Computational Fluid Dynamics of Stenotic Carotid Arteries in Mice with Sickle Cell Disease

Introduction: Sickle cell disease (SCD) is a homozygous recessive genetic blood disorder. People living with SCD have red blood cells that become stiffened and crescent-shaped due to polymerization of hemoglobin into fibers upon deoxygenation. Children with SCD have abnormally higher rates of strokes, of which the main clinical marker for increased stroke risk is elevated velocities of 200 cm/s or higher in the cerebral arteries with underlying mechanisms not fully understood. Previous studies have shown that SCD contributes to arterial remodeling in large arteries including the cerebral vasculature. We hypothesize that arterial remodeling in the carotid artery leads to disturbed blood flow and elevated velocities, contributing to an increased risk of stroke. The usage of the Townes humanized sickle cell transgenic mouse model has also provided novel insights to the biomechanics and pathophysiology of strokes in SCD. High-resolution imaging allows for the visualization of blood movement, which can be used to reconstruct arteries into 3-dimensional models and simulated to observe how different arterial geometries affect hemodynamics. Specifically, blood flow velocities and wall shear stress (WSS) values can inform areas in the carotid artery that are at risk for arterial remodeling. We show through these simulations that sickle cell (SS) genotype arteries have greater amounts of flow recirculation with oscillatory shear stress and greater areas of low WSS, especially in post-stenotic regions of artery dilation. Finally, we show that SS arteries have increased flow velocity and greater velocity variance in the carotid artery.

Materials and

Methods: To investigate how arterial remodeling leads to regions of disturbed flow and elevated velocities, we used magnetic resonance angiography (MRA) to image the Townes humanized sickle cell transgenic mouse models of wild-type (AA), sickle-trait (AS), and sickle cell (SS) genotypes at 1, 3, and 5 months of age. We then used Materialise Mimics to reconstruct the MRA data into 3-dimensional finite element mesh models of the common carotid artery and its bifurcations to the occipital artery, external carotid artery, and internal carotid artery. These models were then smoothed and re-meshed to include vessel wall boundary layers before being simulated with SimVascular using computational fluid dynamics (CFD) under steady-state, no-slip boundary conditions, which were then further analyzed to obtain blood flow velocities and wall shear stress (WSS) values. Using ParaView, velocity streamlines were visualized to show regions of flow recirculation in the carotid artery during diastole. By using time-averaged WSS, the oscillatory shear index (OSI) was calculated to characterize the amount of blood flow disturbance throughout the cardiac cycle. Arterial geometries were also analyzed to observe the effects of cross-sectional area and tortuosity on hemodynamics.

Results, Conclusions, and Discussions: Using 3-dimensional reconstructions, we identified areas of stenosis in transgenic sickle cell (SS) mice by taking cross-sectional area and diameter measurements throughout each artery (Fig. 1A). Then, using CFD, streamlines were visualized to include velocity direction, which showed that post-stenotic regions (Fig. 1B, 1C) had flow recirculation at low velocities less than 10 cm/s. We also visualized time-averaged WSS, which showed that post-stenotic regions had low WSS, defined as less than 5 dyne/cm2 (Fig. 1D). The calculated OSI showed that the post-stenotic regions had the highest amount of flow recirculation throughout the cardiac cycle, which is the degree of derivation of WSS direction (Fig. 1E). These results were performed for both the left and right carotid arteries, and compared to AA (n=10), AS (n=11), and SS (n=8) genotypes at 1, 3, and 5 months of age. Lastly, preliminary results show that SS mice had a much greater variance in velocities at the common carotid artery, when compared to AA and AS mice (Fig. 1F), which is thought to be explained by the variance in arterial geometries.

Taken together, the usage of CFD and the Townes transgenic mouse model showed how SCD mediates differences in arterial geometry, indicated by stenotic regions with higher velocities and post-stenotic regions with flow recirculation. These flow disturbances impact the arterial wall by creating regions of low WSS, along with areas of WSS reversal and oscillation throughout the cardiac cycle that induce arterial remodeling programs in the resident vascular cells that may accelerate damage and increase risk of stroke.

Acknowledgements (Optional): National Institutes of Biomedical Imaging and Bioengineering (NIBIB), Section on Mechanics and Tissue Remodeling Integrating Computational & Experimental Systems (MATRICES) and Center for Biomedical Engineering Technology Acceleration (BETA). Walter H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University.