Growth and hemodynamics after early embryonic aortic arch occlusion

Abstract

The majority of severe clinically significant forms of congenital heart disease (CHD) is associated with great artery lesions, including hypoplastic, double, right or interrupted aortic arch morphologies. While fetal and neonatal interventions are advancing, their potential ability to restore cardiac function, optimal timing, location, and intensity required for intervention remain largely unknown. We here combine computational fluid dynamics (CFD) simulations with in vivo experiments to test how individual pharyngeal arch artery hemodynamics alters as a result of local interventions to obstruct individual arch artery flow. Simulated isolated occlusions within each pharyngeal arch artery were created with image derived three-dimensional (3D) reconstructions of normal chick pharyngeal arch anatomy at Hamburger-Hamilton (HH) developmental stages HH18 and HH24. Acute flow redistributions were then computed using in vivo measured subject-specific aortic sinus inflow velocity profiles. A kinematic vascular growth-rendering algorithm was then developed and implemented to test the role of changing local wall shear stress patterns in downstream 3D morphogenesis of arch arteries. CFD simulations predicted that altered pressure gradients and flow redistributions were most sensitive to occlusion of the IVth arches. To evaluate these simulations experimentally, a novel in vivo experimental model of pharyngeal arch occlusion was developed and implemented using two-photon microscopy guided femtosecond laser based photodisruption surgery. The right IVth arch was occluded at HH18, and resulting diameter changes were followed for up to 24 hours. Pharyngeal arch diameter responses to acute hemodynamic changes were predicted qualitatively but poorly quantitatively. Chronic growth and adaptation to hemodynamic changes however were predicted in a subset of arches. Our findings suggest that this complex biodynamic process is governed through more complex forms of mechanobiological vascular growth rules. Other factors in addition to wall shear stress, or more complex WSS rules are likely important in the long-term arterial growth and patterning. Combination in-silico/experimental platforms are essential for accelerating our understanding and prediction of consequences from embryonic/fetal cardiovascular occlusions, and lay the foundation for non-invasive methods to guide CHD diagnosis and fetal intervention.

Heart function and hemodynamic analysis for zebrafish embryos

“…Embryonic chick model has been used widely for this purpose. Our group and others have documented characteristics of evolving hemodynamics environment for cardiogenesis of this species (Wang et al, 2009;Yalcin et al, 2011;Bharadwaj et al, 2012;Lindsey et al, 2015). Zebrafish is another animal model that commonly used for cardiovascular research.…”

Reduced embryonic blood flow impacts extracellular matrix deposition in the maturing aorta

“…Additional Supporting Information may be found in the online version of this article. *Correspondence to: Jessica E. Wagenseil It is well known that arteries adapt their lumen diameters to regulate wall shear stress (Zarins et al, 1987), especially in developmental processes, such as aortic arch patterning (Lindsey et al, 2015). Yet few have investigated how hemodynamic perturbations affect vascular maturation.…”

Computational modeling and engineering in pediatric and congenital heart disease

“…[97] CFD simulations were also used, together with an experimental platform, to quantify changes in pressure and flow distribution in the fetal circulation using a chick model of aortic arch obstruction. [98]…”