Integrating Volumetric Light-Field with Computational Fluid Dynamics to Study Myocardial Trabeculation and Function

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ABSTRACT Integrating Volumetric Light-Field with Computational Fluid Dynamics to Study Myocardial Trabeculation and Function Non-compaction cardiomyopathy (NCC) is a disease of endomyocardial trabeculation or known as spongy myocardium. NCC carries a high risk of malignant arrhythmias, thromboembolic events, and ventricular dysfunction in association with congenital heart defects or skeletal myopathy. Studies have linked left ventricular non-compaction with autosomal dominant inherited disorders, and mutations in Notch pathways are implicated in defective trabeculation and ventricular NCC. Biomechanical force is intimately connected with mechanotransduction and cardiac morphogenesis. During development, the myocardium differentiates into an outer compact zone and an inner trabeculated zone. Notch receptor- ligand interaction induces EphrinB2-Nrg-ErbB2 signaling to initiate trabecular formation. Our in silico analysis (Alison Marsden, Stanford) revealed elevated oscillatory shear index (OSI) in trabecular ridges, leading to increased viscous dissipation, which was associated with changes in ventricular contractile function and remodeling. However, uncoupling myocardial contraction from intracardiac flow dynamics to elucidate Notch-mediated trabecular organization and subsequent associated changes in local hemodynamics remains an unmet biomechanical challenge. In this context, we hypothesize that hemodynamic shear and myocardial contractile forces coordinate trabecular organization needed to preserve the ventricular structure and contractile efficiency. In combination of laser light-sheet and light- field for super resolution and volumetric imaging, we simultaneously captured myocardial contraction and intracardiac flow dynamics. In collaboration with Stanford Cardiac Mechanics, we integrated fluid structure interaction (FSI) with super resolution imaging to demonstrate 4-D endocardial shear stress in the trabecular ridges and grooves as possible developmental modulator. To test our hypothesis, we propose three specific aims. In Aim 1, we will demonstrate that intracardiac shear stress activates endocardial Delta-Notch signaling to promote trabecular ridge formation. In Aim 2, we will demonstrate that ventricular contraction activates myocardial Jagged-Notch signaling to organize trabecular groove formation. In Aim 3, we will demonstrate that the combination of trabecular ridge and groove formation leads to optimal local hemodynamics and ventricular energetics. The integration of advanced imaging, fluid structure interaction, and zebrafish genetics is uniquely suitable to unveil trabecular organization in relation to kinetic energy dissipation. Our multi-disciplinary approach provides new biomechanical insights into non-compaction cardiomyopathy with pathophysiological significance to ventricular remodeling and function.