The Animal And Clinical Studies About Rapamycin Eluting Stent

BackgroundRestenosis after percutaneous transluminal coronary angioplasty (PTCA) and stent implantation remains the major problem that hampers the procedure's efficacy, occurring in 20-30% of patients.Now, restenosis become a hindrance in the field of interventional cardiology.Regardless of new treatment strategies,including gene therapy,rotational atherectomy,laser angioplasty, cutting balloon angioplasty,intracoronary radiation therapy-the restenosis rate can not be decreased to a satisfactory extent safely. So people turned their attention to the medicine can prevent restenosis.As we known,thrombosis, inflammation,and proliferation of smooth musclar cell can account for the formation of restenosis,so the medicine of anti-restenosis also works by the three channels.Recently,drug-eluting stent,mainly including rapamycin-eluting stent (Cypher ?) and paclitaxel-eluting stent (TAXUS),is expected to become a solution to restenosis.Multicenter clinical trials of rapamycin-eluting stent (Cypher?) ,such as FIM,RAVEL,SIRIUS,have demonstrated the safety and efficacy.But,some problems remain unknown.They are as follows: (1) it is unknown whether rapamycin also inhibit regeneration of endothelial cell and delay the endothelization,which can activate platelet and increase the frequency of subacute thrombosis; (2) it is unknown whether the polymerinflame the vessel wall.Moreover,long-term follow-up of patients received rapamycin-eluting stent is not performed yet in Chinese.It is traditionally believed that main mechanism of anti-proliferation of SMC is inhibiting synthesis of protein and transition of G1 to S by prevent the process of translation,but it is not definite whether rapamycin can inhibit transcription or not.Moreover,it is well known that excess expression of inflammatory factors and high level of inflammation are in relation to restenosis.So,it is unknown that,as a kind of drastic immunosuppressant,rapamycin whether decrease inflammation in vessel wall, which is possible to be one of mechanism of preventing restenosis.Therefore,the present study investigated the process of endothelialization in Cypher? stent,and the levels of inflammation,some genes related to restenosis,activatation of platelet,and the clinical safety and efficacy of Cypher? stent after implantation of Cypher? stent.MethodsThe part I,II,III belong to animal study.Mongrel dogs were implanted Cypher? stents and Bx sonic stents in the same artery.At 1 month,3 months after implantation of stents,the target vessels were ablated after angiography and analyzed for (l)the levels of endothelialization ,activatation and aggregation of platelet by scanning electron microscope;(2)the levels of synthesis of protein and mRNA of bcl-2 in target vessels wall by Western blotting and Northern blotting technology respectively;(3)the levels of inflammatory factors interleukin-6, intercellular adhesion molecule-1 in target vessels wall by Western blotting.The latter four parts belong to clinical study. UA patients were implanted Cypher? stents (Cypher? group) and Bx sonic stents(Bx sonic group)respectively.In both groups,coronary sinus blood samples were collected before PTCA,and some moments (including immediately, or 1 hour,and 6 hours) in 6 hours after implantation of stents,and venous blood samples were taken before,some moments (including immediately,6 hours,24 hours,7days,l month)in 1 month after implantation of stents. The study contents were as follows: part IV investigated the serum or plasma levels of sICAM-l,CRP,IL-6 and P-selectin; part V investigated the serum or plasma levels of ET-1,NO and NOS;part VI investigated the plasma levels of GMP140,GMP140 on platelet surface, andMPAR.Part VII is the follow-up of the patients received Cypher? stents in XiJing hospital from Feb 2003 to Jan 2004. The follow -up of 112 patients were conducted for longer than one year,and clinical restenosis was evaluated by angina pectoris,acute myocardial infarction,cardiac death,and target vessel revascularization. Repeat coronary angiography was performed at some patients. Angiography restenosis was considered