Bilaterally Asymmetric Associations Between Extracranial Carotid Artery Atherosclerosis And Ipsilateral Middle Cerebral Artery Stenosis In Symptomatic Patients

Background:Ischemic stroke has become the most common disease leading to death and severe disability all over the world.Atherosclerotic diseases occurring in extracranial carotid arteries and intracranial arteries are considered to be the main sources of ischemic cerebrovascular events,such as stroke and transient ischemic attack(TIA).As a systemic disease,atherosclerosis commonly involves multiple vascular beds simultaneously and co-existing atherosclerotic plaques in the intracranial arteries and extracranial carotid arteries have been found to be prevalent in stroke patients.Previous studies have shown that co-existing intracranial and extracranial atherosclerotic plaques have stronger predictive values for future ischemic stroke compared with single vessel atherosclerosis.A better understanding of the severity and relationship between intracranial arteries and extracranial carotid arteries in patients with co-existing atherosclerotic plaques will be helpful to optimize the treatment strategies and minimize the clinical detriments caused by ischemic cerebrovascular events.In the past,severity of atherosclerotic disease was usually evaluated by traditional angiographic approaches,which can not determine plaque vulnerability from compositional features and surface conditions,such as lipid-rich necrotic core(LRNC),intraplaque hemorrhage(IPH)and fibrous cap rupture(FCR).In view of above shortcomings,magnetic resonance(MR)imaging techniques with black-blood pre-pulse have been widely used to characterize carotid vulnerable plaques relied upon high resolution,multiparameter and multisequence.There are both differences and similarities between intracranial arteries and extracranial carotid arteries.Although investigators have found that severity of carotid artery atherosclerosis is associated with intracranial artery stenosis,previous studies were limited to the presence or number of plaques,and lumen stenosis,lack of the evaluation from compositional features and surface conditions.However,once atherosclerosis involves multiple vascular beds,co-existing atherosclerotic plaques may not occur on the same side.Few investigators clearly pointed out whether there were relationships between extracranial carotid plaques and ipsilateral middle cerebral artery(MCA)stenosis.The human body is a biological individual with incomplete bilateral symmetry.When atherosclerosis occurs,there may also be bilateral asymmetrical relationships of several physio-pathological features.Previous studies have demonstrated that left-hemispheric ischemic strokes appear to more frequently and bring about worse outcomes than their right-hemispheric counterparts.In addition,atherosclerotic plaques on the left carotid artery are more vulnerable than those in the right carotid artery.Given this information,we hypothesize that the association between the extracranial carotid artery and intracranial artery atherosclerosis on the left and right sides may be asymmetrical.Objective:To determine the bilaterally asymmetric associations between extracranial carotid artery atherosclerosis and ipsilateral MCA stenosis in symptomatic patients using MR vessel wall imaging.Materials and methods:1047 adult patients with recent stroke or TIA(within 2 weeks after onsets of symptoms)and atherosclerotic plaque or intima-media thickness>1.5 mm in at least one carotid artery detected by cervical ultrasound scan,were randomly and consecutively recruited from different regions of China,for Chinese Atherosclerosis Risk Evaluation(CARE-II),a multicenter study.After clinical information collection(including traditional risk factors and whether there was definite symptomatic side),all the patients underwent extracranial carotid artery MR vessel wall imaging and intracranial artery MR angiography(MRA).Multicontrast vessel wall imaging sequences for extracranial carotid arteries included three-dimensional(3D)time-of-flight(TOF)MRA,T1-weighted(T1W)quadruple inversion recovery(QIR),T2-weighted(T2W)multislice double inversion recovery(MDIR),and Magnetization Prepared Gradient Recalled Echo(MP-RAGE)imaging sequences.A 3D TOF MRA was performed for intracranial arteries.The data of extracranial carotid arteries were analyzed by using carotid plaque analysis software(CASADE,USA).In all subjects with symptomatic carotid artery atherosclerosis,image reviews on symptomatic side were evaluated