Introduction: The level of collateral compensation plays a pivotal role in chronic symptomatic intracranial vertebrobasilar stenosis (IVBS). This study aimed to evaluate the association between cerebrovascular risk factors and collateral compensation in chronic symptomatic IVBS. Methods: This single-center cross-sectional study retrospectively reviewed 238 patients with angiographically demonstrated IVBS and divided them into good collateral compensation (GCC) group (collateral grade: 3–4, n = 110) and poor collateral compensation (PCC) group (collateral grade: 0–2, n = 128). The demographic information, laboratory tests, and clinical data of the two groups were compared and assessed using univariate logistic regression. Multivariate logistic regression was employed to analyze the independent related factors of collateral compensation. Results: Hyperlipidemia, high-density lipoprotein (HDL), and fasting blood glucose (FBG) were significantly different between the two groups. Multivariate logistic regression analysis revealed that HDL (odds ratio [OR]: 1.134, 95% confidence interval [CI]: 1.081–1.190), FBG (OR: 0.945, 95% CI: 0.925–0.964), and hyperlipidemia (OR: 0.261, 95% CI: 0.129–0.527) were statistically independent related factors of collateral compensation. The receiver-operating characteristic (ROC) analysis provided cutoff values of 34 mg/dL and 135 mg/dL for HDL and FBG associated with GCC and PCC. Conclusion: Higher HDL levels are associated with higher incidence of GCC, whereas higher FBG levels and hyperlipidemia are associated with higher incidence of PCC.

© 2022 The Author(s). Published by S. Karger AG, Basel

Introduction

Intracranial vertebrobasilar stenosis (IVBS) usually has devastating effects, such as infarction of the cerebellum and brainstem [1]. Collateral circulation, especially the level of collateral compensation, plays a pivotal role in severe IVBS prevention and treatment. As a protective vascular pathway, collateral compensation could influence ischemic injury severity and direct therapy [2].

In most patients with cerebrovascular disease, one or more risk factors, such as hypertension, hyperlipidemia, and diabetes mellitus (DM), among others, are present. There is some evidence that disease development is influenced by these factors, which are also associated with collateral circulation [3]. This study investigated the effects of cerebrovascular risk factors on collateral compensation in chronic severe IVBS. To the best of our knowledge, this is the first study that has directly linked risk factors of cerebrovascular disease and collateral compensation in IVBS.

Materials and Methods

This study protocol was reviewed and approved by the Ethics Committee of Tianjin Huanhu Hospital (approval number: 2021-118). The study was conducted in accordance with the latest revision of Declaration of Helsinki. Written and oral informed consent was obtained from patients.

Inclusion and Exclusion Criteria

Patients with chronic symptomatic IVBS admitted to Tianjin Huanhu Hospital from January 2015 to December 2020 were retrospectively enrolled. The inclusion criteria were as follows: (1) patients suffered from the qualifying ischemic events, including clinically diagnosed transient ischemic attack (TIA) or ischemic stroke confirmed by magnetic resonance imaging in the intracranial vertebrobasilar territory, with the onset >1 month, which is widely considered to have entered into a chronic phase with established collateral circulation [4, 5]; (2) diagnosis by computed tomography angiography confirmed with digital subtraction angiography (DSA) in chronic phase revealing a 70%–99% stenosis rate of vertebral artery V4 segment or basilar artery as defined by the Warfarin-Aspirin Symptomatic Intracranial Disease Trial criteria [6], and for V4 segment lesion, the contralateral vertebral artery was either hypoplastic or occluded; (3) patients without thrombolysis or endovascular treatment; and (4) the age of 18–80 years.

The exclusion criteria were as follows: (1) nonatherosclerotic lesions caused by vasculitis, dissection, embolic disease, reversible cerebral vasoconstrictive syndrome, and radiation factors; (2) brain tumor, cerebral hemorrhage, or ischemic stroke in territories other than the intracranial vertebrobasilar territory; (3) contraindications for contrast media, aspirin, clopidogrel, and other related medicines; (4) concurrent significant stenosis (≥50%) of internal carotid artery system or extracranial vertebral artery; and (5) poor physical condition (modified Rankin Scale scores ≥4) or combination with other severe comorbidities.

At present, the American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology (ASITN/SIR) grading system is the main collateral circulation evaluation method, based on the overall collateral perfusion in ischemic regions, and grade 3–4 is widely recognized as good collateral or sufficient compensation, while grade 0–2 is widely recognized as poor collateral or insufficient compensation (Table 1) [6, 7]. All patients were divided into two groups based on DSA and ASITN/SIR grading systems.

