Bifurcation angle is associated with progression of saccular aneurysms

Animal experiments complied with the National Institute of Health’s Guide for the Care and Use of Laboratory Animals and the Animal Research Reporting In Vivo Experiments (ARRIVE) guidelines. The National Brain and Cardiovascular Center’s Institutional Animal Care and Use Committee approved the protocol (approval number #19036 and #20003). The human study protocol was approved by the Kyoto University Graduate School and Faculty of Medicine Ethics Committee, Medical Center General Hospital Research Ethics Committee of Kobe City, Kurashiki Central Hospital Medical Ethics Committee, Kitano Hospital Medical Ethics Committee and Kokura Memorial Hospital Clinical Committee. Research Ethics Board (approval number #R1682, #zn190206, #3115, #P190100700 and #18121902). The informed consent of individual patients was revoked by the Ethics Committee of Kyoto University Graduate School and Faculty of Medicine, the Research Ethics Committee of General Hospital of Kyoto Medical Center Kobe City, Kurashiki Central Hospital Medical Ethics Committee, Kitano Hospital Medical Ethics Committee, and Kokura Memorial Hospital Clinical Research. ethics committee because of the minimal risk posed by the present study. Alternatively, opt-out patient enrollment was conducted. The study was performed in accordance with the Declaration of Helsinki and the STROBE statement (Strengthing the Reporting of Observational Studies in Epidemiology)20. The datasets analyzed in this study are available from the corresponding author upon reasonable request.

Rat aneurysm model

Seven-week-old male Sprague-Dawley rats were obtained from Japan SLC (Shizuoka, Japan). Rats were maintained on a 12 h/12 ​​h light/dark cycle and had free access to food and water. Saccular aneurysms similar in morphology and histology to human SVAs have been induced at surgically created common carotid artery (ACC) bifurcations, as previously demonstrated21.22. Briefly, under general anesthesia using a combination of intraperitoneal injection of sodium pentobarbital (50 mg/kg) and inhalation of isoflurane (1.5-2.0%), the left CCA was anastomosed side-to-side to the right CCA with a 10-0 nylon thread. Hypervolemia was induced by a high-salt diet and left renal artery ligation. After the surgical manipulation, the rats were fed a special diet containing 8% sodium chloride and 0.12% 3-aminopropionitrile (Tokyo Chemical Industry, Tokyo, Japan), a lysyl oxidase inhibitor which catalyzes the crosslinking of collagen and elastin. Blood pressure was measured by the cuff method. Experimental animals were monitored once daily after aneurysm induction. Since saccular aneurysms in this model are asymptomatic and rupture of lesions causes sudden death, animals were not given analgesics during the observation period. They were sacrificed by an intraperitoneal injection of sodium pentobarbital (200 mg/kg) when their body weight decreased to less than 80% of that of their littermates, they could no longer follow their diet, or they behaved in an agitated manner. All animals that died during the observation period were autopsied to determine cause of death, particularly rupture of induced aneurysms.

MR examination in rats

Morphological and blood flow data were acquired by magnetic resonance imaging (MRI) as previously described.21. Briefly, MRI was performed with a 7 Tesla preclinical scanner (BioSpec 70/20 USR; Bruker BioSpin MRI GmbH, Ettlingen, Germany) and a quadrature transmit-receive volume coil to detect MRI signals ( inner diameter 72 mm, T9562; Bruker BioSpin). During MRI, rats were placed under general anesthesia with inhalation of 3% isoflurane in air at 1.4 L/min through a face mask. CCA morphology was assessed by three-dimensional time-of-flight MRI. Blood flow volume at the right ACC proximal to the bifurcation during one cardiac cycle was estimated by heart-triggered, two-dimensional, phase-contrast MRI. Acquisition parameters for three-dimensional time-of-flight MRI angiography and phase-contrast MRI were the same as in the previous study21.

An MRI examination on the 30th postoperative day was planned for all rats. In a subgroup of rats, sequential MRI examinations at 5th, 10th, 17th and 30th days after the surgical manipulations were planned to detect the time course of morphological changes at the anastomosis site. Morphological data of ACC and induced aneurysms were visualized using three-dimensional volume rendering on Horos visualization software (64-bit, version 3.6.6, The greatest dimension of the induced aneurysms and the angle of bifurcation were measured.

