Effect of collateral circulation in patients with multiple craniocervical artery stenoses

Abstract Based on previous findings, collateral circulation in the brain is vital in mitigating cerebral ischemia's effects and influencing stroke risk. This retrospective study examined collateral circulation, admission ischemic stroke status, and long‐term recurrence in patients with multiple craniocervical artery stenoses. Consecutive symptomatic internal carotid artery (ICA) stenosis patients from the First Affiliated Hospital of Soochow University were recruited. Baseline data including medical histories and neurological function at admission were collected. Imaging techniques assessed collateral compensative capacity. Multivariate logistic regression analysis was used to investigate the association between collateral circulation and case status. A total of 559 patients with symptomatic ICA stenosis were included, among whom 153 (27.4%) had concurrent moderate to severe vertebro‐basilar artery (VBA) stenosis. Dizziness, weakness/numbness, and slurring of speech were the primary symptoms in all patients. Over 36 months, 71 (12.7%) patients experienced a recurrence of acute ischemic stroke (AIS). In multivariate analysis, collateral circulation was found to be negatively associated with AIS (regional leptomeningeal collateral [rLMC] scores: OR: 0.798, 95% CI: 0.743–0.857, p < 0.001; Tan scores: OR: 0.478, 95% CI: 0.336–0.679, p < 0.001). Meanwhile, the collateral circulation scores were significantly associated with the recurrence of AIS within 3 years (rLMC scores: OR: 0.926, 95% CI: 0.860–0.997, p = 0.042; Tan scores: OR: 0.467, 95% CI: 0.306–0.712, p < 0.001). Most associations remained significant in the subgroup of patients with VBA stenosis. Favorable collateral circulation in multiple craniocervical artery stenosis patients reduced long‐term ischemic event recurrence. Stratifying treatment risks is essential for optimizing outcomes.


INTRODUCTION
Ischemic cerebrovascular disease is primarily caused by the narrowing or occlusion of the cervicocerebral arteries. 1,2he degree of stenosis is a well-established risk factor for ipsilateral ischemic stroke, and has therefore been utilized as a clinical criterion. 3However, the location, morphology, and extent of the stenotic lesion(s) are equally important in determining the severity of the disease, in addition to the rate of occlusion.In fact, the cumulative stenotic effect of multiple lesions may result in greater hemodynamic impairment than that of a single lesion with the same degree of stenosis. 4,5Furthermore, multiple stenoses are more likely to contribute to the further deterioration of carotid plaque. 6Therefore, identifying the vessels and mechanisms responsible for ischemic stroke in patients with multiple craniocervical stenoses is imperative.
Previous studies have confirmed a more frequent incidence of ischemic stroke and symptomatic multiple craniocervical artery stenoses in Asians. 7,8In a population-based study conducted in Taiwan, China, it was observed that approximately 18% of patients with large vessel atherosclerosis as the etiology for anterior circulation ischemic stroke or transient ischemic attack (TIA) also had moderate to severe stenosis of the vertebro-basilar artery (VBA). 9The presence of complex multiple and tandem stenoses and collateral circulation contributes to complex hemodynamic differences. 10Stenosis of the basilar artery is an independent high-risk factor for posterior circulation stroke (PCS), as well as early recurrence of TIA. 11Tandem stenosis and multiple lesions in the anterior and posterior circulation lead to additional blood flow restrictions.Moreover, the clinical severity and prognosis of PCS exhibits significant variation, and many clinical and pathological characteristics differ from those of anterior circulation stroke, which further complicates research efforts. 12he role of collateral circulation in internal carotid artery stenosis has been partially elucidated, but its significance in patients with multiple craniocervical artery stenoses, especially those with concomitant internal carotid artery stenosis and moderate to severe VBA stenosis, remains unclear. 13,14Would it have a potential additional effect on delayed stroke in the posterior circulation or early stroke recurrence?To guide subsequent treatment and evaluate the risks associated with surgical interventions, risk stratification may be necessary.
In general, studies on multiple craniocervical artery stenoses, especially on carotid artery stenosis combined with VBA stenosis, are relatively scarce and there are some controversies about the treatment modalities.Therefore, this study aimed to analyze the different clinical signs of multiple craniocervical artery stenoses and to investigate the role of collateral circulation on prognosis.

WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?
While the significance of collateral circulation in internal carotid artery stenosis is partially understood, its role in patients with multiple craniocervical artery stenoses, particularly in those with both internal carotid artery stenosis and moderate to severe vertebro-basilar artery (VBA) stenosis, remains inadequately clarified.

