Shear stress is associated with markers of plaque vulnerability and MMP-9 activity

Vulnerable plaque has been associated with local macrophage accumulation and local high matrix metalloproteinase-2 (MMP-2) and MMP-9 activity. Since shear stress is a known local modulator of plaque location, we have determined whether local shear stress was associated with local plaque composition and with local MMP activity.

In 17 NZW rabbits plaque was generated by denudation of the infrarenal aorta over a region of 5 cm and feeding them a high cholesterol diet for 2 months. After 2 months, a motorised IVUS pullback of the infrarenal aorta was performed with a 40 MHz IVUS catheter (CVIS, Boston Scientific, USA). IVUS derived vessel wall-lumen contours were reconstructed in 3D with in-house developed software. These reconstructions served as an input for a computational fluid dynamics technique, from which the 3-D shear stress field was calculated. Plaque regions were divided in 5 regions (n=8) to identify the location of highest macrophage accumulation or selected on basis of shear stress to identify whether high shear stress selects macrophage accumulation (n=8). In a second series, shear stress values were used to select regions -containing both latent and active MMP-2 and MMP-9. Segments were sectioned with a microtome and stained for smooth muscle cells (SMC), macrophages (MPhi) and collagen (COL). MPhi, displayed the highest density upstream of the plaque (6.9+/-2.4%, p<0.05), while SMC accumulated downstream (74.8+/-1.9%) of the plaque. High shear stress was associated with MPhi accumulation and MMP-9 activity (p<0.05).

Upstream location of macrophages in plaques is associated with high shear stress and MMP-9 accumulation. These findings are discussed in relation to rheological theories reported previously in atherosclerosis.