Cohort-based multiscale analysis of hemodynamic-driven growth and remodeling of the embryonic pharyngeal arch arteries

Abstract

Growth and remodeling of the primitive pharyngeal arch artery (PAA) network into the extracardiac great vessels is poorly understood but a major source of clinically serious malformations. Undisrupted blood flow is required for normal PAA development, yet specific relationships between hemodynamics and remodeling remain largely unknown. Meeting this challenge is hindered by the common reductionist analysis of morphology to single idealized models, where in fact structural morphology varies substantially. Quantitative technical tools that allow tracking of morphological and hemodynamic changes in a population-based setting are essential to advancing our understanding of morphogenesis. Here, we have developed a methodological pipeline from high-resolution nano-computed tomography imaging and live-imaging flow measurements to multiscale pulsatile computational models. We combine experimentalbased computational models of multiple PAAs to quantify hemodynamic forces in the rapidly morphing Hamburger Hamilton (HH) stage HH18, HH24 and HH26 embryos. We identify local morphological variation along the PAAs and their association with specific hemodynamic changes. Population-level mechanomorphogenic variability analysis is a powerful strategy for identifying stage-specific regions of well and poorly tolerated morphological and/or hemodynamic variation that may protect or initiate cardiovascular malformations.

Experimental-based Computational Modeling Distinguishes Early Cardiac Outflow Tract Compensation Mechanisms

“…Occlusion experiments were purposely performed on HH18 embryos and selected to have a narrow (nascent) PAA IV vessel in order to facilitate vessel occlusion. Although PAA IVR was small (~30 µm in diameter) at time of occlusion(HH18), by HH24 it carries approximately 22% of flow exiting the heart [17].…”

“…Though our group has previously studied the effects of arch artery occlusion on HH18 and HH24 embryos [3], the experimental results were not considered in 3D, which allows for a more thorough investigation of pathologies [36]. In our 2018 study we detailed morphological and hemodynamic changes in control HH18 HH24 and HH26 embryos [17]. In light of this work we can quantify the deviation from normal exhibited in HH24 embryos, upon HH18 vessel occlusion.…”

“…In light of this work we can quantify the deviation from normal exhibited in HH24 embryos, upon HH18 vessel occlusion. Using our experimental occlusion pipeline (Figure 3 the individual arches as previously described [17].…”

“…Embryo-specific 3D geometries of HH24 PAAs were generated from experimental occlusion geometries by importing nano-CT images into MIMICS (Materialise, Louvain, Belgium) and 3MATICs (Materialise, Louvain, Belgium), as outlined in [17]. Geomagics Studio 10 (Geomagic Inc., Durham, NC) was also used for the preparation of 3D geometries for CFD.…”

“…Another major limitation in determining causality for cardiac malformations is an inability to create, study or identify what likely begins as a subtle abnormality before propagating into clinically serious malformations. For this reason, we characterized normal PAA development in a cohort-based study that identified a range of normal development in Hamburger Hamilton (HH) staged 18, 24, and 26 embryos, taking into account morphological and hemodynamic parameters and determining a relationship between the two [17]. In this study, we examine the effects of vessel occlusion on PAA development as a biological model for outflow tract malformations resulting from abnormal PAA development.…”