Interventional Treatment For Intracranial Arterial Stenosis And Experimental Study On Sirolimus-eluting Stents

PrefaceIntracranial and internal carotid artery stenosis is an important cause of ischemic stroke events, and in our country nearly 33% of ischemic stroke events are resulted from intracranial artery stenosis. The researchers pay more attention to middle cerebral artery (MCA) stenosis because of the extensive blood supply of MCA and the serious results after MCA stenosis. At present, the prognoses of both traditional medical treatment and surgical bypass are poor in patients with MCA stenosis. Many studies have proved that stent placement and balloon angioplasty could improve the blood supply of stenosed MCA. Both stent placement and balloon angioplasty are becoming important methods for MCA stenosis. The eccentric or angulated stenosis, severe tortuous access, research hysteresis in cranial intervention materials and poor experience in neurointervention doctor lead to poor successful rate and high restenosis. Recently, some researchers screen the case for intervention therapy according to MAC stenosis degree and by evaluating the cerebral vessel compersation ability before cerebral stroke with the perfusion volume in cerebral blood and according to the classifications which are based on the morphology of and the access to stenosis to choose balloon angioplasty and stent placement respectively that rise the operation successful rate. But serious restenosis postprocedure in both stent placement and balloon angioplasty restrict the intervention treatment application for MCA stenosis. Successful experience in Stent coated with sirolimus reducing coronary artery stenosis provide new idea for its cranial application. Resently, some researchers try to application sirolimus-coated stents implanted in intracranial vessel, and results obtained from the near follow-up show that sirolimus-coated stents could effectively restrict the intracranial artery restenosis. Unlike the coronary vasculature, intracranial vessels have paucity of adventitia and are bathed in CSF, The fragility has raised some concerns regarding the safety of sirolimus in cerebral vessels. If vascular injury occurs as a result of the stent implantation, the potential exits for increased pseudoaneurysm formation or disruption of vessel integrity, the sirolimus will leach into CSF through a transmural process. So sirolimus-coated stents neurotoxicity must be answered by animal experiment. The effect was identified on histological analysis by observating the long-term progress in canine brain tissue and vessels tissue. Materials and Methods1 patients: From May 2005 to May 2006, 47 patients with MCA stenosis were admitted to our department. There were 31 men and 16 women, ranging in age from 25 to78 years (median, 64 years). Episodic single limb activities uneffective diagnosed in 29 patients, combination with language disorder in 10, language disorder in 11.2 CTP and CTA examination: 47 paitents with symptomatic MCA stenosis performed CTP and CTA in "one-stop"style examination. Degree of MCA stenosis were classified according to result of CTA: DegreeⅠ: narrow areas＜50%; DegreeⅡ:narrow areas 50%～70%; DegreeⅢ: narrow areas＞70%.The ratios of side-to-side were measured at hypoperfusion areas in regional cerebral ischemia.ResultsDegreeⅠ:11 patients, CBF,CBV,MTT,TTP means ratio were 1. DegreeⅡ:29patients, the means ratio of CBF,CBV,MTT,TTP were 0.94,1.05,1.35andl.41 respectively. DegreeⅢ:7 patients, the means ratio of CBF,CBV,MTT,TTP were 0.58,0.69,1.65and1.64 respectively.Conclusion1 The correspondence relation between stenosis degree and CT perfusion can accurately reflect the hypoperfusion of MCA stenosis.2 CT perfusion can provide objective index for cerebral stroke prophase 3CT perfusion is a functional imaging and should be dynamically analyzed. The state of cerebral artery hypotension has significantly relevance with stenosis positions, grade and lateral branch compensation. Materials and Methods1 patients From June 2004 to June 2006, 37 patients with MCA stenosis and TIA were admitted to our department. There were 24 men and 13 women, ranging in age from 38 to72 years (median, 62.7 years). Transient hemiparesis was diagnosed in 25 patients, (combination with aphasia in 11), sensory disability in 8, and vertigo in 4. Of the 37 patients, 29 were with moderate MCA stenosis (50% to 70% of reduction in diameter) and 8 with severe MCA stenosis (≥70% of reduction in diameter).2 Preprocedural evaluation 37 patients with recurrent transient ischemic attacks (TIA) underwent stent placement or balloon angioplasty according to both the stenosis classification of Mori and the classification