as follows:(1)severe stenosis(stenosis?50%)of MCA and extracranial carotid artery;(2)carotid plaque burden,such as mean lumen area,wall area,total vessel area,wall thickness and normalized wall index(wall area/total vessel area ×100%);(3)carotid plaque compositions,such as the presence or absence of calcification,LRNC,IPH and fibrous cap rupture(FCR),and the volume of each plaque compositional feature;(4)high-risk plaque,which was defined as a lesion with IPH,FCR or maximum percent LRNC(maximum LRNC volume/total plaque volume × 100%)>40%.Patients were divided into left symptomatic vascular(LSV)and right symptomatic vascular(RSV)groups according to the side of the artery responsible for symptoms.Independent sample t test,Mann Whitney U test,chi-square test or Fisher's exact test were used to compare the characteristics of extracranial carotid artery atherosclerotic plaque in LSV group,RSV group and subgroups with or without severe MCA stenosis.Univariate and multivariate logistic regression tests were used to evaluate associations between ipsilateral MCA stenosis and extracranial carotid plaque features respectively,as well as the bilateral asymmetry.Results:A total of 363 patients(mean age:61.2±10.4 years old;254 males)were included in final statistical analysis.684 patients were excluded from statistical analysis due to the following reasons:(1)missing clinical information(n=76);(2)image quality issues(n=98);(3)no intracranial MRA imaging(n=378);(4)no confirmed symptomatic side(n=132).363 patients were divided into LSV group(n=186;mean age,60.8110.9 years old;122[65.6%]males)and RSV group(n=177;mean age,61.6±9.9;132[74.6%]males)according to the symptomatic side.In LSV group,37(19.9%)patients had severe MCA stenosis on the symptomatic side.Compared with 147(80.1%)patients without left severe MCA stenosis,those with ipsilateral severe MCA stenosis showed significantly higher prevalence of carotid IPH(18.9%vs.7.4%;P=0.034)and FCR(16.2%vs.4.0%;P=0.007).Besides,prevalence of carotid severe stenosis(18.9%vs.8.1%;P=0.051),LRNC(70.3%vs.53.0%;P=0.058)and HRP(29.7%vs.16.8%;P=0.074)tended to increase,but the differences were not statistically significant.In RSV group,41(23.2%)patients had severe MCA stenosis on the symptomatic side.Compared with 136 patients(76.8%)without right severe MCA stenosis,those with ipsilateral severe MCA stenosis showed significantly higher prevalence of carotid severe stenosis(26.8%vs.8.8%;P=0.003).No significant differences were found in other plaque morphological or compositional features between patients with and without ipsilateral severe MCA stenosis in both LSV and RSV group(all P>0.10).In LSV group,univariate logistic regression revealed that left symptomatic carotid IPH(OR,2.93;95%CI,1.05-8.17;P=0.040)and FCR(OR,4.61;95%CI,1.39-15.26;P=0.012)were significantly associated with ipsilateral severe MCA stenosis.Besides,marginal associations were observed between left symptomatic carotid severe stenosis(P=0.058),LRNC(P=0.062),HRP(P=0.078)and ipsilateral severe MCA stenosis.After adjusted for related clinical factors,left symptomatic carotid severe stenosis(OR,2.83;95%CI;1.01-7.96;P=0.049),LRNC(OR,2.54;95%CI,1.12-5.77;P=0.026),IPH(OR,3.31;95%CI,1.14-9.65,P=0.028),FCR(OR,5.22;95%CI,1.54-17.71;P=0.008)and HRP(OR,2.57;95%CI,1.08-6.14;p=0.033)were all significantly associated with ipsilateral severe MCA stenosis.In RSV group,univariate logistic regression showed that right symptomatic carotid severe stenosis(OR,3.79;95%CI,1.53-9.41;P=0.004)was significantly associated with ipsilateral severe MCA stenosis.After adjusted for related clinical factors,this association(OR,3.98;95%CI,1.54-10.32;P=0.004)remained statistically significant.No significant association could be found between right symptomatic carotid plaque compositional features(including LRNC,IPH and FCR)and ipsilateral severe MCA stenosis(all P>0.05).Conclusion:In patients with atherosclerosis,left symptomatic extracranial carotid plaque component characteristics were independently associated with ipsilateral severe MCA stenosis,but no correlation was found on the right side,indicating that associations between symptomatic extracranial carotid plaque vulnerability and intracranial artery stenosis in atherosclerotic disease were asymmetric.Our study suggests that different assessments of atherosclerotic burdens and risks should be paid to assessing on different sides of multivascular atherosclerosis,especially the component characteristics of symptomatic extracranial carotid plaque on the left side.