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Original research
Relationship between aneurysm occlusion and flow diverting device oversizing in a rabbit model
  1. Simona Hodis1,
  2. Yong-Hong Ding1,
  3. Daying Dai1,
  4. Ravi Lingineni2,
  5. Fernando Mut3,
  6. Juan Cebral3,
  7. David Kallmes1,
  8. Ramanathan Kadirvel1
  1. 1Neuroradiology Research Laboratory, Mayo Clinic, Rochester, Minnesota, USA
  2. 2Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota, USA
  3. 3Center for Computational Fluid Dynamics, College of Sciences, George Mason University, Fairfax, Virginia, USA
  1. Correspondence to Dr Ramanathan Kadirvel, Mayo Clinic, 200 First St SW, Rochester, MN 55905, USA; kadir{at}mayo.edu

Abstract

Background and purpose Implanted, actual flow diverter pore density is thought to be strongly influenced by proper matching between the device size and parent artery diameter. The objective of this study was to characterize the correlation between device sizing, metal coverage, and the resultant occlusion of aneurysms following flow diverter treatment in a rabbit model.

Methods Rabbit saccular aneurysms were treated with flow diverters (iso-sized to proximal parent artery, 0.5 mm oversized, or 1.0 mm oversized, respectively, n=6 for each group). Eight weeks after implantation, the angiographic degree of aneurysm occlusion was graded (complete, near-complete, or incomplete). The ostium of the explanted aneurysm covered with the flow diverter struts was photographed. Based on gross anatomic findings, the metal coverage and pore density at the ostium of the aneurysm were calculated and correlated with the degree of aneurysm occlusion.

Results Angiographic results showed there were no statistically significant differences in aneurysm geometry and occlusion among groups. The mean parent artery diameter to flow diverter diameter ratio was higher in the 1.0 mm oversized group than in the other groups. Neither the percentage metal coverage nor the pore density showed statistically significant differences among groups. Aneurysm occlusion was inversely correlated with the ostium diameter, irrespective of the size of the device implanted.

Conclusions Device sizing alone does not predict resultant pore density or metal coverage following flow diverter implantation in the rabbit aneurysm model. Aneurysm occlusion was not impacted by either metal coverage or pore density, but was inversely correlated with the diameter of the ostium.

  • Aneurysm
  • Flow Diverter

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Introduction

Even though flow diverters have demonstrated remarkably high rates of complete aneurysm occlusion in preclinical and clinical settings, their mechanism of action remains poorly understood. Leading theories of aneurysm occlusion following flow diverter implantation include the influence of the flow diverter on intrasaccular hemodynamics, with resultant stasis and subsequent thrombosis, versus the role of endothelial cell growth across the pores of the flow diverter, with subsequent exclusion of the sac from the circulation.1–3

The exact ‘dose’ of flow diversion—typically quantified as metal coverage (amount of metal surface area covered by the device) and pore density (number of pores per unit surface area)—required for aneurysm occlusion remains unclear in clinical practice. The pore density and metal coverage at the ostium have been hypothesized to play an important role in the occlusion of aneurysms.4 ,5 Computational fluid dynamics studies predicted that oversizing the flow diverter increases the intra-aneurysmal flow.6 Improved understanding about the exact mechanism of action of flow diverters will both assist in customizing the treatment of individual patients and facilitate the development of next-generation flow diversion devices.

It has further been shown that, for flow diverters constructed of braided metal, the resultant pore size is strongly influenced by the degree of matching between the device diameter and the parent artery diameter.7 ,8 Specifically, close matching of sizes allows braided flow diverters to open fully and achieve trapezoidal-shaped pores; incomplete opening results in relatively square-shaped pores with resultant lower pore density than trapezoidal pores.

The objective of this current study was to characterize the correlation between device oversizing and parameters of metal coverage and subsequent occlusion of aneurysms treated with flow diverters in a rabbit model.

Methods

The Institutional Animal Care and Use Committee approved all procedures before initiation of the study.

Aneurysm creation and flow diverter implantation

Some of the rabbits employed in this study were originally used as part of other investigations, where we probed the mechanism of endothelialization,2 developed methodology for multi-modality image-based subject-specific computational models,9 assessed the relationship between hemodynamics and aneurysm occlusion,10 and analyzed flow changes in side branches11 following flow diverter treatment. These publications were entirely unrelated to the present study. Elastase-induced saccular aneurysms were created in 18 rabbits using well-described techniques.12 At least 3 weeks following aneurysm creation, flow diverters (Pipeline Embolization Device; Covidien, California, USA) were placed across the aneurysm ostium. Rabbits were arbitrarily assigned to three groups: Group 1, in which iso-sized flow diverters were implanted; Group 2, in which flow diverters were oversized by >0.5 and ≤1.0 mm; or Group 3, in which flow diverters were oversized by >1.0 mm to achieve varying degrees of pore density and metal coverage at the ostium of the aneurysm. The size of flow diverters was chosen based on the diameter of the proximal parent artery. Two days before embolization the animals were premedicated with aspirin (10 mg/kg orally) and clopidogrel (10 mg/kg orally); this medication regimen was continued for 1 month after embolization.13

Tissue harvest

Eight weeks following flow diverter implantation the animals were deeply anesthetized. Digital subtraction angiography (DSA) of the aortic arch was performed. The animals were then killed with a lethal injection of pentobarbital. Harvested aneurysms were immediately fixed in 10% neutral buffered formalin.

