Blood flow and mechanical forces in the ventricle are implicated in cardiac development and trabeculation. However, the mechanisms of mechanotransduction remain elusive. This is due in part to the challenges associated with accurately quantifying mechanical forces in the developing heart. We present a novel computational framework to simulate cardiac hemodynamics in developing zebrafish embryos by coupling 4-D light sheet imaging with a stabilized finite element flow solver, and extract time-dependent mechanical stimuli data. We employ deformable image registration methods to segment the motion of the ventricle from high resolution 4-D light sheet image data. This results in a robust and efficient workflow, as segmentation need only be performed at one cardiac phase, while wall position in the other cardiac phases is found by image registration. Ventricular hemodynamics are then quantified by numerically solving the Navier-Stokes equations in the moving wall domain with our validated flow solver. We demonstrate the applicability of the workflow in wild type zebrafish and three treated fish types that disrupt trabeculation: (a) chemical treatment using AG1478, an ErbB2 signaling inhibitor that inhibits proliferation and differentiation of cardiac trabeculation; (b) injection of gata1a morpholino oligomer ( gata1aMO) suppressing hematopoiesis and resulting in attenuated trabeculation; (c) weak-atrium m58 mutant ( wea) with inhibited atrial contraction leading to a highly undeveloped ventricle and poor cardiac function. Our simulations reveal elevated wall shear stress (WSS) in wild type and AG1478 compared to gata1aMO and wea. High oscillatory shear index (OSI) in the grooves between trabeculae, compared to lower values on the ridges, in the wild type suggest oscillatory forces as a possible regulatory mechanism of cardiac trabeculation development. The framework has broad applicability for future cardiac developmental studies focused on quantitatively investigating the role of hemodynamic forces and mechanotransduction during morphogenesis.
We present a novel computational workflow for quantifying hemodynamic forces in developing zebrafish embryos by coupling high resolution 4-D light sheet imaging with a moving domain blood flow solver. Our framework employs deformable image registration to extract the motion of the ventricle from high resolution image data. This produces a robust and efficient workflow, as segmentation is performed at only one cardiac phase, while the wall position in other cardiac phases is found from the displacement field obtained during image registration. This approach avoids a laborious process of manual segmentation in all cardiac phases, and minimizes spurious errors arising from manual processing. Our validated flow solver is optimized for cardiac hemodynamics with backflow stabilization, efficient data management and dynamic remeshing algorithms for moving domains. We demonstrate the utility of the framework in wild type zebrafish and three treated variants in which the formation of cardiac trabeculations is disrupted. In this study, we then quantify the relationship between oscillatory shear forces and the presence or absence of ventricular trabeculation during cardiac development. Our framework has broad applicability in cardiac developmental studies focused on quantitatively investigating the mechanobiology during morphogenesis.