Effects Of Diallyl Trisulfide And ～(32)P Coated Stents On Intima Hyperplasia In Canine Coronary Restenosis Model

Intimal hyperplasia due to migration and proliferation of smooth muscle cells (SMCs) from the media to the intima and extracellular matrix (ECM) deposition is a major component of restenosis after stent implantation. Although intracoronary stent placement reduces restenosis compared with conventional coronary angioplasty alone, in-stent restenosis (ISR) still remains a serious problem in interventional cardiology. No pharmacologic agents were effective in reducing the incidence of ISR. At present, vascular brachytherapy has been shown to be an effective treatment option. Nevertheless, this therapy is not 100% effective and recurrent ISR after brachytherapy occurs. Antirestenosis therapy offered by drug-coated stents has obvious merits in the ability to target therapy locally.Garlic has been used in herbal medicine for thousands of years. Some reports have shown that diallyl trisulfide (DT), a component of garlic, has protective effects against atherosclerosis as well as inhibits platelet function and thrombus formation. Studies in vitro revealed that DT exhibited a profound antiproliferative effect in SMCs. Our previous studies had shown that plasma-coated stent with DT or 32P significantly inhibited intimal hyperplasia in the canine coronary restenosis model.The purpose of this study was thus to test whether DT-coated stent prevented neointimal proliferation in a concentration-dependent manner, and to evaluate the effect of stents coated with DT and 32P concomitantly on neointimal proliferation in canine coronary arteries injury model. In addition, we established a cascade-based study model to explore the mechanism of the effect of DT-coated stents on neointima formation. This experiment included three parts.The first part was designed to investigate the efficacy of DT-coated coronary stents in preventing neointimal proliferation in canine coronary artery injury model. DT-coated stents (0, 60, 130, or 210 ug/stent) were deployed with mild oversizing in both left circumflex coronary arteriy (LCX) and left anterior descending coronary artery (LAD) of 20 dogs. Arteries were harvested 28 days (n=18) and 6 months (n=22) after stenting, One third of the stented region was cut off each one, and fixed in 2.5% Glutaral for scanning electron microscopic (SEM) analysis. One third of stented region was embedded in acrylic plastic, sectioned with a tungsten carbide knife and either stained with elastic-van Gieson or Masson for light microscopic examination. The remaining third of stented region was stored at liguid nitrogon. At 28 days after stenting, SEMshowed >90% stent surface endothelialization in DT (210ug) coated stents group, whereas complete endothelization was exhibited in control group. Masson staining showed that intimal extracellular matrix (ECM) content increased with time after stenting. ECM consisted of 40% of total intimal volume at 28 days and increased to 91% at 6 months (P<0.001), which markedly reduced by DT in a concentration-dependent manner. There was no significant difference in injury score among all groups (P>0.05). Histomorphometric analysis at day 28 indicated that the mean neointimal hyperplasia and neointimal area were similar in high-dose and immediate-dose group (P>0.05), but were less than those in low-dose or control group (.P<0.001). The percent area stenosis deceased with increasing dose (P<0.001), whereas the luminal area increased with escalating dose (P<0.01) in three DT-coated stents groups. After 6 months, the mean neointimal hyperplasia markedly reduced in high-dose group compared with immediate-dose group (P=0.008), low-dose group as well as control group (P<0.001). The neointimal area, the percent area stenosis and the luminal area were no significant difference between in high-dose group and immediate-dose group (P>0.05), but those indices in either group were significantly different from either low-dose or control group (P<0.001). There were no cases of aneurysm or thrombosis. In summary, in a canine model of restenosis, the low-dose DT (60ug) failed to reduce restenosis, w...