†These authors contributed equally.
The
relationship between the severity of intracranial atherosclerotic disease and the
circle of Willis integrity is unclear. In this brief report, we investigate the
associations between symptomatic intracranial atherosclerotic
disease and the integrity of the circle of Willis. Patients with symptomatic
intracranial atherosclerosis were enrolled and underwent intracranial artery
magnetic resonance vessel wall imaging and time-of-flight angiography. The
presence or absence of an intracranial atherosclerotic plaque and its maximum
wall thickness and stenosis were evaluated. The presence or absence of the
A1 segment of the bilateral anterior cerebral arteries (from
the internal carotid artery to the anterior communicating artery segment is
called anterior cerebral artery A1 segment), and anterior
communicating artery, the P1 segment of the bilateral posterior cerebral arteries
(The P1 segment of the posterior cerebral artery is a horizontally outward
segment), and bilateral posterior communicating arteries were
determined. The associations of the intracranial plaque
features with the integrity of the circle of Willis were analyzed. Of the 110
recruited subjects (57.2
Intracranial atherosclerosis is the main cause of ischemic stroke in an Asian population, divided into symptomatic and asymptomatic types. Symptomatic intracranial atherosclerosis refers to ischemic stroke or transient ischemic attack occurring in the stenosis area of the supplying artery [1]. It is well established that the progression of the intracranial atherosclerotic disease will decrease blood perfusion and increase the risk of cerebral ischemic events [2, 3, 4, 5, 6]. During the progression of atherosclerotic cerebrovascular disease, the compensatory system can be initiated through the collateral circulation to preserve perfusion and stabilize cerebral blood flow [7, 8, 9, 10, 11]. As the primary collateral pathway, the circle of Willis (COW) connects the bilateral anterior circulations via the anterior communicating artery (ACoA) or the anterior and posterior circulations via the posterior communicating arteries (PCoAs). The integrity of the COW usually represents the capability of compensation when there is a decline in cerebral blood flow [12, 13]. Since atherosclerosis is a systemic disease that frequently involves multiple vascular beds (including the contralateral carotid artery and basilar artery), knowledge of the dominant communicating arteries is important for developing treatment strategies in patients diagnosed with atherosclerotic diseases multiple vascular beds.
Limited studies have demonstrated that the severity of atherosclerotic carotid disease is associated with the presence of collateral flow in the communicating arteries. Hartkamp et al. [14] demonstrated that patients with internal carotid artery (ICA) obstruction were more likely to have complete anterior parts of the COW, such as the presence of bilateral A1 segments and an ACoA, or an entirely complete COW. Researchers also found that the stenosis of an ICA obstruction was correlated with cross-flow in the ACoA [15, 16]. However, the association between the severity of intracranial artery atherosclerosis and the integrity of the COW (particularly the status of the PCoAs) remains unclear.
It is hypothesized that intracranial atherosclerotic disease may activate the communicating arteries in certain orders that integrate bilateral circulations and/or anterior and posterior circulations as the disease severity increases. This study investigates the associations between the severity of intracranial atherosclerotic disease and the integrity of communicating arteries in the COW using three-dimensional (3D) magnetic resonance (MR) vessel wall imaging.
In this study, patients with recent (within 2 weeks) ischemic stroke or transient ischemic attack (TIA) in anterior circulation determined by either imaging findings or clinical diagnosis were continuously recruited. All patients underwent MR imaging. The exclusion criteria were as follows: (1) cardiogenic stroke, hemorrhagic stroke; (2) patients who failed to complete MR examination due to contraindication, including pacemaker, artificial valve, nerve stimulator, eyeball foreign body and convulsion with a high fever. Clinical information (age, sex, body mass index, cholesterol level, and blood pressure) was recorded. Each patient collected history of hypertension, diabetes mellitus, smoking, hyperlipidemia, stroke, transient ischemic attack, and coronary heart disease.
