Arcilla RA (1983) Intracardiac flow patterns in early embryonic life: a reexamination. Circ Res 53:363–371CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Biomedical EngineeringNational University of SingaporeSingaporeSingapore
  2. 2.Department of Mechanical EngineeringNational University of SingaporeSingaporeSingapore

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