Correlation Analysis Of Intracranial Collateral Circulation With In-stent Restenosis After Internal Carotid Artery Stenting And Its Relationship With Gene Polymorphism

Stroke is a disease that seriously affects the health of Chinese residents.The statistical results show that stroke has become the leading disease in the mortality and disability rate in China.Ischemic stroke accounts for about 80%of strokes,among which the severe large artery atherosclerotic stenosis or occlusive cerebral infarction accounts for about 50%-70%.This type of ischemic stroke is characterized by high morbility,high mortality,high disability rate and high recurrence rate,bring heavy economic burden to the patients and their family,and we need to pay more special attention to reduce the risk of the disease.Severe stenosis of internal carotid artery atherosclerosis is an important cause of cerebral infarction.Some ischemic stroke patients with severe internal carotid artery stenosis still have recurrence or aggravation of cerebral infarction after long-term and standardized medication therapy.In this case,stent implantation at the stenosis site can be considered to restore the artery diameter.Several studies have confirmed that stenting after internal carotid artery stenosis can reduce the risk of cerebral infarction and recurrence in patients with internal carotid artery stenosis,and bring more benefits to those patients.However,it cannot be ignored that some patients who ever received internal carotid artery stenting developed in-stent restenosis during postoperative follow-up,rang from 3%-30%.The occurrence of in-stent restenosis reduced the clinical benefits of stent therapy and increased the risk of recurrence of ischemic cerebrovascular disease events.Therefore,it is very important to identify the risk factors of in-stent restenosis after internal carotid artery stenting.The collateral circulation is an artery-artery connection pathway.When severe stenosis or occlusion occurs in the intracranial arteries,the collateral circulation can provide blood supply to the distal brain tissue of the stenosis and occlusion site.It is also found that abundant collateral circulation can reduce the severity of cerebral infarction,reduce the risk of recurrence after infarction,and facilitate long-term prognosis.The role of collateral circulation in cerebrovascular diseases,especially ischemic cerebrovascular diseases,has been widely concerned.The above effects of abundant collateral circulation on ischemic stroke may be related to reducing the area of ischemic penumbra,releasing the degree of local inflammation,and increasing the perfusion in the distal to the stenosis.However,there is no a clear conclusion on the relationship between collateral circulation and restenosis after internal carotid artery stenting,which is worth further exploration.Collateral circulation is an important factor affecting the occurrence,development and prognosis of cerebrovascular diseases,especially ischemic cerebrovascular diseases.The formation and development of intracranial collateral circulation are influenced by a variety of factors.Animal studies have confirmed that genetic factors play an important role in the formation of intracranial collateral circulation.Mutations of some gene loci affect the number and diameter of collateral vessels,while age,gender and other atherosclerotic risk factors have little influence on the collateral circulation.However,the above conclusions are mainly derived from animal studies,and the influence of genetic factors on cerebral collateral circulation in human is less studied.In this study,we collected the clinical data of patients who had ever received internal carotid artery stenting,and summarized the clinical characteristics of patients with in-stent restenosis.The effect of intracranial collateral circulation on in-stent restenosis after internal carotid artery stenting was analyzed.At the same time,the influence of Rabep2 gene polymorphism on intracranial pia meningeal collateral circulation was determined.Part One Analysis of the clinical features of patients with in-stent reste-nosis after carotid artery stentingObjective: The clinical data of patients who received internal carotid artery stenting were collected.After clinical follow-up,the clinical characteristics of patients with in-stent restenosis were analyzed.Methods: We retrospectively collected the clinical medical records of patients who were hospitalized in the Department of Neurology,the Second Hospital of Hebei Medical University from July 2015 to December 2018 for severe internal carotid artery stenosis and received stent treatment at the stenosis.After stenting,carotid artery Doppler ultrasound was followed up to determine whether in-stent restenosis occurred according to the blood flow velocity at the stent.The clinical features of patients with in-stent restenosis after internal carotid artery stenting were collected and analyzed.Results: A total of 385 patients were included in our study.36 patients occurred in-stent restenosis after internal carotid artery stenting,of which 28 patients were eligible for inclusion.The mean age was(62.3±6.6)years;There were 24 males(85.7%).Before stenting,total cholesterol level was(3.6±0.7)mmol/L,triglyceride level was(1.6±0.8)mmol/L,low density lipoprotein cholesterol level was(2.1±0.6)mmol/L and high density lipoprotein cholesterol level was(1.0±0.2)mmol/L.There were 18 cases complicated with hypertension(64.3%),15 cases complicated with diabetes(53.6%),10 cases complicated with coronary heart disease(35.7%),11 cases complicated with smoking history(39.3%),and 8 cases complicated with drinking history(28.6%).In blood cell count,platelet count was(225±78)×109/L,white blood cell count was(6.1±1.1)×109/L,neutrophil count was(3.8±0.9)×109/L.The