The MR imaging was conducted on a 3.0T MR scanner (Achieva TX, Philips
Healthcare; Best, the Netherlands) with a custom-designed 36-channel
neurovascular coil. Intracranial arteries were imaged by acquiring images of the
vessel wall and angiography with three-dimensional motion-sensitizing driven
equilibrium rapid gradient-echo sequence (3D MERGE), 3D
T1-volume isotropic turbo spine-echo acquisition (VISTA), and 3D time-of-flight
(TOF). The extracranial carotid arteries were imaged by TOF MR angiography. The
parameters for 3D MERGE were as follows: fast field echo; repeat time/echo time,
9.2/4.3 ms; flip angle, 6
Two experienced radiologists interpreted the MR images for consensus using an MR workstation (Extended MR WorkSpace 2.6.3.4; Best, the Netherlands). Intracranial atherosclerosis was defined as eccentric wall thickening occurring in the following arterial segments of anterior circulation: internal carotid artery (C3—C7), M1 segment of the middle cerebral artery (MCA) and A1 segment of the anterior cerebral artery (ACA). The vessel wall images determined the presence or absence of intracranial artery plaques. The maximum wall thickness (Max WT) and stenosis of the corresponding intracranial atherosclerotic plaque were measured when a plaque was present. Luminal stenosis was measured on the maximum intensity projection images of TOF MR angiography (MRA) utilizing criteria for warfarin–aspirin symptomatic intracranial disease (WASID) [17] and North American Symptomatic Carotid Endarterectomy Trial NASCET [18] for intracranial arteries and carotid arteries, respectively. The presence or absence of the A1 segment of the bilateral anterior cerebral arteries, an ACoA, the P1 segment of the bilateral posterior cerebral arteries, and bilateral PCoAs was evaluated on the TOF MRA images.
The Shapiro-Wilk normality test tests the normality of the data distribution.
Continuous variables were reported as the mean and standard deviation, and
discrete variables were described as percentages. The clinical characteristics
were compared between patients with and without an ACoA or PCoAs using the
Mann–Whitney or chi-square test (where appropriate). When there were multiple
plaques in the intracranial arteries of one patient, the most severe plaque
burden (including Max WT and stenosis) among all plaques was selected for
statistical analysis. It is well evidenced that the severity of plaque burden was
associated with plaque vulnerability at the patient level. Thus, an
atherosclerotic plaque with the most severe burden may represent the most
vulnerable plaque among multiple lesions. For patients with bilateral A1 and P1
segments, the Max WT and stenosis of the intracranial plaques were compared
between subjects with and without an ACoA or PCoAs using the non-parametric
Mann–Whitney U test. Univariate and multivariate logistic regressions were
performed to determine the odds ratios and corresponding 95% confidence
intervals (CIs) of the intracranial artery plaque, Max WT, and stenosis in
discriminating the presence of an ACoA or PCoAs. The probability of intracranial
artery stenosis in predicting the presence of an ACoA or PCoAs before and after
adjusting for confounding factors was calculated using C-statistical analysis. A
p-value
One hundred ten patients (mean age, 57.2
| Mean | |||||||
| All patients | *ACoA (+) | *ACoA (–) | p | #PCoA (+) | #PCoA (–) | p | |
| (n = 110) | (n = 79) | (n = 6) | (n = 34) | (n = 45) | |||
| Age, years | 57.2 |
56.7 |
56.8 |
0.976 | 56.5 |
56.8 |
