Increased Regurgitant Flow Causes Endocardial Cushion Defects in an Avian Embryonic Model of Congenital Heart Disease

Overview

Journal Congenit Heart Dis

Specialty Cardiology & Vascular Diseases

Date 2017 Feb 18

PMID 28211263

Citations 21

Authors

Stephanie M Ford

Matthew T McPheeters

Yves T Wang

Pei Ma

Shi Gu

James Strainic

Christopher Snyder

Andrew M Rollins

Michiko Watanabe

Michael W Jenkins

Affiliations

Soon will be listed here.

Abstract

Background: The relationship between changes in endocardial cushion and resultant congenital heart diseases (CHD) has yet to be established. It has been shown that increased regurgitant flow early in embryonic heart development leads to endocardial cushion defects, but it remains unclear how abnormal endocardial cushions during the looping stages might affect the fully septated heart. The goal of this study was to reproducibly alter blood flow in vivo and then quantify the resultant effects on morphology of endocardial cushions in the looping heart and on CHDs in the septated heart.

Methods: Optical pacing was applied to create regurgitant flow in embryonic hearts, and optical coherence tomography (OCT) was utilized to quantify regurgitation and morphology. Embryonic quail hearts were optically paced at 3 Hz (180 bpm, well above intrinsic rate 60-110 bpm) at stage 13 of development (3-4 weeks human) for 5 min. Pacing fatigued the heart and led to at least 1 h of increased regurgitant flow. Resultant morphological changes were quantified with OCT imaging at stage 19 (cardiac looping-4-5 weeks human) or stage 35 (4 chambered heart-8 weeks human).

Results: All paced embryos imaged at stage 19 displayed structural changes in cardiac cushions. The amount of regurgitant flow immediately after pacing was inversely correlated with cardiac cushion size 24-h post pacing (P value < .01). The embryos with the most regurgitant flow and smallest cushions after pacing had a decreased survival rate at 8 days (P < .05), indicating that those most severe endocardial cushion defects were lethal. Of the embryos that survived to stage 35, 17/18 exhibited CHDs including valve defects, ventricular septal defects, hypoplastic ventricles, and common AV canal.

Conclusion: The data illustrate a strong inverse relationship in which regurgitant flow precedes abnormal and smaller cardiac cushions, resulting in the development of CHDs.

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References

Lucitti J, Visconti R, Novak J, Keller B . Increased arterial load alters aortic structural and functional properties during embryogenesis. Am J Physiol Heart Circ Physiol. 2006; 291(4):H1919-26. DOI: 10.1152/ajpheart.01061.2005. View

Wells J, Kao C, Jansen E, Konrad P, Mahadevan-Jansen A . Application of infrared light for in vivo neural stimulation. J Biomed Opt. 2006; 10(6):064003. DOI: 10.1117/1.2121772. View

Hamburger V, HAMILTON H . A series of normal stages in the development of the chick embryo. J Morphol. 2014; 88(1):49-92. View

Jenkins M, Wang Y, Doughman Y, Watanabe M, Cheng Y, Rollins A . Optical pacing of the adult rabbit heart. Biomed Opt Express. 2013; 4(9):1626-35. PMC: 3771833. DOI: 10.1364/BOE.4.001626. View

Wikenheiser J, Wolfram J, Gargesha M, Yang K, Karunamuni G, Wilson D . Altered hypoxia-inducible factor-1 alpha expression levels correlate with coronary vessel anomalies. Dev Dyn. 2009; 238(10):2688-700. PMC: 3724469. DOI: 10.1002/dvdy.22089. View

Lloyd-Jones D, Adams R, Brown T, Carnethon M, Dai S, de Simone G . Executive summary: heart disease and stroke statistics--2010 update: a report from the American Heart Association. Circulation. 2010; 121(7):948-54. DOI: 10.1161/CIRCULATIONAHA.109.192666. View

Sparrow D, Chapman G, Smith A, Mattar M, Major J, OReilly V . A mechanism for gene-environment interaction in the etiology of congenital scoliosis. Cell. 2012; 149(2):295-306. DOI: 10.1016/j.cell.2012.02.054. View

