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 st ress (tau = 5-15 dyne/cm(2)) and experimental vein graft neointimal thicken ing (NIT) support the role of low tau in vein graft failure. However, a sim ple linear relationship between low tau and NIT would underestimate the deg ree of NIT evident in high-grade occlusive lesions of failing human vein gr afts. In this study we used a new experimental model that maintains patency at low tau (< 2 dyne/cm(2)), to delineate possible deviations from lineari ty in the low tau --> NIT hypothesis. Methods: Thirty-two New Zealand White rabbits underwent creation of a commo n carotid vein patch with a segment of ipsilateral external jugular vein. V ery low tau was created in 13 patches by ligation of the distal common caro tid artery, leaving the only outflow through a small muscular branch. Norma l tau was created in 11 patches by leaving the common carotid artery outflo w intact. High tau was created in eight patches by ligation of the contrala teral common carotid artery. Six patches were harvested after 2 weeks for m easurement of cell cycle entry by proliferating cell nuclear antigen (PCNA) immunohistochemistry. The remaining 26 patches were harvested after 4 week s, perfusion fixed, and excised for morphometric analysis. Results: Mean blood flow and tau at implantation ranged from 0.5 to 41 mL/m in 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 immunohist ochemistry showed a significantly higher level of cell cycling in patches e xposed to low tau (40 +/- 5 vs 1.6 +/- 0.3 PCNA-positive cells per high-pow er 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 32 8 mum and significantly correlated with mean tau at implantation. Patches w ith very low z exhibited histologic characteristics similar to those of fai ling human bypass grafts, including laminar thrombus and flow-limiting lumi nal stenosis. The relationship between tau and NIT was nonlinear in that ex tremely 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 smo oth muscle cellular proliferation in arterialized vein patches. NIT is acce lerated in these regions of low tau far beyond that predicted by a simple l inear model. The nonlinear nature of the cellular proliferative response an d NIT at tau less than 2 dyne/cm(2) may explain the rapid progression of ne ointimal lesions in failing bypass grafts.