Mechanism Of Influence Of Fluid Shear Stress On Catheter Fibrin Sheath Formation And Intimal Hyperplasia

Background: Until now, tunneled cuffed catheter(TCC) is one of the main types of vascular access. Although there are advantages of tunneled cuffed catheters, the disadvantage of TCC cannot be ignored. Catheter insertion may lead to vein stenosis, which is the main cause of thrombosis of TCC, resulting in low flow rate of TCC. Vein damage after catheter insertion is also involved in the mechanism of vein stenosis, which is the same procedure of thrombosis. As there is no large autopsy report, random controlled trials cannot be done in terms of complicated mechanism of TCC dysfunction. Despite all of the advances in technology of dialysis catheters in the last 50 years, the long-term issues of catheter dysfunction, namely infection and thrombosis, have not been conquered.Objectives: The effect of fluid shear stress on venous wall has not been fully investigated after catheter placement. Some studies have reported that Caveolin on the endothelium can sensed the change of fluid shear stress, which may play an important role in mediating the hyperplasia of venous intima. This study will investigate the biological change and signal transduction of fibrin sheath formation as well as intimal hyperplasia mediated by caveolin after catheter insertion.Methods: Tunneled silicone 14.5-F catheters were inserted into a left jugular vein in eight dogs. The dogs were separated into two groups according to catheter indwelling time of 14 and 28 days. All dogs underwent extracorporeal circulation three times a week. Multi-Detector Computed Tomography Venography(MDCTV) examination were used to exam the catheter tip thrombosis. After the animals were sacrificed, histological and immunohistochemistry evaluations were performed to confirm specific cell populations. Then we used computer modeling to derive wall shear stress as well as velocity profiles for the blood flow in the catheter of different fluid field. Western Blot Analysis and Real-time PCR were performed to investigate the expression of caveolin,smooth muscle cell and extracellular signal-regulated kinase(ERK) in different venous intimal during different period. Data are expressed as mean土 SEM. Statistical analysis involved independent Student t test for comparing 2 groups and one-way ANOVA for multiple comparisons.P<0.05 was considered statistically significant.Results: Catheter-related sheaths were identified in all catheter specimens, but there was no fibrin sheath around the catheter tip. There were also differences in wall shear stress between the different sites of venous wall. Difference of vein wall thickening at different sites had been found both at 14 days(IM ratio S1 vs S2: p=0.01 S3 vs S4: p<0.01) and 28 days(IM ratio S1 vs S2: p<0.01S3 vs S4: p<0.05). At the 14-day time point, there was no obvious thrombosis at the tip of the catheter, but at the 28-day time point, there was thrombosis at the tip of the catheter. Smooth muscle cells were detected under the intimal layer at day 28 by their positive staining for the anti-actin antibody. We calculated the maximal and minimal values of WSS as there was variation of WSS during extracorporeal circulation. The data shows that the maximal WSS were higher in S1 and S3, and lower in S2 and S4. Furthermore, value of WSS was highest on S3 site compared to other three sites. The value of WSS was calculated at S1 site during peaks and valleys of blood flow circulation. Velocity vectors for both the cross-sectional and longitudinal sections have also been analyzed. In this paper, the blood flow around catheter was simulated. The results show that the distribution of wall shear stress on vessel near catheter side holes is very uneven. There was laminar blood flow in S1 and S4, while there was turbulence in S2 and S3 due to different structure of the catheter. There was overexpression of caveolin, SMA and ERK protein level in S1 and S3 as compared with that in S2 and S4 after 28 days of indwelling time. Meanwhile,the caveolin,SMA and ERK protein level was high in S1 compared with gain control, while the caveolin,SMA and ERK protein level was low in S2. There was same trend for S3 and S4(p<0.05).The m RNA level of caveolin, SMA and ERK were high in S1 and S3 as compared with those in S2 and S4.Conclusions: After catheter placement, fibrin sheath formation partially covered the catheter. Meanwhile, focal areas of intimal thickening were also seen in the venous wall adjacent to the sites of high wall shear stress. Smooth muscle cell migration was influenced by fluid shear stress. Moreover, high shear stress stimulate smooth muscle cell migration in a dynamic way as long as study time. Thrombosis formation was also associated with high wall shear stress, while the likelyhood of thrombosis was increasing with time extending. Wall shear stress in different sites of venous wall was different according to time average and temporal fluctuation of pump blood flow. The tendency was obvious in export terminal as well as side hole areas. The similar trend had also been found in blood flow direction. The caveolin, SMA and ERK protein level was different according to different sites of venous wall, as well as m RNA level. While there was over expression of caveolin, SMA and ERK in areas of high wall shear stress. These findings indicate an important role of Caveolin mediating the effect of fluid shear stress on intimal hyperplasia by stimulating signal transduction pathways of ERK.