Angiographic evaluation

Aneurysmal dimensions (ostium, height and width) were determined with DSA measurements, which were calibrated using an external sizing device of known diameter. Angiographic evaluation was performed for angiograms conducted immediately after device implantation as well as the pre-sacrifice angiograms. The follow-up angiography assessed using a trichotomous scale (patent, near-complete occlusion, and complete occlusion).

Imaging of the aneurysm ostium

The flow diverter-implanted parent artery was bisected longitudinally to expose the luminal surface. The ostium of the aneurysm covered with the flow diverter struts was then photographed and used for metal coverage and pore density analysis. The lengths of the metal struts covering the aneurysm ostium and the angle of intersection of the struts were measured using Photoshop software (Adobe, California, USA). The metal coverage and pore density were calculated using the following formula:Embedded Image where d represents the strut diameter, which is 0.03 mm, and α denotes the angle between struts. L1 and L2 represent the width and length of the struts covering the ostium of the aneurysm, respectively, and N1 and N2 represent the number of pores across L1 and L2, respectively.

Figure 1 illustrates measurement of the parameters. Owing to non-uniformity in the pore density, we calculated the porosity by using a sample area over multiple pores, between 6 and 8 pores across the ostium.

Figure 1

Measurement of parameters at the ostium of the aneurysm implanted with flow diverter. (A) Gross image showing aneurysm ostium covered with flow diverter struts. (B) Schematics of measurements in the flow diverter struts.

Similarly, porosity, pore size, and pore density were estimated from a reference configuration, taking into account the longitudinal stretching (foreshortening) due to oversizing as in computational models.6 First, the effective (target) cell angle was computed based on the flow diverter reference angle and diameter and the vessel (target) mean diameter following:Embedded Image

Second, a pixelization of the stretched stent design (straight cylinder of constant but smaller diameter) was performed by drawing each of the stent wires over a planar image that represented the stent surface. Next, measurements of porosity, pore size, and pore density were taken from the pixelization by counting marked (covered by metal) and unmarked (free space) pixels from the total image and from enclosed groups (pores). The procedure was repeated with different pixel sizes to ensure grid independence of the pixelization procedure.

Statistical analysis

The aneurysm geometry, metal coverage, and pore density between groups were analyzed using the Kruskal–Wallis test. The correlations between aneurysm occlusion and aneurysmal geometry, metal coverage, and pore density were assessed by Spearman rank correlation. The association between aneurysm occlusion and effective factors were then analyzed using the logistic regression.

Results

Angiographic findings

There were no statistically significant differences in ostium diameter or aneurysm width or height between the groups (table 1). Angiography showed incomplete occlusion of four aneurysms and complete/near-complete occlusion of two aneurysms in Group 1, incomplete occlusion of two aneurysms and complete/near-complete occlusion of four aneurysms in Group 2, and incomplete occlusion of five aneurysms and complete occlusion of one aneurysm in Group 3.

Table 1

Characteristics of aneurysms by group

The mean ratios of the parent artery diameter to the flow diverter diameter in Groups 1, 2 and 3 were 1.0±0.1, 1.2±0.1, 1.5±0.1, respectively. There was a statistically significant difference in parent artery to flow diverter ratio in Group 2 (p=0.02) and Group 3 (p=0.001) compared with Group 1, but the difference between Groups 2 and 3 was not statistically significant.

Metal coverage and pore density

The mean metal coverage and pore density were 25.9±4.9% and 19.2±7.1 pores/mm2 in Group 1, 23.6 ± 8.7% and 15.2±8.5 pores/mm2 in Group 2, and 23.5 ± 7.5% and 14.2±7.7 pores/mm2 in Group 3, respectively. Neither the percentage metal coverage nor the pore density showed statistically significant differences among groups. Geometrical features of the proximal parent artery and devices implanted are shown in table 2. The actual measured porosity and pore density are comparable to that of computational models in most cases (table 3). In virtual device oversizing, the pore geometry changes from a diamond shape stretched in the circumferential direction to a diamond shape stretched in the longitudinal direction.6

Table 2

Flow diverting devices and parent artery measurements calculated from the gross images taken at the ostium of the aneurysm

Table 3

Porosity, pore density, and pore size of the flow diverting devices calculated from the gross images and from their reference configuration accounting for cell stretching due to oversizing

Aneurysm occlusion

Aneurysm occlusion was negatively correlated (ρ=−0.76, p<0.001) with larger ostium diameters after adjusting for the groups. Logistic regression analysis (table 4) showed that the odds of aneurysm occlusion significantly decreased by 4.9-fold (OR 4.93, 95% CI 1.19 to 20.46, p=0.03) for every millimeter increase in the ostium width. There was no significant association between aneurysm occlusion and percentage of metal coverage (OR 1.09, 95% CI 0.92 to 1.29, p=0.33) and pore density (OR 1.06, 95% CI 0.92 to 1.22, p=0.42) The relationship between metal coverage, ostium width, and occlusion is plotted in figure 2.

