An anatomically informed computational fluid dynamics modeling approach for quantifying hemodynamics in the developing heart.

Congenital heart defects occur in approximately 1% of newborns in the US annually. Currently, less than a third of congenital heart defects can be traced to a known genetic or environmental cause, suggesting that a large proportion of disease-causing mechanisms have yet to be fully characterized. Hemodynamic forces such as wall shear stress are critical for heart development and are known to induce changes in embryonic cardiac patterning leading to malformations. However, measuring these hemodynamic factors in vivo is infeasible due to physical limitations, such as the small size and constant motion of the embryonic heart. This serves as a significant barrier towards developing a mechanics-based understanding of the origins of congenital heart defects. An alternative approach is to recapitulate the hemodynamic environment by simulating blood flow and calculating the resulting hemodynamic forces through computational fluid dynamics modeling. Thus, we have developed a robust computational fluid dynamics modeling pipeline to quantify hemodynamics within cell-accurate anatomies of embryonic chick hearts. Here we describe the implementation of single plane illumination light sheet fluorescent microscopy to generate full three-dimensional reconstructions of the embryonic heart in silico, quantitative geometric morphometric methods for identifying anatomic variability across samples, and computational fluid dynamic approaches for calculating flow, pressure, and wall shear stress within complex tissue architectures. Together, these methods produce a fast, robust, and accessible system of analysis for generating high-resolution, quantitative descriptions of anatomical variability and hemodynamic forces in the embryonic heart.