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Assessing Early Cardiac Outflow Tract Adaptive Responses Through Combined Experimental-Computational Manipulations

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Abstract

Mechanical forces are essential for proper growth and remodeling of the primitive pharyngeal arch arteries (PAAs) into the great vessels of the heart. Despite general acknowledgement of a hemodynamic-malformation link, the direct correlation between hemodynamics and PAA morphogenesis remains poorly understood. The elusiveness is largely due to difficulty in performing isolated hemodynamic perturbations and quantifying changes in-vivo. Previous in-vivo arch artery occlusion/ablation experiments either did not isolate the effects of hemodynamics, did not analyze the results in a 3D context or did not consider the effects of varying degrees of occlusion. Here, we overcome these limitations by combining minimally invasive occlusion experiments in the avian embryo with 3D anatomical models of development and in-silico testing of experimental phenomenon. We detail morphological and hemodynamic changes 24 hours post vessel occlusion. 3D anatomical models showed that occlusion geometries had more circular cross-sectional areas and more elongated arches than their control counterparts. Computational fluid dynamics revealed a marked change in wall shear stress-morphology trends. Instantaneous (in-silico) occlusion models provided mechanistic insights into the dynamic vessel adaptation process, predicting pressure-area trends for a number of experimental occlusion arches. We follow the propagation of small defects in a single embryo Hamburger Hamilton (HH) Stage 18 embryo to a more serious defect in an HH29 embryo. Results demonstrate that hemodynamic perturbation of the presumptive aortic arch, through varying degrees of vessel occlusion, overrides natural growth mechanisms and prevents it from becoming the dominant arch of the aorta.

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Acknowledgments

We thank the Cornell BRC imaging facility and Randolph Linderman (reconstructions). This work was funded by NSF GRFP, NSF GROW, an Alfred P. Sloan Foundation fellowship, CMMI-1635712, an Inria International Internship grant and by the National Institutes of Health (HL110328, S10OD012287 and S10OD016191).

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The authors have no disclosures.

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Author notes

  1. Stephanie E. Lindsey

    Present address: Department of Mechanical and Aerospace Engineering, University of California, San Diego, La Jolla, CA, 92093, USA

  2. This collaborative study is accomplished by joint corresponding senior authors (Irene E. Vignon-Clementel and Jonathan T. Butcher).

Authors and Affiliations

  1. Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, 304 Weill Hall, Ithaca, NY, 14853-7202, USA

    Stephanie E. Lindsey & Jonathan T. Butcher

  2. Centre de Recherche Inria de Saclay-IDF, rue Honoré d’Estienne d’Orves, 91120, Palaiseau, France

    Irene E. Vignon-Clementel

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  1. Stephanie E. Lindsey
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Correspondence to Irene E. Vignon-Clementel or Jonathan T. Butcher.

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Associate Editor Stefan M. Duma oversaw the review of this article.

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Lindsey, S.E., Vignon-Clementel, I.E. & Butcher, J.T. Assessing Early Cardiac Outflow Tract Adaptive Responses Through Combined Experimental-Computational Manipulations. Ann Biomed Eng 49, 3227–3242 (2021). https://doi.org/10.1007/s10439-021-02802-2

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