0.938 |
| Male sex | 72 (65.5) | 52 (65.8) | 2 (33.3) | 0.185 | 24 (70.6) | 28 (62.2) | 0.438 |
| BMI, kg/m |
25.3 |
25.3 |
25.4 |
0.951 | 25.4 |
25.3 |
0.864 |
| Smoking | 58 (52.7) | 42 (53.2) | 2 (33.3) | 0.423 | 18 (52.9) | 24 (53.3) | 0.972 |
| Hypertension | 74 (67.3) | 48 (60.8) | 5 (83.3) | 0.402 | 21 (61.8) | 27 (60) | 0.874 |
| Hyperlipidemia | 77 (70) | 55 (69.6) | 5 (83.3) | 0.756 | 23 (67.6) | 32 (71.1) | 0.939 |
| LDL, mmol/L | 2.86 |
2.94 |
2.16 |
0.074 | 3.20 |
2.75 |
0.323 |
| HDL, mmol/L | 1.12 |
1.10 |
0.99 |
0.635 | 1.19 |
1.03 |
0.152 |
| TC, mmol/L | 4.53 |
4.51 |
4.00 |
0.313 | 4.63 |
4.42 |
0.444 |
| TG, mmol/L | 1.60 |
1.64 |
1.62 |
0.951 | 1.46 |
1.77 |
0.373 |
| DM | 35 (31.8) | 22 (28.2) | 4 (66.7) | 0.071 | 11 (32.4) | 11 (25.0) | 0.474 |
| Statin use | 82 (74.5) | 56 (70.9) | 6 (100) | 0.184 | 23 (67.6) | 33 (73.3) | 0.582 |
| History of stroke | 62 (56.4) | 38 (48.1) | 6 (100) | 0.026 | 16 (47.1) | 22 (48.9) | 0.872 |
| History of CHD | 16 (14.5) | 12 (15.2) | 0 (0) | 0.588 | 5 (14.7) | 7 (15.6) | 0.917 |
| BMI, body mass index; LDL, low-density lipoprotein; HDL, high-density lipoprotein; TC, total cholesterol; TG, total glyceride; DM, Diabetes mellitus; CHD, coronary heart disease. *For patients with the presence of bilateral A1 and P1 segments. #For patients with bilateral A1 and P1 segments and ACoA. | |||||||
Of the 110 patients, 51 (46.4%) and 44 (40%) were found to have atherosclerotic plaques and stenosis in the intracranial arteries, respectively. Of all 51 patients with intracranial plaques, 75 plaques were detected, and 45 plaques were located in C3—C7 segments of intracranial internal carotid arteries, 23 plaques were located in the M1 segment of MCA and 7 plaques located in the A1 segment of ACA.
The presence of bilateral A1 segments, bilateral P1 segments, and both bilateral A1 and P1 segments were observed in 100 (90.9%), 92 (83.6%), and 85 (77.3%) patients, respectively. In addition, 91 (82.7%) patients had an ACoA, and 58 (52.7%) patients had PCoAs. The whole anterior part of the COW (presence of bilateral A1 segments and an ACoA) and the whole posterior part of the COW (presence of bilateral P1 segments and PCoAs) were found in 91 (82.7%) and 15 (13.6%) patients, respectively. An entirely complete COW was found in 13 (11.8%) patients.
For patients with both bilateral A1 and P1 segments (n = 85), the intracranial
stenosis in patients with an ACoA was significantly more severe than in patients
without an ACoA (19.7%
| Mean | ||||||
| *ACoA (+) | *ACoA (–) | p | #PCoA (+) | #PCoA (–) | p | |
| (n = 79) | (n = 6) | (n = 34) | (n = 45) | |||
| Presence of plaque | 48 (60.8) | 3 (50) | 0.679 | 26 (76.5) | 22 (48.9) | 0.013 |
| Max WT, mm | 2.2 |
1.7 |
0.268 | 2.2 |
2.2 |
0.748 |
| Stenosis, % | 19.7 |
1.4 |
0.046 | 27.9 |
13.5 |
0.007 |
| *For patients with presence of bilateral A1 and P1 segments. #For patients with presence of bilateral A1 and P1 segments and ACoA. | ||||||
Fig. 1.MR images of a 60-year-old man with severe intracranial artery stenosis who also had an anterior and posterior communicating artery (ACoA and PCoA, respectively). (a) and (b) represent the MIP images of TOF MRA. ACoA and left PCoA are present (thin white arrows in a and b), and severe stenosis in the C2 segment of the left internal carotid artery was observed (thick arrows in a and b). (d) and (f) represent the curved reconstructed images of MERGE. Two plaques in the C2 segments of the bilateral internal carotid arteries (arrows in c and e) are shown.