of location, morphology, and access of lesions (LAM). Stent placement was performed in patients with Mori type A and LMA typeⅠorⅡand balloon angioplasty in patients with Mori type B or C and LMA typeⅢ.3 Interventional procedures The 6-French guiding catheters were placed via femoral route under local anesthesia. Then a bolus dose of heparin (3000 to 5000 U), followed by 1000 U every hour, was administered intravenously during the operation. Three-dimensional angiography followed by routine cerebral angiography were performed for evaluating the stent size, the location, length, and angulation of the stenosis, and the access to the lesion, which are the bases of Mori or LMA classifications. Stent placement was performed in patients with Mori type A and LMA typeⅠorⅡ, and balloon angioplasty was performed in patients with Mori type B or C and LMA typeⅢ.A 6F Envoy guiding catheter (Cordis corporation, US) was placed in the carotid artery directly or with an exchange wire. Guided by a road-map image, a floppy-tipped 0.014-inch microguide wire was advanced carefully through the stenosis to M3 or M4 segment of MCA. Rapid exchange balloon catheter or balloon-expandable stent was placed across the stenosis, and catheter angiography was performed to identify the location of balloon or stent. Then the balloon or stent was advanced over the microguide wire and accurately positioned across the lesion. The diameter of the stent was slightly less than that of adjacent distal normal vessel, and the length of the stent was slightly more than that of the lesion. The diameter of balloon was 2.0-3.0 mm. The balloon was inflated gradually by infusing 50% of contrast medium, the inflation pressure was less than or equal to the release pressure. After technical success defined as≤20% of residual stenosis, which was identified by catheter angiography, was achieved, the balloon was withdrawn. The microguide wire and guiding catheter were withdrawn after excluding acute occlusion and distal embolism. Plain CT scans were performed immediately to rule out hemorrhage. Continuous anticoagulation with low-molecular weight heparin was performed in all patients for 72 hours after operation.4 Postprocedural management and follow-up The patients were followed up for 3 to 24 months. Transcranial Doppler (TCD) examination was routinely performed to assess the blood flow velocity. The restenosis was evaluated with angiography in 11 patients, among whom 4 underwent stent placement and 7 underwent balloon angioplasty.Results1 Stent placement results The stent placement was done successfully in 20 of the 21 patients with Mori type A and LMA typeⅠorⅡ, and a 12% to 76% of increment in lumen diameter was obtained in these 20 patients. One patient died of vascular rupture after operation. The symptoms of TIA disappeared in 17 patients and were markedly improved in 2 patients. TCD examination showed the blood flow velocity increased markedly in 2 patients experiencing recurrent TIA. No restenosis was found in the 4 patients undergoing angiography during the follow-up.2 Balloon angioplasty results The balloon angioplasty was done successfully in 14 of the 16 patients with Mori type B or C and LMA typeⅢ, and a 15% to 69% of increment in lumen diameter was obtained in these 14 patients. No severe complication was found. The symptoms of TIA disappeared in 12 patients and recurred in 4 patients. TCD examination showed the blood flow velocity increased markedly in 6 patients. MCA stroke occurred in 2 patients. Restenosis was found in 3 of the 7 patients undergoing angiography during the follow-up.Conclusions1 Both stent placement and balloon angioplasty are effective in treating MCA stenosis.2 To choose the suitable procedure according to the morphology of and the access to the stenosis may be an effectivle approach to minimize the severe complications of stent placement or balloon angioplasty in treating MCA stenosis.3 Date obtained from follow-up show that high restenosis rate after both stent placement and balloon angioplasty is still the important problem. Part threeCanine model of sirolimus-eluting stents in intracranial arteries Materials and methods1 stent preparation(1) bare stent design;(2) sirolimus-eluting stent and surface treatment(this part was assisted by Metal material department of Dalian University of Technology)2 Animal preparation(1) twelve mongrel dogs(each weighing at least 25kg) were randomized group A, B and C(four per group) to receive either bare-metal 2.0×8mm stents or sirolimus-eluting stents contained 50ug or 100 ug of sirolimus respectively and the same dimensions as group A.(2) The animal were quarantined for 1 week before stent implantation to exclude from the study any dog found to have an infection or to exhibit aggressive behavior.