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

Objective Previous studies demonstrating a correlation between low shear stress (tau = 5-15 dyne/cm(2)) and experimental vein graft neointimal thickening (NIT) support the role of low tau in vein graft failure. However, a simple linear relationship between low tau 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 tau (< 2 dyne/cm(2)), to delineate possible deviations from linearity in the low tau --> 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 tau was created in 13 patches by ligation of the distal common carotid artery, leaving the only outflow through a small muscular branch. Normal tau was created in 11 patches by leaving the common carotid artery outflow intact. High tau 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 tau at implantation ranged from 0.5 to 41 mL/min and 0.07 to 15 dyne/cm(2), 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 tau (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 mum and significantly correlated with mean tau at implantation. Patches with very low z exhibited histologic characteristics similar to those of failing human bypass grafts, including laminar thrombus and flow-limiting luminal stenosis. The relationship between tau and NIT was nonlinear in that extremely low tau (< 2 dyne/cm(2)) resulted in NIT beyond that predicted by a simple linear correlation (P = .003). Conclusion: Extremely low tau (< 2 dyne/cm(2)) stimulates high rates of smooth muscle cellular proliferation in arterialized vein patches. NIT is accelerated in these regions of low tau far beyond that predicted by a simple linear model. The nonlinear nature of the cellular proliferative response and NIT at tau less than 2 dyne/cm(2) may explain the rapid progression of neointimal lesions in failing bypass grafts.