Table 4

Results from regression analysis for aneurysm occlusion

Figure 2

Relationship between metal coverage, ostium width, and occlusion.

Discussion

In this study we purposefully varied the fidelity of size matching between flow diverter devices and the proximal parent artery. While we noted a strong trend toward higher pore densities with good matching between devices and parent arteries, the degree of metal coverage did not vary substantially among groups. Further, final occlusion rates were not substantially impacted by the resultant pore density or metal coverage, but were strongly influenced by aneurysm ostium width. Indeed, for each incremental increase in ostium width, the propensity for complete aneurysm occlusion decreased by nearly an order of magnitude. An ostium smaller than 3 mm in width was related to complete and near-complete occlusion in all seven cases, except for two near-complete cases where the ostium width was 3.71 mm and 4.65 mm.

These findings suggest that it remains difficult to predict resultant pore density and metallic coverage based exclusively on sizing, and that other factors may strongly influence the morphology of flow diverters after implantation. In real deployment, we obtained different pore geometry from that estimated from the device reference configuration and degree of oversizing owing to the user-dependent techniques of deployment. Therefore, the oversizing criterion should not be the only parameter to analyze in order to explain the aneurysm occlusion, but also the ostium size. Further, ultimate occlusion may not relate closely to implanted device morphology.

In the original study of the Pipeline Embolization Device,13 similarly low rates of aneurysm patency were observed at 1 and 3 months while those in the 6 month group showed a much higher occlusion rate (83%). It is possible that the findings of the current study relating aneurysm non-occlusion rate to aneurysm ostium size are confounded by the relatively short follow-up interval. Previous work has shown that factors beyond simple device sizing may affect in vivo device morphology. For example, deformation of the flow diverter, where the device ‘herniates’ into the aneurysm ostium, led to higher metal coverage over the ostium area compared with coverage of adjacent parent arteries.14 We did not notice any device deformation in our studies. Sadasivan et al4 ,15 analyzed the occlusion of aneurysms implanted with flow diverters with three different porosities and metal coverage, and suggested that pore density is crucial for the occlusion of aneurysms. In contrast, Wong et al5 predicted that a flow diverter with a 35% actual metal coverage at the ostium can predict >95% of angiographic aneurysm occlusions in rabbits. In our series, the average metal coverage of iso-sized flow diverters was much lower than the predicted 35%. This could partially be due to the smaller diameter of the struts of the device compared with the flow diverter used by Wong et al.5 We achieved >35% metal coverage in only three cases, two of which showed incomplete aneurysm occlusion while the third showed complete occlusion. Our findings suggest that other factors such as the geometry of the aneurysm and parent vessel, endothelialization, wall apposition, and hemodynamic factors may strongly influence the closure of aneurysms.

Our study has several limitations. We did not use the diameter of the parent artery at the ostium for choosing appropriate devices for treatment but instead we used the proximal parent artery, as normally used in clinical practice. We used gross images of formalin-fixed tissue samples for the calculation of metal coverage and pore density. To calculate the metal coverage we measured the strut lengths and the angle between the struts from the gross images of the tissue sample at the ostium, which may be subject to some measurement errors. The device configuration in the implanted vessel may have changed after tissue harvest. The majority of the periphery of the ostium was covered with a portion of the pore, which was counted as a single pore in our measurement. The pore density varies in different parts across the entire ostium. In addition, there is high variability in the sizes of aneurysm and parent vessel between animals and cohorts. A controlled study of aneurysms with similar geometries is needed to validate our findings.

Conclusions

In the rabbit aneurysm model, device sizing alone does not predict resultant pore density or metal coverage following flow diverter implantation. Aneurysm occlusion was not affected by either metal coverage or pore density, but was inversely correlated with the diameter of the ostium in the rabbit model.

Numerous previous studies have addressed concerns about device sizing, especially regarding the propensity for lower pore density and less metal coverage with oversized devices. However, because current flow diverters are not tapered longitudinally and many or most vessels decrease in diameter as they go distally, one is often required to choose a device that is ‘oversized’ at the level of the neck in order to achieve good apposition proximally. Our study should temper those concerns about oversizing and give confidence that even slightly oversized devices will retain efficacy.

Acknowledgments

We thank Covidien for generously providing the flow diverters for this study.

References

Footnotes

  • Contributors SH contributed to the conception and design of the study, analysis and interpretation of data and drafting the article. DD and Y-HD contributed to the animal experiments and analysis of angiographic data. RL contributed to the statistical analysis and interpretation of data. FM contributed to the virtual computational analysis and interpretation of data. JC, DK and RK contributed to the conception and design of the study and revision of the article critically for important intellectual content. All the authors have read and approved submission of the manuscript.

  • Funding This work was supported by National Institutes of Health grant NS 076491.

  • Competing interests None.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement All authors have access to the raw data.