Growth and hemodynamics after early embryonic aortic arch occlusion

The majority of severe clinically significant forms of congenital heart disease (CHD) are 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. Here, we combine computational fluid dynamics (CFD) simulations with in vivo experiments to test how individual pharyngeal arch artery hemodynamics alter as a result of local interventions obstructing 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 h. 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 noninvasive methods to guide CHD diagnosis and fetal intervention.