WHAT QUESTION DID THIS STUDY ADDRESS?
In this retrospective study, we examined the relationships between collateral circulation, admission acute ischemic stroke status, and long-term recurrence in patients with multiple craniocervical artery stenoses.Our goal was to confirm the hypothesis that collateral circulation might exert an additional impact on posterior circulation stroke or contribute to early stroke recurrence.

WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?
Patients who exhibit favorable collateral circulation in the context of multiple craniocervical artery stenosis are more likely to experience a reduced long-term recurrence rate of ischemic events.Stratifying treatment risks for these patients is essential.

HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?
These findings shed light on potential avenues for improving stroke risk assessment and management in this specific patient population.

Study population
We conducted a retrospective analysis of data from a consecutive cohort of patients presenting with symptomatic internal carotid artery (ICA) stenosis at the Emergency Stroke Center of the First Affiliated Hospital of Soochow University (3A-level public hospital).The data encompassed the period from January 2017 to June 2019 and included a review of follow-up data.
According to the current guidelines, all patients received the same medical advice, including a reasonable diet, effective blood pressure control, and intensive medical treatment.Routine blood, biochemical tests, cardiac ultrasound, and electrocardiography were performed for all patients at admission.This study involving human participants was reviewed and approved by the Institutional Review Board of The First Affiliated Hospital of Soochow University.The procedures used in this study adhere to the tenets of the Declaration of Helsinki.The experiments comply with the current laws of the country in which they were performed.All patients gave written informed consent.
The initial sample included 592 patients.Exclusion criteria were as follows: (1) patients younger than 18 years old; (2) patients without available radiological parameters; (3) patients with stroke caused by intracranial hemorrhage, subarachnoid hemorrhage, or sinus venous thrombosis; (4) patients with cerebral infarction or TIA due to cardioembolic risk factors (atrial fibrillation, atrial flutter, atrial septal defect, ventricular septal defect, patent ductus arteriosus, valvular heart disease, bioprosthetic or mechanical heart valve replacement, myocardial infarction within a month, dilated myocardial infarction, sick sinus syndrome, endocarditis, etc.); and (5) patients with confirmed vertebral dissection.

Clinical information collection
We retrospectively collected all the study population's data, including demographic, medical histories, and clinical characteristics, through electronic patient records and administrative databases.Hypertension was determined by the previous use of antihypertensive medication, a systolic blood pressure (SBP) ≥ 140 mm Hg, or a diastolic blood pressure ≥ 90 mm Hg.Diabetes was defined as previous use of hypoglycemic drugs, fasting blood glucose ≥7.0 mmol/L, or postprandial blood glucose ≥11.1 mmol/L.Dyslipidemia was defined as low-density lipoprotein cholesterol (LDL-C) ≥ 3.4 mmol/L, total cholesterol (TC) ≥ 5.2 mmol/L, or triglycerides (TG) ≥ 1.7 mmol/L, or a history of dyslipidemia or receiving lipid-lowering treatments.Blood count analysis was carried out by autoanalyzer (Sysmex XS-500i; Sysmex Corporation, Kobe, Japan).Serum biochemical parameters were assayed by automatic biochemical analyzer (Siemens ADVIA 1800; Siemens Healthcare, Malvern, PA, USA).We also assessed the neurological function at admission based on the National Institutes of Health Stroke Scale (NIHSS).

