The effects of extremely low shear stress on cellular proliferation and neointimal thickening in the failing bypass graft

Abstract

Objective: Previous studies demonstrating a correlation between low shear stress (τ = 5-15 dyne/cm2) and experimental vein graft neointimal thickening (NIT) support the role of low τ in vein graft failure. However, a simple linear relationship between low t and NIT would underestimate the degree of NIT evident in high-grade occlusive lesions of failing human vein grafts. In this study we used a new experimental model that maintains patency at low τ (< 2 dyne/cm2), to delineate possible deviations from linearity in the low τ → NIT hypothesis. Methods: Thirty-two New Zealand White rabbits underwent creation of a common carotid vein patch with a segment of ipsilateral external jugular vein. Very low τ was created in 13 patches by ligation of the distal common carotid artery, leaving the only outflow through a small muscular branch. Normal τ was created hi 11 patches by leaving the common carotid artery outflow intact. High τ was created in eight patches by ligation of the contralateral common carotid artery. Six patches were harvested after 2 weeks for measurement of cell cycle entry by proliferating cell nuclear antigen (PCNA) immunohistochemistry. The remaining 26 patches were harvested after 4 weeks, perfusion fixed, and excised for morphometric analysis. Results: Mean blood flow and τ at implantation ranged from 0.5 to 41 mL/min and 0.07 to 15 dyne/cm2, respectively. At the time of harvest, 30 of 32 patches remained patent, and the artificially created aberrations in blood flow were maintained (range, 0.7-41 mL/min). After 2 weeks PCNA immunohistochemistry showed a significantly higher level of cell cycling in patches exposed to low τ (40 ± 5 vs 1.6 ± 0.3 PCNA-positive cells per high-power field; P < .001), which is equivalent to approximately 20% of the total cells present. In patches harvested after 4 weeks, NIT ranged from 42 to 328 μm and significantly correlated with mean τ at implantation. Patches with very low τ exhibited histologic characteristics similar to those of failing human bypass grafts, including laminar thrombus and flow-limiting luminal stenosis. The relationship between τ and NIT was nonlinear in that extremely low τ