The effects of extremely low shear stress on cellular proliferation and neointimal thickening in the failing bypass graft
The effects of extremely low shear stress on cellular proliferation and neointimal thickening in the failing bypass graft
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DOI：
10.1067/mva.2001.114819
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发表时间：
2001-07-01
影响因子：
4.3
通讯作者：
Schwartz, LB
中科院分区：
文献类型：
--
作者：
Meyerson, SL;Skelly, CL;Schwartz, LB
目的已有研究表明低切应力(tau=5~15dyne/cm(2))与实验性移植静脉新生内膜增厚(NIT)相关，支持低tau在移植静脉失败中的作用。然而，低tau和NIT之间的简单线性关系低估了在失败的人静脉移植物的高级别闭塞病变中NIT的明显程度。在这项研究中，我们使用了一种新的实验模型，保持低tau(<；2dyne/cm(2))的通畅率，以描述在低tau；>；NIT假设下可能偏离线性的可能性。方法：新西兰大白兔32只，用同侧颈外静脉的一段建立颈总静脉斑块。通过结扎颈总动脉远端，在13个斑块中形成了非常低的tau，留下了唯一通过一个小肌肉分支流出的斑块。正常的tau是在11个斑块中通过保持颈总动脉流出完整而产生的。通过结扎对侧颈总动脉，在8个斑块中产生了高tau。2周后取6块，用增殖细胞核抗原免疫组织化学方法检测细胞周期进入情况。结果：植入时平均血流量为0.5~41mL/min，平均tau为0.07~15dyne/cm(2)，32个斑块中有30个保持通畅，并保持了人工造成的血流异常(0.7~41mL/min)。2周后，增殖细胞核抗原免疫组织化学显示暴露于低tau的斑块的细胞周期显著增加(40+/-5vs1.6+/-0.3个/高倍视野的增殖细胞核抗原阳性细胞；P<；.001)，相当于总细胞的20%。在4周后收获的斑块中，NIT范围为42~328微米，并与植入时的平均tau显著相关。Z非常低的补片表现出与失败的人类搭桥术相似的组织学特征，包括板层血栓和限流性管腔狭窄。Tau和NIT之间的关系是非线性的，极低的tau(<；2dyne/cm(2))导致NIT超出了简单的线性相关(P=0.003)。结论：极低的tau(<；2dyne/cm(2))可以刺激动脉化静脉斑块中高比率的平滑肌细胞增殖。NIT在这些低tau的区域被加速，远远超过简单的线性模型所预测的结果。细胞增殖反应和tau低于2dyne/cm(2)的NIT的非线性本质可能解释了失败的搭桥术后新生内膜病变的快速进展。
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.