Radiological parameters
Regardless of the patient's age, various methods were used to determine the patient's condition.All patients underwent cervical cerebrovascular ultrasonography to screen for artery stenosis.Patients suspected to have arterial stenosis were further investigated with computed tomography angiography (CTA), digital subtraction angiography (DSA), or high-resolution magnetic resonance imaging (HR-MRI).New ischemic lesions were confirmed by MRI.Imaging sequences obtained included three-dimensional (3D) time-of-flight magnetic resonance angiography (MRA), axial T2-weighted, T1-weighted imaging, fluid-attenuated inversion recovery (FLAIR) sequences, and diffusion-weighted imaging (DWI).All the abovementioned sequences except MRA employed 5 mm slice thickness and 1.5 mm interslice gap.Patients who present with neurological deficits lasting less than 24 h, but with DWI results suggestive of a new ischemic lesion, are classified as having experienced an acute ischemic stroke (AIS).When patients experience a stroke affecting both the internal carotid and posterior circulation regions it is categorized as a PCS.
The degree of intracranial artery stenosis was judged by the method of the Warfarin-Aspirin Symptomatic Intracranial Disease Study. 15The degree of extracranial artery stenosis was judged by the North American Symptomatic Carotid Endarterectomy Trial (NASCET) criteria. 16,17Although these measurements were initially validated using DSA, there is a good correlation between CTA and MRA images. 17,18The measurement is conducted in a similar manner.A degree of luminal stenosis less than 50% was considered mild, while a degree of luminal stenosis greater than 50% was considered to be severe. 19ccording to the severity of the stenosis, we classified the responsible cerebral vessels into three groups: mild = 0% to 50% stenosis, moderate to severe = 50% to 99% stenosis, and the occlusion group.We assessed the following arterial segments: ICA, external carotid artery (ECA), middle cerebral artery (MCA), vertebral artery, and basilar artery.
The collateral compensative capacity on all CTAs was assessed using the Tan score and regional leptomeningeal collateral (rLMC) score.In the four-point Tan score scale, a score of 0 refers to absent collateral supply, 1 indicates poor collateral supply (>0% and ≤50%), 2 indicates moderate collateral supply (between 50% and 99%), and 3 points to good collateral supply (with a 100% filling of the MCA territory). 20In the rLMC score with a total of 20 points, a high score represented good collateral circulation.The area dominated by the ICA was divided into nine parts, namely the MCA M1-6 areas, basal ganglia area, anterior cerebral artery (ACA) area, and lateral fissure area.The scores of the first eight areas were 0, 1, and 2 points, and the lateral fissure area had a higher score of 0, 2, and 4 points, which represented no arterial display, a less-affected side than the healthy side, and the affected side being equal to or more than the healthy side. 21he degree of collateral circulation to the basilar artery (BA) was assessed based on the presence of posterior communicating arteries (PCOMs). 22Whenever possible, we reviewed DSA or CTA to determine the PCOMs' patency.A score was assigned according to the presence and diameter of the PCOMs: dominant = 2 points; hypoplastic = 1 point; and absent = 0 points.The total score ranged from 0 (no PCOMs) to 4 (two dominant PCOMs), with 0-1 points considered poor collateral flow and 2-4 points good collateral flow.
The retrospective re-evaluation of imaging findings involves a collaborative assessment by a panel comprising two radiologists and one neurologist.In the event of any disagreements, a consensus opinion is required to be reached.

Evaluation of outcome
At 6, 12, 24, and 36 months after onset, patients or their relatives were contacted by trained study staff members for routine follow-up.The primary outcome was AIS recurrence within 3 years.Other outcomes were acute cerebral infarction at admission and acute PCS at admission.All recurrent AIS were verified by new emerging neurological deficits documented in the medical records and combining them with computed tomography (CT) or MRI.

Statistical analyses
For descriptive purposes, the differences among continuous variables were analyzed by Student's t-test or Mann-Whitney U test, while Chi-square test assessed differences among categorical variables.Pearson's correlation coefficients were calculated to assess the relationship between the variables.Multivariate logistic regression analysis was used to investigate the association between collateral circulation and case status after adjusting for other variables.The 95% confidence intervals (CIs) reported for the logistic regression odds ratios (ORs) were calculated by the maximum likelihood estimation.Stratified analyses by concomitant VBA stenosis were performed to examine the stability of the association between collateral circulation and poor outcome.We conducted a multiplicative interaction analysis to determine whether collateral compensative capacity and gender had an impact on the AIS recurrence rate.No statistical power calculation was conducted prior to the study.The level of significance for these descriptive comparisons was established at 0.05 for two-sided hypothesis testing.Statistical analysis was performed in SPSS 26.0, R programming language 4.3.0,and GraphPad Prism 9.3.0.

Participants and their clinical characteristics
A total of 559 patients with symptomatic ICA stenosis were included in our study and formed the basis of this article; 153 (27.4%) of them suffered concomitant moderate to severe VBA stenosis, which was slightly higher than the previous study results.The flowchart of patient enrollment is presented in Figure S1.
The admission symptoms and signs of all 559 patients, including those with acute PCS at admission (n = 39), are presented in Figure 1.Dizziness (43.5%), weakness/ numbness (55.4%), and slurring of speech (22.5%) were the primary symptoms in all patients.Furthermore, these symptoms were found to be more pronounced in patients who had been diagnosed with PCS (74.4%, 79.5%, and 41.0%, respectively).