For patients with bilateral A1 and P1 segments, the presence of an ACoA was not
significantly associated with the presence of plaques, Max WT, and stenosis
before and after adjusting for the clinical confounding factors of age, sex, body
mass index, hypertension, smoking, diabetes mellitus, hyperlipidemia, history of
stroke and the stenosis degree of extracranial carotid atherosclerosis (all
p
| Presence of ACoA* | ||||||
| Univariate regression | Multivariate regression# | |||||
| OR | 95% CI | p | OR | 95% CI | p | |
| Presence of plaque | 1.548 | 0.294–8.166 | 0.606 | 0.455 | 0.045–4.618 | 0.505 |
| Max WT, mm | 2.588 | 0.406–16.494 | 0.314 | 1.823 | 0.132–25.274 | 0.654 |
| Stenosis†, % | 1.692 | 0.792–3.617 | 0.175 | 2.087 | 0.768–5.675 | 0.149 |
| *For patients with the presence of bilateral A1 and P1 segments. #Adjustment for age, gender, BMI, hypertension, smoking, diabetes mellitus, hyperlipidemia, history of stroke and stenosis of the extracranial carotid artery. †With increment of 5%. | ||||||
| Presence of PCoA* | ||||||
| Univariate regression | Multivariate regression# | |||||
| OR | 95% CI | p | OR | 95% CI | p | |
| Presence of plaque | 3.398 | 1.269–9.095 | 0.015 | 4.374 | 1.145–16.701 | 0.031 |
| Max WT, mm | 0.883 | 0.421–1.851 | 0.742 | 1.108 | 0.433–2.832 | 0.831 |
| Stenosis†, % | 1.174 | 1.051–1.313 | 0.005 | 1.214 | 1.054–1.398 | 0.007 |
| *For patients with the presence of bilateral A1, P1 segments and ACOA. #Adjustment for age, gender, BMI, hypertension, smoking, diabetes mellitus, hyperlipidemia, history of stroke and stenosis of the extracranial carotid artery. †With increment of 5%. | ||||||
The results demonstrated a significant difference in stenosis of the intracranial arteries between patients with and without an ACoA and PCoAs. It was also determined that characteristics of intracranial artery atherosclerosis, including the presence of plaques, and stenosis, were independently associated with PCoAs in patients with bilateral A1 and P1 segments and an ACoA. The findings indicate that the severity of intracranial artery atherosclerosis may be an independent indicator of the integrity of the COW.
A complete COW was only found in 11.8% of the patients. The data showed that 82.7% and 13.6% of the patients had complete structures of the anterior and posterior parts of the COW, respectively. Two previous studies reported similar results regarding the prevalence of a complete anterior part of the COW (78%–80.95%) [19, 20]. In the present study, the prevalence of whole complete and complete posterior structures of the COW was slightly lower than that reported in the two former studies; one study reported a prevalence of 20.9% and 16.6%, respectively, whereas the other reported a prevalence of 21.0% and 33.0%, respectively. These differences may be due to this study’s smaller sample size. In addition, the findings are consistent with a previous study for the presence of bilateral A1 (this study’s data vs. previous data: 90.9% vs. 95.0%) and bilateral P1 (this study’s data vs. previous data: 83.6% vs. 86.7%) segments.
In patients diagnosed with bilateral A1 and P1 segments, intracranial stenosis was more severe in patients with the presence of an ACoA than those without, and a marginal association was found between the stenosis and the presence of an ACoA. The results are consistent with previous studies [14, 21]. Hartkamp et al. [14] demonstrated that patients with an ICA obstruction had a significantly higher percentage of entirely complete COW configurations (55% vs. 36%, p = 0.02) and complete anterior configurations (88% vs. 68%, p = 0.002) when compared with control subjects. Furthermore, patients with an ICA occlusion were found to have a higher prevalence of collateral flow through the anterior COW.
Kablak-Ziembicka et al. [21] reported that the ACoA was instrumental in maintaining collaterals within the COW. Similar results were found in patients with carotid occlusion [22]. Zhu et al. [23] demonstrated that the flow of ACoA is the most sensitive index to the morphology change of ipsilateral ICA in-vitro study. These results revealed that communicating arteries (as collateral pathways of cerebral blood flow) might play a key role in the compensational capability of cerebral arteries, and their presence may be associated with the severity of stenosis.
In addition to the ACoA, collateral circulation through the PCoAs was reported in previous studies [14, 21, 24, 25]. However, the ACoA was more likely to be present than PCoAs when unilateral ICA stenosis occurred [14, 21, 25]. This study’s data demonstrated that for patients with bilateral A1 and P1 segments and an ACoA, intracranial stenosis was more severe in those with PCoAs. Hartkamp et al. [14] also found that patients with an ICA obstruction had a significantly higher percentage of complete posterior COW configurations than the control group. As such, it is suggested that the COW tends to be complete, and collateral circulation seems to integrate from the anterior to posterior communicating arteries with an increase in the severity of intracranial stenosis. This hypothesis can be evidenced in part by previous in vitro or model studies [23, 26, 27]. For example, investigators reported the reduction of ipsilateral blood flow from the ICA, which is most sensitively detected by the flow of ACoA. The collateral function of the PCoAs will not be activated until severe stenosis in the ICA occurs.
This study had several limitations. First, this was a cross-sectional study lacking the dynamic changes of the COW with the progression of cerebral vascular stenosis. Second, the integrity of the COW was analyzed with TOF MRA that is insensitive to blood flows with slow velocities; therefore, the absence of communicating arteries may have been overestimated. Contrast CTA or MRA are superior to TOF MRA for evaluating the morphology of cerebral vasculatures because of a contrast agent. TOF MRA measures luminal stenosis, and the criteria used to define luminal stenosis are originally digital subtraction angiography (DSA). Third, the logistic regression analysis could not represent the general population since the conditions of Circle of Willis are complicated. Utilizing one regression model could not stratify different conditions of Circle of Willis. Fourth, although the degree of extracranial carotid atherosclerosis slightly affected the association between intracranial plaques and COW morphology, the carotid stenosis in this study population was dominantly mild to moderate, suggesting further investigation by including individuals with a broader range of luminal stenosis in future studies for minimizing patient selection bias. In addition, only the most severe plaque burden was assessed in patients with multiple intracranial plaques, ignoring differences in atherosclerotic burden among patients.
In conclusion, the severity of intracranial artery atherosclerosis is independently associated with the presence of PCoAs for patients with a complete anterior part of the COW. Future prospective studies are warranted to determine the causal relationship between the increase of severity of intracranial artery atherosclerosis disease and the time course of integration of collateral circulation.
YLX searched the literatures, analyzed the data and drafted the manuscripts. DYL and WD collected and analyzed the data. ZZZ and XHZ provide supervision, analyzed the data and edited the manuscript.
The local ethics committee approved the study, and these patients obtained informed consent. The Ethics Committee of our hospital reviewed and approved this study (No. 20110017), and all involved patients provided written consent forms.
We thank Dongxiang Xu from University of Washington in USA for the management of MR imaging data.
This study was supported by grants of Beijing Municipal Administration of Hospitals’ Youth Program (QML20180902), National Natural Science Foundation of China (81801694, 81771825), Beijing Municipal Science and Technology Commission (D171100003017003), and Ministry of Science and Technology of China (2017YFC1307904).
The authors declare no conflict of interest.