Study On Risk Factors Of Restenosis After Carotid Angioplasty And Stent Placement

Background: According to the report of 2017 global burden of disease(GBD)study,stroke has become the second deadly disease and the leading cause of disability in the worldwide.In China,there are 2 million new stroke patients and about 1.5 million people died from stroke each year.There are 6 to 7 million patients who have survived the stroke and 3/4 of them have lost their ability to work.Survivors from emergency treatment have a recurrence rate of 20%-47% within 5 years.With the rapid development of Chinese economy,the changing lifestyle of residents and the aging of the population,the incidence of stroke in China have increased year by year.In 2016,it has become the leading cause of death.Among them,ischemic stroke accounts for about 70% of all strokes,and its high morbidity,high mortality,and high disability rate not only give the patients themselves,but also bring great pressure and burden to their families and the society.Carotid atherosclerotic stenosis is one of the major causes for ischemic stroke,accounting for about 20% of all ischemic strokes.The annual incidence of stroke is about 2-5% for asymptomatic carotid stenosis.For untreated symptomatic carotid stenosis,the risk of recurrent stroke was nearly 21% within 72 hours.Therefore,effective treatment of carotid stenosis has become an important means to prevent the occurrence of stroke.Currently,carotid endarterectomy(CEA)and carotid angioplasty and stenting(CAS)are two main treatment strategies for carotid stenosis.Although CAS has some advantages such as less invasiveness and shorter hospitalization,CEA remains the gold standard for treating carotid stenosis,a series of randomized controlled trials were performed to verify the safety and efficacy of CAS.These trials have demonstrated the safety and efficacy of CAS,and CAS has been recommended an alternative treatment for CEA in “Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline for healthcare professionals from the American Heart Association(AHA)/American Stroke Association(ASA)” which was published by AHA/ASA in 2014 year.However,CAS also has some disadvantages such as higher incidence of perioperative death,stroke and postoperative restenosis.One follow-up study of CREST showed that the risk of ipsilateral ischemic stroke in patients with restenosis after CAS was 4.37 times than that of patients without restenosis within 2 years.A large-scale,observational research showed that restenosis was associated with ipsilateral ischemic stroke during follow-up.Another small-scale,single-center study found that restenosis was a predictor of ipsilateral ischemic stroke during follow-up and the risk ratio of it is 3.6.So,the restenosis may affect the long-term effectiveness of CAS.In conclusion,identifying the risk factors and predictors associated with restenosis after carotid stenting could be helpful to identify patients who were under high risk for restenosis and avoid their restenosis by close follow-up or aggressive therapies.The occurrence of restenosis after carotid stenting is mainly attributed to neointimal hyperplasia.After mechanical injuries of stents to the vascular endothelium,platelets adhere to the injured site and then leukocytes are recruited to the site through leucocyte–platelet interactions.On the one hand,endothelial cells,platelets and inflammatory cells release various growth factors such as vascular endothelium growth factor(VEGF),platelet-derived growth factor(PDGF),transforming growth factor(TGF),insulin-like growth factor(IGF)and fibroblast growth factor(FGF)cause proliferation of vascular smooth muscle cells(VSMCs)in the middle layer.On the other hand,inflammatory cells release matrix metalloproteinases(MMPs)which promote the migration of VSMCs from medial layer to the intima.VSMCs which migrate to the inner membrane further secrete the extracellular matrix and result in the thickening of the intima.Therefore,platelets and inflammatory reactions play a very important role in the occurrence of in-stent restenosis.Previous studies have shown that platelet mean volume and neutrophil to lymphocyte ratio are biomarkers of platelet activity and inflammation respectively.In addition,recent studies suggest that the geometry of the carotid bifurcation is closely related to the shear stress distribution,and the low shear stress may play a synergistic role in neonatal intimal hyperplasia through endothelium-dependent,direct action on vascular smooth muscle cells or promoting the transition of vascular smooth muscle cells to synthetic phenotype.Objective: To