Comparison of clinical and radiological characteristics
The participants were classified into two groups based on the presence or absence of concomitant moderate to severe VBA stenosis: the ICA stenosis group, which included 406 patients, and the concomitant VBA stenosis group, which included 153 patients.
The admission symptoms and signs of the ICA stenosis group and the concomitant VBA group are presented in Figure 2.Both groups still presented with primary symptoms of dizziness, weakness/numbness, and slurring of speech.However, some non-focal symptoms (dizziness, nausea, and vomiting) were more frequent in patients with concomitant VBA stenosis than ICA stenosis.
Furthermore, we calculated the correlation coefficients between age, gender, smoking history, hypertension, diabetes, hyperlipidemia, CHD, AF, LDL-C, baseline SBP, NIHSS at admission, rLMC scores, Tan scores, PCOMs scores, ICA stenosis, VBA stenosis, MCA stenosis, ECA stenosis, AIS at admission, PCS at admission, and AIS recurrence in 3 years.The observed correlation coefficients were as follows: r = −0.26 between the NIHSS at admission and the rLMC scores (p < 0.001); r = −0.29 between the AIS at admission and the rLMC scores (p < 0.001), r = 0.24 between the NIHSS at admission and recurrence of AIS Recurrence of AIS in 3 years had significant correlations with NIHSS at admission and VBA stenosis; the rLMC scores had significant negative correlations with NIHSS at admission (Figure 3).

Collateral circulation association with poor outcome
Further multivariate analysis was performed using binary logistic regression to evaluate the predictive value of collateral circulation in patients with symptomatic ICA stenosis.This analysis also included patients with concomitant moderate to severe VBA stenosis.
For further study, we performed a subanalysis including patients with concomitant VBA stenosis.After analysis with a similar modeling strategy, significant associations were observed between AIS recurrence within 3 years and the Tan scores (OR: 0.066, 95% CI: 0.020-0.221,p < 0.001), AIS recurrence within 3 years and the PCOMs scores (OR: 10.973, 95% CI: 3.035-39.681,p < 0.001), and AIS at admission and the Tan scores (OR: 0.341, 95% CI: 0.122-0.951,p = 0.040; Table 3).Although rLMC was found to be associated with poor outcomes and recurrence in univariate analyses, no significant association was detected between rLMC scores and outcomes in multivariate analyses (Table 3).
In multiplicative interaction analyses, P interaction of rLMC scores was 0.267, P interaction of Tan scores was 0.611, and P interaction of PCOMs scores was 0.124, implying that neither collateral compensative capacity nor gender had an interactive impact on the AIS recurrence rate.