(3) Double-blind method was performed by intervention doctor.3 stent placement(1) General anesthesia was performed and stent was placed(2) Each animal received 2000U heparin everyday and aspirin(80 mg/d) were orally administered continuously.(3) neurological loss of function score(NIH-NINDS score): score were performed in 1,3,7,30,60,90 days after operation. Contents including①level of consciousness;②upper limb movement;③lower limb movement;④incoordination;⑤eating;⑥stool and piss4 specimen collection At 30,60,90 days after stent placement, repeated angiography was performed for 1 dog from the four groups respectively to document the position of stent placed in the basilar artery(BA), the lumen of BA, BA perforating vessels and posterior cerebral artery(PCA). The animals were then killed for cerebrum histological examination. After formalin fixation was completed, a craniotomy were performed with en bloc removal of the brain and the BA and brainstem were exposed. On gross inspection of the brain was performed to make sure if there was subarachnoid. If the dissection and aneurysm was found in the BA section where stent was placed. If the stent molposition and deformation were found. Microdissection techniques were used to remove en bloc, maintaining the integrity of the vertebrobasilar artery, formalin(50ml of 10% concentration)was then perfused through the guide catheter to BA. Then BA and the rest brain tissues were placed in the separate container of 10% formalin.5 Stent section(1) Eight large sections from each of the brain samples were submitted for paraffin embedding and LUXO fast blue staining in cassettes labeled as followed: 1 midpons 2 midpons 3 cerebellum 4 medulla and pontomedullary junction 5 frontal lobe watershed region 6 third ventricle hypothalamus, and mammillary bodies 7 rhinencephalon and posted-or parietal lobe 8 occipital lobe with line of Gennari.(2)Scoring of the Specimens①Inflammation Score. An inflammation score was assigned that was based on the presence of any significant inflammation surrounding the stent struts. As follows: 1. involvement of less than 25% of the artery; 2 more than 25% but less than 50% of the artery; 3 more than 50% of the artery.②intimal SMC Content. This feature was scored according to the following scheme: 1. spare SMC density that involved and portion of the artery or moderate SMC infiltration less than the full thickness of the neointima that involved less than 25% of the circumference of the artery;2 moderate infiltration less than the full thickness of the neointima that involved more than 25% of the circumference of the artery or dense SMC content over the full thickness of the neointima that involved less than 25% of the circumference of the artery; and 3. dense SMC content over the full thickness of the neointima that involved greater than 25% of the circumference of the artery. Endothelialization. This was defined as the extent of the circumference of the arterial lumen that was covered by endothelial cells and was scored according to the following scheme:1. less than 25%;2.26 to 74%; 3.75% or more. Results1 Stents were successfully implanted in the BAs of 11(A=4,B=3, C=4)2 Neurological loss of function score show that there was no significant different between group A,B and C, in 1,3,7,30,60days, but the neurological score in group A was significantly higer than that in group B and C.3 Conventional angiography did not demonstrated any evidence of constriction in dogs from three groups in 30 days, Decreased lumen diameters of BA was seen in one dog from group A in 60 days, constriction was found in two dogs from group A and group B respectively, emphraxis was found in one dog from group B,and constriction was not found in group C in 90 days.4 No statistacally significant differences in BA inflammation score and endothelialization between group A,B and C. SMC Contents: Significant differences in SMC contents were found between group bare-metal and sirolimus-coated stents in 30,60,90days. no statistacally significant differences between group B and C in 30,60days, but significant differences were found in 90 days.5 Examination of the brainstem sections obtained in three group failed to demonstrate evidence of infarction in 30 and 60 days, but infarction was found in one dog from group A in 90 days.Conclusions1 neurological loss of function score and the histological evidence of brainstem and brain tissue prove that sirolimus-eluting stents contained 50ug or 100 ug of sirolimus has no neurotoxicity to brain.2 Sirolimus-coated stents have demonstrated the ability to inhibit SMC proliferation and in-stent stenosis.