Human study design

Clinical and radiological data were collected retrospectively from the five large-volume centers in western Japan. A case-control study was performed to determine if bifurcation angles are associated with the progression of Acom aneurysms. Consecutive patients who visited each facility during the study period were assessed for eligibility. Inclusion criteria were patients with an Acom aneurysm. Fusiform, mycotic and dissecting aneurysms were excluded. Patients whose radiological data at the time of diagnosis were unavailable, of poor quality or whose Acom was not identifiable were also excluded. Patients were categorized into the progression group if there was growth or rupture during follow-up. Aneurysm growth was defined as an increase in greatest dimension of ≥ 1 mm. Patients with Acom aneurysms without progression for ≥ 36 months from diagnosis were included in the control group. Growth assessments were performed independently by two investigators (i.e., one investigator was KS and the other was TM at Kyoto University Hospital, HI at Kyoto Medical Center General Hospital). Kobe City, RI at Kurashiki Central Hospital, MG at Tazuke Kofukai Medical Research Institute and Kitano Hospital, or MK at Kokura Memorial Hospital). Discrepancies between assessments were resolved after discussion.

Acquisition of clinical and radiological data

Medical records and radiological data were reviewed to identify patients with Acom aneurysms showing progression between June 2006 and April 2019. To enroll control cases, consecutive outpatients with Acom aneurysms who visited hospitals for a follow-up radiological examination were enrolled, and their medical records and radiological data at the time of diagnosis were reviewed between June 2006 and April 2019. Patient characteristics included age, gender, smoking status and history of hypertension , dyslipidemia and diabetes mellitus. The radiological characteristics analyzed were the largest dimension and the size of the neck of the aneurysms, the diameters of the vessels (the ipsilateral A1 and A2 segments, the Acom and the contralateral A1 segment), the angles formed between the Acom and the A2 (angle Acom/A2) and the angles formed between the A1 and the plane comprising the proximal Acom and A2 (plane angle A1/Acom-A2). Radiological data from three-dimensional rotational angiography, computed tomography angiography or magnetic resonance angiography were acquired in DICOM format. In the assessment of aneurysm growth, aneurysm size was compared between the same modalities.

The diameter and angle of the arteries were measured using a method similar to previous studies8.10. The diameters of the A1 segment and the Acom were measured in the middle of the segments. The diameter of the A2 segment was measured 5 mm beyond the apex of the Acom/A2 bifurcation. The angles of the Acom/A2 and A1/Acom-A2 plane were defined by fixing three lines passing through the central axis of the distal A1 segment, the Acom and the proximal A2 segment (Fig. 1A,B). The Acom/A2 angle was measured on the plane containing the distal part of the ipsilateral A1 segment. The view measuring the Acom/A2 angle was produced by performing a 90° rotation around the central axis of the distal segment A1 from the view measuring the angle of the A1/Acom-A2 plane. Two investigators independently performed the angle measurement. First, the initial analysis was performed using First Observer (KS) data. Then, the reproducibility of the results was assessed using data from the second observer (AO). Diameters and angles were measured using a three-dimensional image processing station, the Ziostation2 (Ziosoft Inc., Tokyo, Japan).

Figure 1

Schematic diagrams showing the angle measurement at the anterior communicating artery (Acom)-anterior cerebral artery (ACA) bifurcation. The angles formed between the segment Acom and the segment A2 (the angle Acom/A2) (A) and between segment A1 and the plane containing both segment Acom and segment A2 (the angle of the plane A1/Acom-A2) (B) are presented.


Inter-observer agreement for the presence or absence of Acom aneurysm growth was assessed by overall percent agreement and unweighted κ statistics. Continuous variables were assessed with the Wilcoxon rank sum test. Categorical variables were compared to Pearson χ2 test or Fisher’s exact test as appropriate. Nonparametric multiple comparisons were performed using the Steel-Dwass test. Univariate and multivariate logistic regression models were applied to assess the association of each variable with progression. A P– a value less than 0.10 in univariate analysis was used as a threshold value for the multivariate logistic regression model. Odds ratios (OR) with 95% confidence intervals (CI) were calculated, and a P-a value less than 0.05 was defined as significant. To investigate the correlation between the largest dimension of Acom aneurysms and Acom-A2 bifurcation angles, scatterplots with a linear regression line were prepared and Spearman’s correlation analysis was performed.

It was thought that the results of the association between bifurcation angle and progression in the case-control study might be affected by very small or large aneurysms due to a potential correlation between bifurcation angle and progression. AVS size. Therefore, a sensitivity analysis was performed to assess factors associated with progression using subgroup data acquired from patients with Acom aneurysms of 3–7 mm in greatest dimension. All statistical analyzes were performed with EZR version 1.54 (Saitama Medical Center, Jichi Medical University, Saitama, Japan)23.

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