Table 1.

Group 1 represented good collateral compensation (GCC) group, in which collateral circulation could provide sufficient compensation without perfusion defects in the ischemic region on DSA. This was also equivalent to the collateral grades (ASITN/SIR) of 3–4 (shown in Fig. 1).

Fig. 1.

A 53-year-old man in GCC group. This patient with combined DM presented with a 1-month history of dizziness diagnosed as TIA. a CTA showed 85% stenosis of the V4 segment of the right vertebral artery and complete occlusion of the left vertebral artery. b–d DSA of right vertebral and bilateral internal carotid arteries revealed that the collateral compensation was good. CTA, computed tomography angiography.

Group 2 represented poor collateral compensation (PCC) group, in which collateral circulation could not provide sufficient compensation with perfusion defects in the ischemic region on DSA. This was also equivalent to the collateral grades (ASITN/SIR) of 0–2 (shown in Fig. 2).

Fig. 2.

A 65-year-old woman in PCC group. This patient with combined hypertension presented with a 2-month history of intermittent vertigo, nausea, and vomiting. a MRI (DWI) at onset confirmed infarctions in the cerebellopontine arm and cerebellar hemisphere. b CTA showed 90% stenosis in the middle segment of the basilar artery. c–f DSA of bilateral vertebral and internal carotid arteries showed that collateral compensation was poor. MRI, magnetic resonance imaging; CTA, computed tomography angiography.

Clinical Evaluation

Based on previously reported risk factors for cerebrovascular disease [8, 9], the study recorded demographic information, including age and sex, current smoking, and history of coronary heart disease, hypertension, DM, and hyperlipidemia; biochemical tests, such as fasting blood glucose (FBG), low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglyceride (TG), and total cholesterol (TC); prior medications, including aspirin, clopidogrel, and statins; and qualifying event and time from qualifying event to DSA-evaluated collaterals.

Hypertension was recognized as systolic blood pressure >140 mm Hg and/or diastolic blood pressure >90 mm Hg identified at least twice on admission or as taking any antihypertensive drugs. DM was defined as FBG level >126 mg/dL or blood glucose level >200 mg/dL at any measurement or use of an antidiabetic agent. Hyperlipidemia was defined as serum TC ≥240 mg/dL, TG ≥200 mg/dL, LDL cholesterol ≥130 mg/dL, or HDL cholesterol <35 mg/dL. Current smoking was defined smoking as at least 7 cigarettes per week for at least 6 months at diagnosis.

Radiographic images of each patient were reviewed. Magnetic resonance imaging was performed to evaluate the ischemic lesions in the intracranial vertebrobasilar territory. Computed tomography angiography was utilized to assess the severity and stenosis sites. As the gold standard of evaluating the collateral status, DSA was performed to assess the level of collateral compensation in each patient. All angiograms and collateral grading were performed independently by two experienced interventional neuroradiologists who were blinded to patients’ clinical characteristics and laboratory results.

Statistical Analyses

Data analysis was performed using the SPSS27.0. Quantitative variables were examined for normal distribution using Shapiro-Wilk test and were presented as mean ± standard deviation for normally distributed variables and median with interquartile range for nonnormally distributed variables. Independent samples t test was adopted for the comparison of normally distributed variables. Mann-Whitney U test was used to compare nonnormally distributed variables. Categorical variables, expressed as percentages, were compared using the χ2 test. Univariate logistic regression was utilized to assess significant variables (p < 0.05) entered into the multivariate logistic regression to analyze the independent related factors for collateral compensation. Receiver-operating characteristic (ROC) analysis was performed to detect the optimal cutoff value of continuous variables. p < 0.05 was considered statistically significant.

Results

The study population comprised 302 consecutive patients with severe IVBS who underwent DSA in our institution. Those who had severe medical disease (n = 6), brain tumor (n = 5), cerebral hemorrhage (n = 3), vertebrobasilar artery dissection (n = 10), embolic disease (n = 13), vasculitis (n = 1), contraindications for contrast media (n = 3), and concurrent significant stenosis (≥50%) in the internal carotid artery system or extracranial vertebral artery (n = 23) were excluded. Finally, a total of 64 patients were excluded, and 238 patients were eventually enrolled in the study.