present if the diameter stenosis at follow-up was greater than 50%.ResultsPart I At 1 month after implantation of stents,target vessels of Cypher? stent were covered with endothelium partly. Platelet activation were observed.Target vessel of Bx sonic stent were entirely covered with endothelium.Platelet activation weren't observed.But at 3 months after implantation of stents,target vessels of Cypher? and Bx sonic were entirely covered with endothelium.There wasn't platelet activation on the vessel surface in both groups.Part II At 1 month,3 months after implantation of stents,there no restenosis occured in Cypher? group and Bxsonic group,but the area ofneointima in Bxsonic group is significantly higher than Cypher? group at 3 months (P<0.05) .At 1 month after implantation of stents,the expression levels of Bcl-2 protein,Bcl-2 mRNA in Cypher? group were significantly lower than Bx sonic group (P<0.05) .At 3 months after implantation of stents,there wasn't significantly expression of Bcl-2 protein,Bcl-2 mRNA in Cypher? group,but the expression remains in Bx sionc group.Part III At 1 month after implantation of stents,the levels of ICAM-l,IL-6 in Cypher? group were significantly lower than in Bx sonic group (P<0.05) ;at 3 months after implantation of stents,there wasn't statistical difference about the levels of ICAM-1 in both groups,but the level of IL-6 in Bxsonic group was significantly higher than in Cypher? group (.PO.05) .Part IV At 6 hours after angioplasty,the levels of sICAM-l,IL-6,and P-selectin in Cypher? group were significantly lower than Bx sonic group when the samples from coronary sinus were measured(p<0.05). At 6 hours,24 hours,7 days after angioplasty, there were statistical difference in Cypher? group and Bx sonic group about the levels of sICAM-l,IL-6,P-selectin,and CRP when the samples from venous were measured(p<0.05).But,there no significant difference between two groups at 1 months(p>0.05) except for P-selectin (/?<0.05) .Part V At 1 hour,6 hours after angioplasty,the levels of NO,NOS in Cypher? group were significantly lower than Bx sonic group when the samples from coronary sinus were measured(p<0.05), whereas,the level of ET-1 in Cypher? was significantly higher than Bxsonic group(p<0.05).At24 hours,7 days and 1 month after angioplasty,the levels of NO,NOS in Cypher? group were significantly lower than Bxsonic group when the samples from venous were measured(p<0.05),whereas the level of ET-1 in Cypher? wassignificantly higher than Bxsonic group(p<0.05) except for at 1 month.Part VI At 6 hours after angioplasty,the levels of plasma GMP140, GMP140 on platelet surface, and MPAR in Cypher? group were significantly lower than Bxsonic group when the samples from coronary sinus were measured(p<0.05).At24 hours,7 days and 1 month,the levels of plasma GMP140, GMP140 on platelet surface, and MPAR in Cypher? group were significantly higher than Bxsonic group except for plasma GMP140 and MPAR at 1 month when the samples from venous were measured(p<0.05).Part VII 173 lesions of 112 patients were treated and 227 stents were implanted. 159 rapamycin eluting stents were implanted in 132 lesions.Cypher? stents were successfully implanted in 156/159(98.1%). High pressure balloon was used for stent deployment in two lesions with severe calcification.Dissection was occurred in distal of stent in one lesion.No serious complications were found in hospital.Clinical follow-up of 102 patients were conducted for 12 months,there was one patient died of cardiac death.Angina pectoris occurred in 10 patients.repeat angiography was all 10 patients,there were 6 restenosis in bare metallic stents (including one restenosis in Cypher? stent) ,and there were 4 new lesions in other coronary arteries.Repeat angiography was performed at 30 of 112 patients,and restenosis in Cypher? stent only occurred in one patient.Conclusions1 Endothelium regeneration after impantation of Cypher? stent was much slower than bare metallic stent, and at 3 months, the endothelialization is finished. Incomplete endothelium can lead to platelet activation and aggregation.Intensively antiplatelet treatment maybe ensure safety of Cypher? stent.