investigate the correlation between mean platelet volume,neutrophil to lymphocyte ratio and carotid bifurcation morphology and restenosis after CAS.Currently,the research in this area has not been reported at domestic and foreign country.Methods Consecutive patients who underwent CAS treatment in the Nanjing Stroke Registry from March 2004 to December 2016 were collected.Patients who were death or loss of followe-up were exclued.Demographic characteristics,major vascular risk factors,and laboratory and imaging results were collected.Follow-up consisted of clinical examination and radiographic evaluation such as digital subtraction angiography,computed tomography angiography,or Doppler ultrasound that was performed at 6 months and repeated annually after the procedure.Radiographic evaluation was also performed if any new neurological symptom was indicated in the follow-up period.In-stent restenosis was defined as≥ 50% stenosis in the treated lesion.Preoperative neutrophil to lymphocyte ratio(NLR)was considered as a sensitive inflammatory marker,all these data were used to establish a database,and the value of preoperative inflammatory status in predicting restenosis after CAS was confirmed by Cox regression.Patients who underwent CAS for ≥50% symptomatic stenosis of the extracranial carotid artery or ≥70% asymptomatic stenosis were screened from the database.The preoperative mean platelet volume was used as the study object,and Cox regression was used to confirm the predictive role of mean platelet volume on the occurrence of restenosis in patients who underwent CAS.The benchmark model was established according to the tuning-fork-sharped model of the average human carotid bifurcation.Computer fluid dynamics(CFD)was used to analyze the carotid geometry and hemodynamic parameters.Patients who underwent simultaneous bilateral CAS were screened from the database.A three-dimensional model of carotid bifurcation after CAS was reconstructed from the digital subtraction angiography.Patients were divided into NIH symmetric group and NIH asymmetric group based on its intraindividual difference of bilateral NIH rate.The carotid bifurcation model of the patient was analyzed by CFD,and the effects of hemodynamics and geometric morphology on NIH were compared between the two groups.Results:Of the 459 arteries(in 427 patients)with CAS,72(15.7%)were identified with ISR during a mean follow-up of 14.6(±19.1)months(range,0.7-120.7).Increased NLR levels(≥ 2.13)was significantly related to restenosis in patients with asymptomatic stenosis in univariate analysis(P = 0.001);this significance was not observed in symptomatic carotid stenosis.In the multivariate analysis,baseline NLR ≥ 2.13(hazard ratio [HR],2.74;95% confidence interval [CI],1.46-5.14),smoking(HR,1.99;95% CI,1.11-3.58),residual stenosis(HR,1.12;95% CI,1.09-1.15),baseline blood glucose levels(HR,1.01;95% CI,1.01-1.02)were associated with in-stent restenosis.Preoperative elevated NLR may be a predictor of ISR after CAS for asymptomatic stenosis.A total of 261 patients who underwent CAS for ≥50% symptomatic stenosis and ≥70% of asymptomatic stenosis of the extracranial carotid artery were screened from the database.During a mean follow-up of 12.1±16.1months(range,2.1–120.7),46 patients(17.6%)were determined with ISR.Multivariate analysis showed baseline MPV > 10.1 f L(hazard ratio,3.20;95% confidence interval 1.28-8.03),lesion length(HR,1.05;95% CI 1.02-1.08),residual stenosis(HR,1.07;95% CI 1.05-1.10)and baseline blood glucose(HR,1.01;95% CI 1.00-1.02)were associated with restenosis.From the database,25 patients who underwent simultaneous bilateral CAS were selected.In the patient-derived data,a low time-average wall shear stress(TAWSS)and a high oscillatory shear index(OSI)were often found at the location of NIH.Compared with the NIH symmetry group,bilateral carotid arteries had larger difference values of the PAOSI(10.56±20.798% vs-5.87±18.259%,P=0.048)and the ECA/CCA diameter ratio(5.64±12.751% vs-3.59±8.697%,P = 0.047)in the NIH asymmetric group.ConclusionsPatients with CAS were selected to study in the Nanjing Stroke Registry 1)As a marker of systemic inflammation,NLR may be a predictor of restenosis after CAS for asymptomatic carotied stenosis;2)Elevated MPV may be associated with ISR after CAS.Patients with high preprocedural MPV may benefit from an intensified antiplatelet therapy after CAS;3)Blood flow distribution in carotid artery of patients indicated a low TAWSS and a high OSI as predictors of neointima,ICA angle and ECA/CCA diameter ratio may be noteworthy characteristics of carotid arteries to predict a relative severe NIH.