Baseline Characteristics of the Two Groups

The mean patients’ age (168 men and 70 women) was 57.87 ± 6.57 years. There were 110 and 128 patients in GCC and PCC groups, respectively. This cross-sectional study included 91 (38.2%) patients with basilar artery stenosis and 147 (61.8%) patients with stenosis of the V4 segment. Considering all patients, the qualifying event was stroke in 54.6%, and the mean time from qualifying event to DSA-evaluated collaterals was 44.52 ± 7.76 days, revealing that both groups were in the chronic phase with established collateral circulation. Baseline patients’ characteristics in the two groups are summarized in Table 2.

Table 2.

Demographics and potential factors related to collateral compensation were compared and analyzed using univariate logistic regression

By χ2 test, the frequency of hyperlipidemia was lower in the GCC group (p < 0.001), whereas the frequency of DM and hypertension was similar between the two groups. Especially for laboratory measurements by independent samples t test and Mann-Whitney U test, patients in GCC group exhibited higher HDL (p < 0.001) and lower FBG levels (p < 0.001). LDL, TC, and TG levels were similar between the two groups (p > 0.05). There were no statistical differences in other variables between the two groups.

Univariate Analysis of Variables in PCC/GCC Group

Through univariate logistic regression analysis shown in Table 2, hyperlipidemia and FBG levels in GCC group were significantly lower than those in the PCC group (p < 0.001). HDL levels were significantly higher in the GCC group than those in the PCC group (p < 0.001). Elevated HDL levels (odds ratio [OR]: 1.126, 95% confidence interval [CI]: 1.083–1.171) and lowered FBG levels (OR: 0.942, 95% CI: 0.925–0.958) were correlated with GCC, while hyperlipidemia was correlated with PCC (OR: 0.391, 95% CI: 0.231–0.661). In contrast, collateral compensation was not related to other variables (p > 0.05).

Multivariate Logistic Regression Analysis for Independent Related Factors of Collateral Compensation

Based on the results of univariate analysis, hyperlipidemia, HDL levels, and FBG levels were included in the multivariate logistic regression for collateral compensation. As shown in Table 3, HDL (OR: 1.134, 95% CI: 1.081–1.190), FBG (OR: 0.945, 95% CI: 0.925–0.964), and hyperlipidemia (OR: 0.261, 95% CI: 0.129–0.527) were statistically independent related factors of collateral compensation. Higher HDL levels were associated with higher incidence of GCC, whereas higher FBG levels and hyperlipidemia were associated with higher incidence of PCC.

Table 3.

Multivariate logistic regression analysis for collateral compensation in chronic severe IVBS

The ROC analysis provided a cutoff value of 34 mg/dL for HDL associated with GCC with 79% sensitivity, 60% specificity, and 0.758 area under the ROC curve (95% CI: 0.698–0.818). Similarly, the ROC analysis provided a cutoff value of 135 mg/dL for FBG associated with PCC with 57% sensitivity, 96% specificity, and 0.789 area under the ROC curve (95% CI: 0.733–0.846).

DiscussionHistory and Practical Significance of the Study

The natural course of chronic severe IVBS is dismal, with a high rate of disability and mortality [10]. More importantly, chronic severe IVBS refractory to medical therapy is challenging to treat because of the high rates of complications and technical difficulty [11, 12]. Conventionally, it was believed that collateral circulation could provide sufficient blood flow as patients enter in chronic phase. However, not all collaterals actually provide sufficient compensation, and many patients experience recurrent TIA and stroke for a long time [13, 14]. The annual stroke recurrence rate in patients with VBS has been as high as 10%–15% or even up to 33% in the first month [15]. Therefore, it is significant to study the related factors for collateral compensation.

The cerebral collateral circulation simultaneously includes primary (the circle of Willis) and secondary collaterals (leptomeningeal anastomoses, ophthalmic arteries, other arteriole anastomoses, and neovascularization). It is different from the coronary collateral and others. Previous research paid more attention to its formation. It has been reported that the establishment of cerebral collateral circulation is related to age, genetic factors, hypertension, metabolic syndrome, statin use, and other factors, and there are widespread controversies on the various factors and the specific roles they play [16-18]. This study mainly assesses the level of collateral compensation in IVBS based on DSA evaluation and ASITN/SIR grading system, which have been incorporated into the indications for endovascular treatment by many scholars [6, 19]. Compared with previous research, the results of this study show that hyperlipidemia, HDL, and FBG were more correlated with the level of collateral compensation. Below, we discuss the association between each factor and collateral compensation in severe IVBS.

