A method to quantify mechanobiologic forces during zebrafish cardiac development using 4-D light sheet imaging and computational modeling

<div><p>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 <i>ErbB2</i> signaling inhibitor that inhibits proliferation and differentiation of cardiac trabeculation; (b) injection of <i>gata1a morpholino oligomer</i> (<i>gata1aMO</i>) suppressing hematopoiesis and resulting in attenuated trabeculation; (c) <i>weak-atrium</i>^<i>m</i>58 mutant (<i>wea</i>) 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 <i>gata1aMO</i> and <i>wea</i>. 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.</p>