Design and evaluation of a novel anti-reflux biliary stent with cone spiral valve.

Endoscopic placement of biliary stent is a well-established palliative treatment for biliary obstruction. However, duodenobiliary reflux after stent placement has been a common problem which may lead to dreadful complications. This paper designed a novel anti-reflux biliary stent with a cone spiral valve. Fluid-Structure Interaction (FSI) simulations were established to evaluate the efficiency of the anti-reflux stent comparing with a clinically applied standard stent. According to the stress distribution of the valve, the fatigue performance in the stress concentration area was analyzed. The results show that when the antegrade flow through the valve, the cone spiral valve could stretch and open to realize adequate drainage under the normal physiological pressure of biliary tract; When the duodenal reflux through the valve, the valve would be compressed and close with a result of nearly zero at the outlet flow rate. Furthermore, the anti-reflux stent achieved improved radial mechanical performance with 2.7 times higher radial stiffness than standard stent. Finite element analysis (FEA) also indicates that compared with the standard stent, the addition of the anti-reflux valve had little negative effect on flexibility of the stent. Fatigue analysis results showed that the valve was reliable. This research provides the new stent with a cone spiral valve and proves that it is technically feasible and effective for preventing the duodenobiliary reflux while ensuring the antegrade bile flow without compromising the other biomechanical performances.

Haemin-enhanced expression of haem oxygenase-1 stabilizes erythrocyte-induced vulnerable atherosclerotic plaques.

BACKGROUND AND PURPOSE: Previous studies demonstrated that intraplaque haemorrhage increased the contents of cholesterol and oxidants in atherosclerotic plaques. The present study was aimed to test the hypothesis that enhanced expression of haem oxygenase-1 (HO-1) may stabilize vulnerable plaques. EXPERIMENTAL APPROACH: Intravascular ultrasound (IVUS) was performed to identify three similar abdominal aortic plaques in each of 58 fat-fed New Zealand rabbits after aortic balloon injury. With the guidance of IVUS, 50 microL autologous erythrocytes (RBC) or normal saline (NS) were injected from adventitia into two of the pre-selected plaques, respectively, whereas the third plaque served as a blank control. All rabbits were randomly divided into two groups, receiving intraperitoneal injection of haemin and saline respectively. KEY RESULTS: Compared with NS or control plaques, RBC plaques had more macrophage infiltration and lipid content, thinner plaque fibrous cap, and higher expression of inflammatory factors and incidence of plaque rupture. RBC plaques in the haemin group had about a 50% lower incidence of plaque rupture than those in the control group. CONCLUSIONS AND IMPLICATIONS: Haem oxygenase-1 may eliminate haem or other oxidants, exert unexpected anti-oxidative and anti-inflammatory effects and serve as a promising approach to the direct inhibition of erythrocyte-induced plaque instability.

Traditional Chinese medication Tongxinluo dose-dependently enhances stability of vulnerable plaques: a comparison with a high-dose simvastatin therapy.

This study was carried out to test the hypothesis that Tongxinluo (TXL) as a Chinese herbal medicine enhances stability of vulnerable plaque dose dependently via lipid-lowering and anti-inflammation effects, similar to a high-dose simvastatin therapy. After abdominal aortic balloon injury, 75 rabbits were fed a 1% cholesterol diet for 10 wk and were then divided into five groups for 8-wk treatment: control group, low-dose TXL group, moderate-dose TXL group, high-dose TXL group, and high-dose simvastatin group. At the end of week 16, an adenovirus containing p53 was injected into the abdominal aortic plaques. Two weeks later, plaque rupture was induced by pharmacological triggering. The incidence of plaque rupture in all treatment groups (14.3%, 7.1%, 7.7%, and 7.1%) was significantly lower than that in control group (73.3%; P>0.01). TXL dose-dependently lowered serum lipid levels and inhibited systemic inflammation. Corrected acoustic intensity and fibrous cap thickness of the aortic plaques were significantly increased, whereas plaque area, plaque burden, vulnerable index, and expression of oxidized low-density lipoprotein (ox-LDL) receptor 1, matrix metalloproteinase 1 (MMP-1), MMP-3, tissue inhibitor of MMP 1, and NF-kappaB in plaques were markedly reduced in all treatment groups when compared with the control group. Similar to high-dose simvastatin group, high-dose TXL group exhibited a low serum level of low-density lipoprotein cholesterol and ox-LDL, a low expression level of systemic and local inflammatory factors and a low plaque vulnerability index, with no differences in the incidence of plaque rupture among all treatment groups. TXL dose-dependently enhances the stability of vulnerable plaques and prevents plaques from rupture. Simvastatin and TXL offer similar protection in terms of lipid-lowering, anti-inflammation, and antioxidation effects.

