Influence of shear stress magnitude and direction on atherosclerotic plaque composition

Abstract

The precise flow characteristics that promote different atherosclerotic plaque types remain unclear. We previously developed a blood flow-modifying cuff for ApoE−/− mice that induces the development of advanced plaques with vulnerable and stable features upstream and downstream of the cuff, respectively. Herein, we sought to test the hypothesis that changes in flow magnitude promote formation of the upstream (vulnerable) plaque, whereas altered flow direction is important for development of the downstream (stable) plaque. We instrumented ApoE−/− mice (n = 7) with a cuff around the left carotid artery and imaged them with micro-CT (39.6 µm resolution) eight to nine weeks after cuff placement. Computational fluid dynamics was then performed to compute six metrics that describe different aspects of atherogenic flow in terms of wall shear stress magnitude and/or direction. In a subset of four imaged animals, we performed histology to confirm the presence of advanced plaques and measure plaque length in each segment. Relative to the control artery, the region upstream of the cuff exhibited changes in shear stress magnitude only (p < 0.05), whereas the region downstream of the cuff exhibited changes in shear stress magnitude and direction (p < 0.05). These data suggest that shear stress magnitude contributes to the formation of advanced plaques with a vulnerable phenotype, whereas variations in both magnitude and direction promote the formation of plaques with stable features.

Temporal and spatial changes in wall shear stress during atherosclerotic plaque progression in mice

“…These differences in disease progression rate were not related to the initial degree of stenosis at week 5 or plaque size observed at week 9. Immediately after cast placement, flow reduction of 23.3 ± 19.8% was observed in the RCCA, comparable with previously reported values [ 33 , 37 ]. During plaque progression, as stenotic degree increased over time, blood flow in the RCCA decreased gradually from week 5 to 9.…”

“…Since the distance to the proximal edge of the cast was known (0.5 mm), we could pinpoint it as our second landmark. The average longitudinal shrinkage was 51% ± 20%, comparable to that reported previously [ 37 ]. On the three-dimensional WSS maps, location of the cast was identified from the micro-CT images.…”

“…To obtain the time-averaged WSS, we can use steady flow simulations, using the average flow through the vessel as input [ 44 ]. In previous studies, it was demonstrated that other time-dependent WSS-derived parameters such as oscillatory shear index (OSI) are not relevant due to the geometry and flow conditions in this model [ 37 , 40 ], unlike in other vascular territories [ 45 , 46 ]. Furthermore, we assumed the WSS values are not influenced by the distensibility of the vessel wall.…”

“…We previously summarized the use of surgically manipulated flow models [ 38 ] and found that WSS distribution was studied only in some of these models and usually not taking full three-dimensional vessel geometry into account [ 34 , 36 , 39 ], while calculation of WSS critically depends on detailed vessel geometry and blood flow velocity [ 40 ]. In a previous cross-sectional study, using a tapered cast model [ 33 ], Pedrigi et al [ 37 ] discovered that certain WSS metrics co-localized to the presence of a plaque with increased Oil Red O-lipid staining. However, quantitative analysis of plaque composition was not performed in this study and thus spatial correlations between WSS metrics and plaque composition could not be studied.…”

Association of Coronary Wall Shear Stress With Atheromatous Plaque Vulnerability: A Systematic Review

“…In an experimental study on ApoE-/mice, in whom a cuff was placed around the carotid artery, regions located upstream of the cuff exhibited significant changes in ESS whereas segments located in the downstream area of the cuff exhibited changes in both ESS and direction [36]. Exposure of endothelial cells to low ESS lead to cell missalignement, allowing penetration by inflammatory mediators [37,38,39].…”