median of blood homocysteine was 11 mmol/L(8,14),the median of hypersensitive C-reactive protein was 8 mg/L(1,11),and the median of uric acid level was(312.8±87.1)μmol/L.Among the types of stents used,including 16 EV3 stents and 4 Acculink stents.The closed stents including 5Wallstent stents and 3 Enterprise stents.The rate of carotid artery stenosis before stenting was(82.5±6.9)%,and the rate of residual stenosis after stenting was(12.8±8.4)%.There were 18 cases(64.3%)with a history of ischemic stroke,7 cases(25.0%)with a family history of ischemic stroke,and8 cases(28.6%)with a history of in-stent restenosis.During the follow-up,5patients had recurrent ischemic stroke(17.9%)and 6 patients did not receive standard medication after stenting(21.4%).The median time for in-stent restenosis after carotid stenting was 6 months.Conclusions: The incidence of in-stent restenosis after internal carotid artery stenting was 9.5%(28/296).The majority of patients with in-stent restenosis after internal carotid artery stenting were middle-aged and elderly males,and the proportion of patients with history of hypertension,diabetes and ischemic stroke was more than 50%.The median time for in-stent restenosis was 6 months after stenting.Part Two The correlation between poor collateral circulation and in-stent restenosis after internal carotid artery stentingObjective: We aimed to evaluate the effect of cerebral collateral circulation on in-stent restenosis after carotid artery stenting and to establish a clinical prediction model for in-stent restenosis.Methods: It was a retrospective case-control study.From June 2015 to December 2018,296 patients with severe carotid artery stenosis(≥70%)who underwent stent therapy were enrolled.Based on follow-up data,the patients were divided into the in-stent restenosis and no in-stent restenosis groups.According to the criteria of the American Society for Interventional and Therapy Neuroradiology/Society for Interventional Radiology,the collateral circulation of the brain was graded.Clinical data were collected,such as age,sex,traditional vascular risk factors,blood cell count,high sensitivity C-reactive protein,uric acid,stenosis degree before stenting and residual stenosis rate,and medication after stenting.Binary logistic regression analysis was performed to identify potential predictors of in-stent restenosis,and a clinical prediction model for in-stent restenosis after carotid artery stenting was established.Results: Importantly,we found that poor collateral circulation was an independent predictor of in-stent restenosis by binary logistic regression analysis(P=0.003).We also found that a 1% increase in residual stenosis rate was associated with a 9% increase in the risk of in-stent restenosis(P=0.02).Ischemic stroke history(P=0.03),family history of ischemic stroke(P<0.001),in-stent restenosis history(P<0.001),and no-standard medication after stenting(P=0.04)were predictors of in-stent restenosis.The risk of in-stent restenosis was lowest when the residual stenosis rate was 12.5% after carotid artery stenting.Further,we used some significant parameters to construct a binary logistic regression prediction model for in-stent restenosis after carotid artery stenting in the form of a nomogram.Conclusions: Collateral circulation is an independent predictor of instent restenosis after successful carotid artery stenting,residual stenosis rate tends to below 12.5% to reduce restenosis risk.The standard medication should be strictly carried out for patients after stenting to prevent in-stent restenosis.Part Three The effect of Rabep2 gene polymorphism on collateral circu-lation in patients with severe symptomatic anterior circula-tion stenosis or occlusionObjective: Genetic factors are important aspect that affecting the establishment of intracranial collateral circulation.We analyzed the relationship between Rabep2 gene polymorphism and collateral circulation in patients with symptomatic severe stenosis or occlusion of the cerebral anterior circulation.Methods: This prospective cohort study included patients with acute cerebral infarction admitted to the Department of Neurology,the Second Hospital of Hebei Medical University from September 2021 to May 2022.All patients underwent cranio-cervical CTA examination to identify severe atherosclerotic stenosis or occlusion of large arteries involving the internal carotid artery and/or the middle cerebral artery as the cause of cerebral infarction.Clinical data of patients were collected,and the regional pia meningeal collateral circulation scoring based on cranio-cervical CTA was used to evaluate the pia meningeal collateral circulation of the distal responsible vessel.At the same time,the blood samples of the included patients were extracted and the polymorphisms of rs35979293 and rs2904880 sites of Rabep2 gene were analyzed.Results: A total of 180 patients were included in the study.At rs35979293 site,there were 109 GG genotypes,63 GT genotypes and 8 TT genotypes.At rs2904880 site,there were 2 CC genotypes,46 CG genotypes and 132 GG genotypes.Different genotypes of rs35979293 and rs2904880 did not predict collateral circulation status in patients with symptomatic severe anterior circulation artery stenosis or occlusive cerebral infarction.Conclusions: The ratio of neutrophil to lymphocyte was increased and the NIHSS score was higher at admission,NIHSS score at discharge and m RS Score at 90 days after discharge was higher in patients with severe stenosis of symptomatic anterior circulation large artery atherosclerosis cerebral infarction with poor collateral circulation.The polymorphism of rs35979293 and rs2904880 of Rabep2 gene does not predict the degree of pia collateral circulation in patients with severe atherosclerotic stenosis or occlusion cerebral infarction.