Midgett M, Goenezen S, Rugonyi S . Blood flow dynamics reflect degree of outflow tract banding in Hamburger-Hamilton stage 18 chicken embryos. J R Soc Interface. 2014; 11(100):20140643. PMC: 4191090. DOI: 10.1098/rsif.2014.0643. View

Pierpont M, Basson C, Benson Jr D, Gelb B, Giglia T, Goldmuntz E . Genetic basis for congenital heart defects: current knowledge: a scientific statement from the American Heart Association Congenital Cardiac Defects Committee, Council on Cardiovascular Disease in the Young: endorsed by the American Academy of.... Circulation. 2007; 115(23):3015-38. DOI: 10.1161/CIRCULATIONAHA.106.183056. View

10.

Wang Y, Gu S, Ma P, Watanabe M, Rollins A, Jenkins M . Optical stimulation enables paced electrophysiological studies in embryonic hearts. Biomed Opt Express. 2014; 5(4):1000-13. PMC: 3985989. DOI: 10.1364/BOE.5.001000. View

11.

Karunamuni G, Gu S, Doughman Y, Peterson L, Mai K, McHale Q . Ethanol exposure alters early cardiac function in the looping heart: a mechanism for congenital heart defects?. Am J Physiol Heart Circ Physiol. 2013; 306(3):H414-21. PMC: 3920145. DOI: 10.1152/ajpheart.00600.2013. View

12.

Hove J, Koster R, Forouhar A, Acevedo-Bolton G, Fraser S, Gharib M . Intracardiac fluid forces are an essential epigenetic factor for embryonic cardiogenesis. Nature. 2003; 421(6919):172-7. DOI: 10.1038/nature01282. View

13.

Jenkins M, Watanabe M, Rollins A . Longitudinal Imaging of Heart Development With Optical Coherence Tomography. IEEE J Sel Top Quantum Electron. 2015; 18(3):1166-1175. PMC: 4520323. DOI: 10.1109/JSTQE.2011.2166060. View

14.

Yashiro K, Shiratori H, Hamada H . Haemodynamics determined by a genetic programme govern asymmetric development of the aortic arch. Nature. 2007; 450(7167):285-8. DOI: 10.1038/nature06254. View

15.

Peterson L, Jenkins M, Gu S, Barwick L, Watanabe M, Rollins A . 4D shear stress maps of the developing heart using Doppler optical coherence tomography. Biomed Opt Express. 2012; 3(11):3022-32. PMC: 3493225. DOI: 10.1364/BOE.3.003022. View

16.

Liu Y, Guo L, Tian Z, Zhu W, Yu B, Zhang S . A retrospective study of congenital scoliosis and associated cardiac and intraspinal abnormities in a Chinese population. Eur Spine J. 2011; 20(12):2111-4. PMC: 3229744. DOI: 10.1007/s00586-011-1818-2. View

17.

Huang D, Swanson E, Lin C, Schuman J, Stinson W, Chang W . Optical coherence tomography. Science. 1991; 254(5035):1178-81. PMC: 4638169. DOI: 10.1126/science.1957169. View

18.

Larina I, Sudheendran N, Ghosn M, Jiang J, Cable A, Larin K . Live imaging of blood flow in mammalian embryos using Doppler swept-source optical coherence tomography. J Biomed Opt. 2009; 13(6):060506. DOI: 10.1117/1.3046716. View

19.

Serrano M, Han M, Brinez P, Linask K . Fetal alcohol syndrome: cardiac birth defects in mice and prevention with folate. Am J Obstet Gynecol. 2010; 203(1):75.e7-75.e15. DOI: 10.1016/j.ajog.2010.03.017. View

20.

Vermot J, Forouhar A, Liebling M, Wu D, Plummer D, Gharib M . Reversing blood flows act through klf2a to ensure normal valvulogenesis in the developing heart. PLoS Biol. 2009; 7(11):e1000246. PMC: 2773122. DOI: 10.1371/journal.pbio.1000246. View