DISCUSSION
In our study, the collateral compensative capacity of symptomatic ICA stenosis was analyzed with related radiological parameters as well as clinical data.The main findings of this study are as follows: (1) collateral circulation was found to be negatively associated with AIS in symptomatic ICA stenosis patients; (2) improved collateral circulation was identified as an independent factor associated with a decreased risk of long-term recurrence in patients with multiple craniocervical artery stenosis; and (3) no significant association was detected between the collateral compensative capacity and the PCS.To our knowledge, this is the first study to investigate the association between collateral compensatory capacity and clinical outcomes in patients with multiple craniocervical artery stenosis.In Asian atherosclerotic stenosis of the extracranial intracranial arteries is the primary cause of ischemic stroke. 23Previous research has found that stenosis is more commonly located in the anterior circulation than in the posterior circulation among the Chinese population.This finding is consistent with our own study. 24owever, aging and hypertension are more associated with posterior circulation arterial stenosis than anterior circulation. 24Additionally, hypertension is an independent risk factor for stenosis development. 10Likely due to the high prevalence of hypertension and the aging population in China, approximately 25% of the patients in our study, as well as in previous studies, exhibited concurrent stenosis in the anterior and posterior circulations. 24hile the degree of arterial stenosis is a commonly recognized risk factor for stroke, emerging evidence suggests that other factors, particularly those affecting the hemodynamics of the entire craniocervical artery such as collateral compensatory capacity, may also play a role in stroke risk. 10Unlike coronary artery disease, stenosis and occlusion of the cranial carotid arteries due to progressive atherosclerosis can lead to the development of robust collateral circulation over time. 25As a result, collateral circulation can be observed in varying degrees of intracranial atherosclerosis.According to our study, there was a meaningful but only moderate correlation between arterial stenosis and collateral scores, which may be attributed to the fact that our sample only included symptomatic patients.The development of collateral branches from the meningeal artery, as well as from the anterior and posterior communicating arteries, is often associated with well-established intracranial collateral circulation.In patients with chronic arterial stenosis, this pressure drop downstream triggers collateral circulation through the activation of the endothelium and subsequent signaling events, including the release of various cytokines and inflammatory cells.This process is commonly referred to as arteriogenesis. 26The establishment of collateral circulation is a dynamic process that evolves over time and in response to arterial obstruction. 10ccording to previous studies, it is possible that the brain's collateral circulation is one of the most influential determinants in alleviating the potentially effects of cerebral ischemia.However, studies investigating the relationship between collateral circulation and hemodynamics are limited and have yielded partially contradictory findings.On one hand, favorable collateral circulation has been linked to better prognoses in acute ischemic events.In patients with VBA stenosis, robust evidence also suggests that superior collateral circulation is strongly correlated with a more favorable functional prognosis. 27The development of collateral circulation can positively affect the maintenance of perfusion in the ischemic penumbra and permit longer delays in achieving reperfusion. 28Conversely, while collateral circulation can help compensate for arterial obstruction, it may also indicate the presence of an underlying vascular disease.Improved collateral circulation often corresponds with more severe stenosis and a greater impact on distal blood supply, thereby implying a potentially higher risk of stroke. 10In patients with severe symptomatic carotid stenosis, collateral circulation is limited in its effectiveness in reducing cerebral circulation time and improving hemodynamics to prevent ischemic events. 29Previous studies have associated higher stroke recurrence rates with higher contralateral ICA flow and more frequent collateral flow via the circle of Willis. 30The conflicting results suggest that the role of collateral circulation in stroke pathophysiology requires further investigation.The intricate interplay between collateral circulation and arterial occlusion in the context of multiple arterial stenoses gives rise to a complex phenomenon, and its effects on morbidity and long-term prognosis remain uncertain.In patients with carotid stenosis, previous investigations have demonstrated that better collateral circulation is independently associated with a decreased risk of cerebral ischemic events, regardless of whether they are managed medically or surgically. 25,31Notably, our study further illustrates that even in patients with concomitant stenosis of both carotid and vertebral-basilar arteries, better collateral circulation is still independently associated with a reduction in the occurrence of cerebral ischemic events and long-term recurrence.However, there was only a moderate correlation between the status of the collateral circulation and the severity of baseline neurological deficits or functional status, which is consistent with previous research. 25The relationship between collateral circulation and neurological deficits is likely to be complex and multifaceted.That could partly be attributed to potential changes in collateral circulation over time.Interestingly, while collateral circulation was important in stroke, the correlation between collateral circulation and the development of PCS in our analysis was not statistically significant, suggesting that there may not be a meaningful association.
Our data should be interpreted with some caution due to the limitations of the study.This was an exploratory analysis, that was not powered, and did not account for multiple comparisons.The exclusive recruitment of participants from only one clinical unit and the omission of asymptomatic multiple stenoses in this study may have potentially affected the generalizability of the results.Another limitation of this study is the utilization of a single cutoff value (>50%) to identify moderate to severe stenosis, without exploring alternative cutoff values such as >70% stenosis.However, it is worth noting that the accuracy of non-invasive measurement for vertebral artery stenosis is comparatively lower than that for the carotid artery due to the smaller diameter.Therefore, the chosen cutoff method may not be inappropriate when considering multiple intracranial carotid artery stenoses.Furthermore, the application of different imaging methods (DSA, CTA, MRA) for plaque feature measurement introduces heterogeneity and may result in reduced accuracy.Nevertheless, it is essential to emphasize that the percentage of stenosis should not be affected by this variation in imaging techniques. 17,18

CONCLUSIONS
In summary, patients with favorable collateral circulation in the context of multiple craniocervical artery stenosis are more likely to experience a lower long-term recurrence rate of ischemic events.As a result, it is essential to stratify the subsequent risks in the treatment queue for these patients.

T A B L E 1
Comparison of clinical and radiological characteristics between patients with internal carotid artery stenosis and concomitant vertebro-basilar artery stenosis.

F I G U R E 1
Radar plots for the admission symptoms and signs of all subjects, encompassing those with posterior circulation stroke (PCS) at admission.

F I G U R E 2
Radar plots for the admission symptoms and signs of both the internal carotid artery stenosis group and the concomitant vertebro-basilar artery (VBA) group.
These factors were adjusted in the multivariate regression analysis: age, gender, smoking, hypertension, diabetes, hyperlipidemia, coronary heart disease, atrial fibrillation, low-density lipoprotein cholesterol, and internal carotid artery stenosis.Binary logistic regression analysis for collateral circulation on poor outcomes and long-term recurrence in the overall sample.These factors were adjusted in the multivariate regression analysis: age, gender, smoking, hypertension, diabetes, hyperlipidemia, coronary heart disease, atrial fibrillation, low-density lipoprotein cholesterol, and internal carotid artery stenosis.
Note: T A B L E 2Note: