Association Between Configuration of Basilar Artery and Vessel Wall Features: A Prospective High-resolution MR imagine Study

We aimed to investigate the relationship between distal and proximal anatomical configurations of basilar artery (BA) and vessel wall features on high resolution magnetic resonance imaging (HRMRI).


Conclusions
The complete and incomplete groups configuration of BA did not associate with vessel wall features. The proximal configuration of BA was related with intraplaque hemorrhage and the distal configuration of BA was associated with strong plaque enhancement. These findings are continuously needed to confirmed in future studies. 4 Background Basilar artery (BA) atherosclerotic occlusive disease is the most common reason of posterior circulation strokes, and it can cause disastrous outcome and patients with it had a high risk of recurrent stroke [1][2]. The complete configuration of BA including bilateral vertebral arteries (VA), branches of cerebellar artery and bilateral posterior cerebral arteries (PCA). The VA size is various individually and 6-26% of cases with equal size in angiographic studies [3]. The previous studies found that VA hypoplasia was predisposing factor for posterior circulation stroke [4][5]. Dominant VA often caused BA curvature and development of peri-vertebrobasilar junction infarcts [4][5]. There were also studies showed that fetal type PCA (fPCA) may predispose to ischemic events in the posterior circulation [6][7].
The grade of intracranial artery stenosis and vulnerability of plaques are indications being considered to guide the clinical management [8]. The study had demonstrated that symptomatic vertebrobasilar artery stenosis was associated with a greatly increased risk of recurrent stroke [9]. The studies had proved that vulnerability of intracranial artery plaque and hypoperfusion of blood flow at the distal stenotic site were highly associated with stroke events and recurrence [10][11]. Anterior circulation acute ischemic stroke study had proved the associations between collateral circulation and thrombus characteristics, that patients with higher collateral scores had lower thrombus burden and more previous thrombi [12][13].
However, the relation between vessel configuration and intracranial vessel wall features is not well investigated. Configurations of BA play a role in posterior circulation hemodynamics, and may influence the vessel wall features of BA. To test this hypothesis, we investigate the demographics, variants of VA and PCA, vessel wall features of BA. We compared the relationship between different configurations of BA and vessel wall features of BA on HRMRI.

Methods
The study was a prospective and registry study, had been approved by ethics committee of our hospital. Written informed consent was obtained from the patients or their legally relatives.

Enrollment of Patients
Patients suspected to symptomatic intracranial atherosclerotic stenosis (ICAS) at admission were enrolled. All patients received thorough evaluations to determine the cause of ischemic events including transit ischemic attack (TIA) or ischemic stroke, including carotid duplex, transcranial Doppler, echocardiography, electrocardiogram, computer tomography (CT), magnetic resonance imaging (MRI), CT angiography (CTA), magnetic resonance angiography (MRA) and digital subtract angiography (DSA). Patients were enrolled in this study according to the following criteria: 1) age≥18 years; 2) ischemic stroke or TIA in the target territories posterior circulation within 90 days; 3)basilar artery stenosis ≥70%, and without coexistent≥50% ipsilateral extracranial vertebral artery stenosis; 4) Without potential sources of cardioaortic embolism based on the modified Trial of ORG 10 172 in Acute Stroke Treatment (TOAST) classification [14], 5) one or more atherosclerotic risk factors; 6) all the patients received DSA examination.
Risk factors were recorded including hypertension, dyslipidemia, diabetes, smoking and obesity.
Patients with the following conditions were excluded: 1) nonatherosclerotic vasculopathy such as vasculitis and arterial dissection, diagnosed by comprehensive laboratory examinations (such as erythrocyte sedimentation rate or C-reactive protein elevations, antinuclear antibody, or antiphospholipid antibody positivity), vascular imaging, and clinical evaluation. 2) contraindication to MR examination, medical instability precluding MR examination.

HRMRI acquisition and analysis
All HRMRI studies were performed on a 3T GE DISCOVERY MR 750 (GE Healthcare, Waukesha, WI, USA) or a 3T Siemens Trio MR scanner (Siemens Healthcare, Ehrlangen, Germany). The details were presented in study protocol (see the supplemental etable 1). Image reconstruction were conducted by Reformate tool in AW 4.5 workstation (GE Healthcare) and 3D multiple planer reconstruction tool in Siemens workstation. MR images were then processed for all identified plaques using commercially available software (Vessel Mass; Leiden University Medical Center, Leiden, The Netherlands).
A culprit plaque was defined as the single lesion at the supplying artery for the infarct zone or the most severe stenotic lesion when multiple plaques were present at the supplying artery [15][16].
Arterial remodeling index (RI) was calculated as the ratio of outer wall area (OWA) at the site of maximal lumen narrowing to that at the reference site (RI=OWA lesion/OWA reference) [17]. The reference site was selected based on the Warfarin-Aspirin Symptomatic Intracranial Disease (WASID) trial method [18]. There are three remodeling categories as previously described, following RI ≥1.05 as positive remodeling, 0.95 <RI< 1.05 as intermediate remodeling, RI≤0.95 as negative remodeling. Plaque distributions were dichotomized into diffuse and non-diffuse patterns at culprit lesion. The anatomical location of the plaque was recorded as ventral, dorsal, left, and right quadrants [19].
Plaques spreading across four quadrants were defined as diffuse and that involving ≤3 quadrants were defined as non-diffuse. Intraplaque hemorrhage (IPH) was defined as a signal intensity greater than 150% of T1 signal of adjacent muscle [20]. As to plaque enhancement, non-enhancement was defined as similar to or less than that of normal intracranial arterial walls nearby, while enhancement meant signal intensity was greater than non-enhancement, and less than or greater than that of the pituitary infundibulum [15]. We adopted the same principal when interpreting HRMRI vessel wall imaging over arterial remodeling and vessel wall features as we have published before with small intrao-bserver and inter-observer variability [10,17,21]. The intra-and inter-observer variability of the two scanners and vessel wall features of HRMRI were good to excellent (weighted k =0.82, 95% CI: 0.46, 1.00 and 0.83, 95% CI: 0.41-1.00, respectively).

Definition of configurations of BA
Configurations of BA were divided as complete and incomplete configuration. (see figure   1) The patients with normal bilateral vertebral arteries and posterior cerebral arteries were categorized as complete configuration. If the patients had one VA dysplasia and (or) fPCA were defined as incomplete configuration on DSA and(or) CTA, MRA. The presence of posterior communicating arteries was also recorded. The presence of hypoplastic VA was defined as with a diameter <2 mm, ended in the posterior inferior cerebellar artery, or lumen diameter more than 50% difference [4][5]. The fPCA was defined as the blood flow of posterior cerebral artery from internal carotid artery, and without P1 segment of PCA or dysplasia of P1 segment of PCA [6][7]. Two neurologists (Z.Q.X. and N.M) reviewed the DSA images independently and discrepancies were resolved by consensus.

Statistical analysis
Continuous variables were presented as means ± SD or median with interquartile range.
Categorical variables were presented as percentages. All baseline characteristics, plaque enhancement, intraplaque hemorrhage, arterial remodeling patterns and plaque distribution were compared with χ2 test for categorical variables and 1-way analysis of variance or the Kruskal-Wallis test for continuous variables between complete and incomplete configurations group. The analyses were performed using SPSS 23.0 statistical software (IBM, Chicago, IL, USA). A two-tailed P value less than 0.05 was considered statistically significant.

Baseline characteristics
From September 2014 to January 2017, among 298 consecutively enrolled patients, 34 patients were included in our study. Among them, 6 patients were TIA and 28 were stroke.  [22]. In our study, 23.5% patients with fPCA, consistent with previous report [22]. Lochner et al found that fPCA accompanied by hypoplastic BA may predispose to ischemic events in the posterior circulation [23]. The study found that unequal VA may cause the BA curvature and development of peri-vertebrobasilar junctional infarcts [5]. Ravensbergen  Our study showed proximal configuration tree of BA was associated with strong plaque enhancement. In the present study, 64.2% of plaques had enhancement. A previous study had found that BA plaque enhancement and composition correlated with stroke events [25]. Plaque enhancement reflects the extent of inflammation of vessel wall. The incomplete configuration of proximal VA may cause difference in longer outcome, but this hypothesis needs to be confirmed or refuted in further studies.
Our study also found the proximal configuration tree of BA was associated with strong plaque enhancement and the distal configuration tree of BA was closed related with intraplaque hemorrhage. In the present study, 64.2% with plaque enhancement and 20.6% with intraplaque hemorrhage on HRMRI. Plaque enhancement and intraplaque hemorrhage on HRMRI are markers of plaque destabilization and progression strongly associated with stroke events [25], which are also associated with endothelial dysfunction and neovascularization of the artery wall [26][27]. The relationship of incomplete distal configuration of BA and intraplaque hemorrhage is hard to explain in the present understanding. The incomplete distal configuration of BA indicated different hemodynamics and blood flow reserve on the top of BA. The fPCA indicated that most or all the blood flow of PCA was from ipsilateral internal carotid artery. When complete BA tree, the most common distribution pattern of blood flow within the top of the BA is parallel [28]. The fPCA will change this the flow pattern causing the changing of regional wall shear force. The study showed that blood flow shear stress act on wall causing endothelial injury and plaque instability, presenting with plaque enhancement [29]. Poor collaterals circulation and high grade of stenosis produced the high-speed blood flow around the plaque causing erosion of fibrous cap or endothelium injury in the middle cerebral artery and carotid artery, and causing plaque enhancements [30][31]. The underlying mechanism of plaque enhancement correlated with distal incomplete configuration of BA is need to be studied further.
The previous study found that unequal VA may cause the BA curvature and development of peri-vertebrobasilar junctional infarcts [5]. Dominant VA flow acted on the contralateral wall of BA caused the tortuous of BA geometry which strongly affected velocity and wall shear stress distribution [32], and finally, trigger the formation of BA plaque and affect intraplaque hemorrhage. The studies showed that the geometry of vertebrobasilar artery correlated with occurrence of atherosclerotic plaque and plaque distribution [32].
Asymmetric VAs causing the BA bending is a chromic process, and not only influenced by shear stress but also vascular risk factors [32][33]. The underlie mechanism of intraplaque hemorrhage correlated with incomplete proximal configuration of BA is also need to further study.
This study has some limitations. First, the number of subjects is little small and come from the single stroke center, selection bias should be concerned. Second, our study population was exclusively high degree of stenosis. Therefore, caution should be taken when generalizing the findings to other degree of stenosis.
In summary, we found that the complete configuration of BA was not associated with

Author's contributions
All authors have reviewed and approved the submitted manuscript for publication. ZX contributed to writing the manuscript and interpretation of the data. ZKH, XL and MYL contributed to acquisition the data. NZ and JHL contributed to acquisition of HRMRI data.
ZRM and NM contributed to the critical revision of the manuscript for intellectual content.

Ethics approval and consent to participate
Current study was approved by the first affiliated hospital Zhejiang University and Beijing Tiantan Hosptial. Written informed consent was obtained from the patients or their legally relatives.

Consent for publication
All enrolled patients had been signed an informed consent form regarding publication of the study in all formats hard and electronics including personal data and images irrespective of time and language.