Intraplaque injection of Ad5-CMV.p53 aggravates local inflammation and leads to plaque instability in rabbits.

This study aims to develop a new animal model of vulnerable plaques and investigate the potential mechanisms of exogenous p53-induced plaque instability. Forty rabbits underwent aortic balloon injury, were fed a 1% cholesterol diet for 10 weeks and then normal chow for 6 weeks. Rabbits were divided into Ad5-CMV.p53-treated group (n = 16), Ad5-CMV.lac Z-treated group (n = 16) and blank control group (n = 8). Under the guidance of intravascular ultrasound, a 50-microl suspension of adenovirus containing p53 or lac Z was injected into the largest plaque of the first two groups, respectively, and these rabbits received pharmacological triggering 2 weeks later. In 76.9% of rabbits with p53 transfection, plaque rupture was found, which was significantly (P < 0.05) higher than that in the Ad5-CMV.lac Z-treated plaques (23.1%), or blank controls plaques (0%). Increased apoptotic cells, and subsequently, decreased vascular smooth muscle cells and collagen content, enhanced intima macrophage accumulation, increased C-reactive protein (CRP) and matrix metalloproteinases staining and high serum levels of high sensitive CRP (hs-CRP) and monocyte chemoattractant protein-1 (MCP-1) were observed in Ad5-CMV.p53-treated rabbits. However, a binary logistic regression model revealed that hs-CRP concentration rather than apoptosis rate played an independent role in plaque rupture with an odds ratio as 1.314 (95% CI: 1.041-1.657, P = 0.021), and there were high positive correlations between inflammatory biomarkers (hs-CRP or MCP-1) and apoptosis (R(2) = 0.761, and R(2) = 0.557, respectively, both P < 0.01). Intraplaque injection of p53 gene provides a safe and effective method for inducing plaque vulnerability in rabbits. The destabilizing effect of p53 overexpression is mediated mainly through apoptosis-enhanced inflammation rather than cell apoptosis itself.

Pathological mechanisms of erythrocyte-induced vulnerability of atherosclerotic plaques.

Erythrocytes are considered a new culprit contributing to atherosclerosis. Plaques with intraplaque hemorrhage are prone to new plaque hemorrhage, which may not only stimulate the progression of atherosclerosis but also promote the transition from a stable to an unstable lesion. However, the role of erythrocytes in inducing the vulnerability of plaque with intraplaque hemorrhage and the possible mechanism involved are not well understood. Recently, increased cholesterol level from erythrocytes was reported to expand the lipid core of plaque. As well, heme, iron and phospholipids derived from erythrocytes trigger peroxidization in vitro, which is strongly associated with the progression of atherosclerosis. We speculate that erythrocytes trapped in plaque may induce vulnerability of atherosclerotic plaques not only by accumulating lipids but also by promoting peroxidization within plaques, thereby expanding the lipid core, increasing the infiltration of inflammatory cells and attenuating the fibrous cap of plaques. This proposition may provide clues into the development of novel treatments to increase the stability of atherosclerotic plaques.

Pathological mechanisms and dose dependency of erythrocyte-induced vulnerability of atherosclerotic plaques.

To test our hypothesis that erythrocytes may induce plaque vulnerability and investigate the mechanism involved, we established a novel model of intraplaque hemorrhage in 56 New Zealand white rabbits with established plaques. Three distinct abdominal aortic plaques with similar thickness were identified in each rabbit with use of intravascular ultrasound (IVUS) imaging. Rabbits were equally divided into 4 groups depending on dosage of treatment; with the guidance of IVUS, one of the three plaques from each rabbit was injected from adventitia with autologous erythrocytes (RBC) or cholesterol (CH) for the following groups: RBC, 50 microL or 100 microL, and CH, 50 microL or 100 microL. One of the other two plaques in each rabbit received an equal volume of normal saline (NS) and one received no injection. Plaques in the 100 microL RBC group had a higher plaque rupture rate than its respective NS or blank controls plaques (57.1% vs. 14.3% or 14.3%, P<0.05). Plaques from the RBC or cholesterol groups showed, dose-dependently, more macrophage infiltration, more superoxide and lipid content, thinner plaque fibrous cap, higher mRNA level of MCP-1, IL-1 or IFN-gamma and higher vulnerability index than controls, especially in the RBC group. Thus, erythrocyte treatment can dose-dependently induce the vulnerability of plaques. Accumulation of lipid content and augmentation of oxidative stress and inflammation in the plaques are the probable pathological mechanisms involved.