ABC | Volume 112, Nº1, January 2019

Original Article Arq Bras Cardiol. 2019; 112(1):3-10 Tianshu-Chu et al Rapamycin combined with α -cyanoacrylate In order to investigate the effect of α -CA-RPM on inflammatory responses, we performed ELISA assays to examine serum levels of ET-1. We found the ET-1 level of the control, α -CA, RPM, and α -CA-RPM groups gradually increased 36 hours after operation; those of the control, α -CA, and RPM groups was still high 4 weeks after operation and that of the α -CA-RPM group had basically returned to normal. The ET-1 level in the control group was significantly higher than that of the α -CA, RPM, and α -CA-RPM groups 36 hours and 4 weeks after operation (96.1 ± 7.9 ng/l vs. 84.0 ± 10.9 ng/l, 79.5 ± 5.7 ng/l, and 72.7 ± 9.9 ng/l; 99.7 ± 7.7 ng/l vs. 87.1 ± 13.3 ng/l, 65.4 ± 23.4 ng/l, and 43.7 ± 20.1 ng/l; p < 0.05, respectively). Additionally, at 4 weeks after surgery, the ET-1 level of the α ‑CA‑RPM group was significantly lower than in the α -CA, RPM, and control groups (43.7 ± 20.1 ng/l vs. 87.1 ± 13.3 ng/l, 65.4 ± 23.4 ng/l, and 99.5 ± 7.7 ng/l; p < 0.05, respectively) (Figure 4C). These findings indicate that α -CA, RPM, and α -CA-RPM seem to reduce inflammatory responses and that α -CA-RPM is more effective. Discussion The main finding of our study is that the application of α -CA, RPM, or α -CA-RPM can improve the patency of the vein graft in rat models by inhibiting intimal hyperplasia. 8 More importantly, the use of RPM combined with α -CA is more effective than either α -CA or RPM alone. The complicated remodeling process of vessels leads to restenosis of vein grafts, but the exact mechanism is not explicit. Studies have shown that restenosis is related to dysfunction of intima endothelial cells, proliferation, immigration of vascular smooth muscle cells, adventitial fibroblasts, inflammatory reaction, shear force, and hemodynamic changes. 9,10 The pathological process of restenosis of bridge vessel may include early thrombosis, intimal hyperplasia, and atherosclerosis; intimal hyperplasia is the most important reason. When separating, ligaturing, dividing, transplanting, and revascularizing bridge vessels, factors such as aggregation of platelets and neutrophils, release of cytokine and chemokine, activation of transduction pathway, and enzymatic reaction may prompt hyperplasia of vascular smooth muscle cells and accumulation of endothelial cells. All these factors are expected to result in intimal hyperplasia, and restenosis of grafted vessels follows. 11,12 In 1963, Parsonnet and colleagues first pointed out that extravascular supporters could enhance the patency rate of grafted veins. 5 Several foundational and clinical tests have proved that extravascular supporters could inhibit intimal hyperplasia and enhance patency rate. Four extravascular Figure 2 – α-CA-RPM reduced intimal thickening of the vein graft. The vessel tissue was harvested 4 weeks after the operation, fixed in formalin, sliced to 4 μm tissue sections and stained with HE. Images (×100 objective lens) were collected and analyzed by Olympus micro-imaging system. The rats were divided into 5 group: Sham group (A), control group (B), α-cyanoacrylate group (C), Rapamycin group (D) and α-CA-RPM group (E). (F) Represented the statistical graph of each group’s intima thickness. The intima of control group was dramatically thicker than that of α-CA, RPM and α-CA-RPM groups; the difference was statistically significant (91.3 ± 3.9, 133.6 ± 8.0, 50.6 ± 5.4 vs. 233.6 ± 29.1 μm, p < 0.01); the intima of the RPM group was thicker than that of α-CA group (133.6 ± 8.0 vs. 91.3 ± 3.9 μm, p < 0.05); the intima of α-CA group and RPM group was thicker than that of α-CA-RPM group (50.6 ± 5.4 vs. 91.3 ± 3.9 μm, 133.6 ± 8.0 μm, p < 0.05). * The control group had obvious difference with other groups, p < 0.05. # The α-cyanoacrylate group had obvious difference with other groups, p < 0.05. △ The rapamycin group had obvious difference with other groups, p < 0.05. ☆ The α-CA-RPM group had obvious difference with other groups, p < 0.05. 400 300 200 100 0 sham control α -CA α -CA-RPM RPM *#∆ *# * Intima thickness (μm) *#∆ 6