The Related Factors of Collateral Compensation

In our study, hyperlipidemia was an independent related factor of collateral compensation. Kitayama et al. [20] found in a study that hyperlipidemia inhibited collateral vessel growth and led to a mismatch between supply and demand of blood flow to brain tissue by disrupting the function of vascular endothelial cells, smooth muscle cells, and cerebral vessels. This is in line with our results demonstrating that hyperlipidemia negatively influences collateral compensation, and hyperlipidemia frequency in the GCC group was significantly lower than that in the PCC group.

As an important indicator of blood lipid levels, HDL was also an independent related factor of collateral compensation in our study. With an OR >1, it promotes sufficient compensation of collateral circulation. The possible mechanism was that HDL possessed antiatherogenic properties, and it could promote cholesterol efflux from macrophage foam cells and protect the endothelium [21]. Moreover, HDL increases the quantity and functions of endothelial progenitor cells that play an important role in the endothelial repair process [22]. Besides, HDL also decreases inflammatory activity associated with impaired collateral circulation. Wadham et al. [23] proved that HDL inhibits C-reactive protein inducing expression on multiple inflammatory factors. With β = 0.126 and OR = 1.134, elevated HDL positively influences the collateral compensation.

Our study demonstrated that FBG was an independent related factor of collateral compensation. There were significant differences in the levels of FBG between GCC and PCC groups. With β = −0.057 and OR = 0.945, raising the FBG levels was inversely associated with the collateral compensation, and it has been reported that the modest increase in FBG levels was associated with an increased incidence of TIA and stroke [24], just as Zhou et al. [25] previously pointed out that raising blood sugar levels weakened the ability of monocytes to participate in angiogenesis and remodeling, which is harmful to collateral circulation. The possible mechanisms also included that elevated FBG can induce oxidative stress in endothelial cells and impair the endothelium by inflammation [26]. Menon et al. [27] reported that moderate elevations of glucose affected the oxidative status. In this study, higher FBG levels were associated with higher incidence of PCC, and FBG levels in GCC group were significantly lower than that in PCC group.

In our study, there was no significant difference in statin use between the two groups. However, Obviagele et al. [28] suggested an association between statin use and better collateralization during acute stroke, where cardioembolic was the major pathogenic mechanism. Lee et al. [29] also reported that excellent collaterals (grade 3–4) were more frequently observed in statin users (11/22 patients, 50%) than in statin-naive patients (21/76 patients, 27.6%; p = 0.049) with acute middle cerebral artery infarction due to atrial fibrillation. This difference with our results might be due to the stroke mechanism, the stage of the disease, the difference in ethnicity, etc.

Also, the role of genes is being increasingly recognized. Lucitti et al. [30] reported that naturally occurring variants of Rabep2 were major variation determinants in collateral extent and stroke severity in mice. Matsuda et al. [31] reported that a histological section treated with hypoxia-inducible factor (HIF)-1α DNA showed an increased expression of HIF-1α and vascular endothelial growth factor with collateral circulation in rats. The HIF-1α transcription factor can promote angiogenesis. Anan et al. [32] also reported that a histological section treated with HIF-1α DNA showed a well-developed collateral circulation in rats.

However, this study has some limitations. We have drawn limited conclusions of the cross-sectional study without the temporality assumption. Second, risk factors influencing cerebrovascular disease are still being explored; thus, the related factors analyzed in this study are not comprehensive, requiring an in-depth study in the future.

Conclusions

Higher HDL levels are associated with higher incidence of GCC, whereas higher FBG levels and hyperlipidemia are associated with higher incidence of PCC. As a preliminary cross-sectional study, the related factors of collateral compensation still need further analysis by prospective cohort studies.

Statement of Ethics

This study protocol was reviewed and approved by the Ethics Committee of Tianjin Huanhu Hospital (approval number: 2021-118). The study was conducted in accordance with the latest revision of Declaration of Helsinki. Written and oral informed consent was obtained from patients.

Conflict of Interest Statement

The authors have no conflicts of interest.

Funding Sources

This study was supported by Major Special Projects of Tianjin Science and Technology Commission (No. 18ZXDBSY00180) and Tianjin Health Science and Technology Project (No. KJ20045).

Author Contributions

Qi Li: methodology, data collection, formal analysis, and writing – original draft preparation. Benlin Wang, Yang Sun, and Jie Qiao: material preparation and data collection. Xiaoguang Tong: conceptualization, methodology, writing – reviewing and editing and funding acquisition.

Data Availability Statement

All data generated or analyzed during this study are included in this article. Further enquiries can be directed to the corresponding author.

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