Abstract
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-atriumm58 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.
Highlights
Ventricular trabeculation is tightly regulated by both genetic programming and biomechanical forces such as hemodynamic pressure and shear stress. [1,2,3,4,5,6,7,8] Trabeculae formation leads to a complex network of endocardial protrusions into the ventricle that form ridges and grooves. [9] During cardiac morphogenesis, the ventricular myocardium differentiates into two layers, an outer compact zone and an inner trabeculated zone
In response to chemical treatment AG1478, stroke volume (SV) increases by 48% whereas ejection fraction (EF) marginally increases by *7% compared to the wild type (Fig 5a)
We have developed a novel computational framework to quantify time-dependent hemodynamic forces in developing embryos based on 4-D light sheet imaging data
Summary
Ventricular trabeculation is tightly regulated by both genetic programming and biomechanical forces such as hemodynamic pressure and shear stress. [1,2,3,4,5,6,7,8] Trabeculae formation leads to a complex network of endocardial protrusions (trabeculae) into the ventricle that form ridges and grooves. [9] During cardiac morphogenesis, the ventricular myocardium (heart tissue) differentiates into two layers, an outer compact zone and an inner trabeculated zone. Ventricular trabeculation is tightly regulated by both genetic programming and biomechanical forces such as hemodynamic pressure and shear stress. While the genetic mechanisms underlying cardiac morphogenesis have been extensively studied, the impact of biomechanical forces such as hemodynamic shear remains elusive, due in part to the significant challenges associated with quantifying hemodynamic forces in developing hearts. [19,20,21,22,23,24,25,26] CFD has been applied to study developmental dynamics in chick embryos such as aortic arch morphogenesis, [27, 28] aortic valve and outflow tract morphogenesis, [29,30,31] and the onset of congenital heart disease such as HLHS. CFD has been widely applied to simulate blood flow, to facilitate clinical decision-making, and to study the progression of cardiovascular disease. [19,20,21,22,23,24,25,26] CFD has been applied to study developmental dynamics in chick embryos such as aortic arch morphogenesis, [27, 28] aortic valve and outflow tract morphogenesis, [29,30,31] and the onset of congenital heart disease such as HLHS. [14]
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