The Geometry of Arteriovenous Fistulas Using Endothelial Nitric Oxide Synthase Mouse Models

Abstract

BackgroundArteriovenous fistula (AVF) maturation failure is a significant clinical problem in the hemodialysis population. Geometric parameters of human AVFs were associated with AVF development, but causative studies are lacking. We characterized mouse AVF geometry using endothelial nitric oxide synthase (NOS3) mouse models.MethodsCarotid-jugular AVFs were created in NOS3 overexpression (OE), knockout (KO), and wild-type (WT) mice. At 7 and 21 days postcreation, black-blood magnetic resonance images of AVFs were acquired and used to build three-dimensional reconstructions of AVF lumens. We used these reconstructions to calculate the lumen area, lumen centerline, and centerline-derived parameters: anastomosis angle, tortuosity, nonplanarity angle, and location of maximal distance between the feeding artery and AVF vein. Inter- and intrauser variabilities were also determined.ResultsWhen all mice were considered, increased minimum AVF venous lumen area was accompanied by increased venous tortuosity and increased distance between the artery and vein, with both remaining in plane with the anastomosis. At day 7, the lumen area of AVFs from all strains was 1.5- to 2.5-fold larger than native veins. Furthermore, at day 21, AVF lumen in NOS3 OE (4.04±1.43 mm2) was significantly larger than KO (2.74±1.34 mm2) (P<0.001) and WT (2.94±1.30 mm2) mice (P<0.001). At day 21, the location of maximal artery-vein distance on the vein was further away from the anastomosis in OE (4.49±0.66 mm) than KO (2.87±0.38 mm) (P=0.01). Other geometric parameters were not significantly different between mouse strains or time points. Inter- and intrauser variabilities were small, indicating the reliability and reproducibility of our protocol.ConclusionsOur study presents a detailed characterization of mouse AVF geometry, and a robust protocol for future mechanistic studies to investigate the role of molecular pathways in AVF geometry. Identifying a geometry related to desired AVF remodeling can help inform surgery to enhance AVF maturation.

Analysis of Geometric and Hemodynamic Profiles in Rat Arteriovenous Fistula Following PDE5A Inhibition

“…The linear correlation between the following was also analyzed because we found them to be significant in a carotid-jugular mouse AVF model ( Falzon et al, 2020 ): maximum venous CSA and average venous CSA, the minimum venous CSA and maximum A-V distance, tortuosity and maximum A-V distance, vein length at the maximum A-V distance and the maximum A-V distance, the nonplanarity angle magnitude and the maximum A-V distance, and the nonplanarity angle and the vein length at the maximum A-V distance. However, none of the correlations were significant in the femoral rat AVF model ( Supplementary Figure S4 ).…”

“…Centerline-based approaches for geometric analysis of blood vessels have been reported in the literature ( Kamenskiy et al, 2012 ; Aristokleous et al, 2018 ; Corbett et al, 2018 ). Therefore, our group used this approach to characterize AVFs in human ( He et al, 2021 ) and mouse ( Falzon et al, 2020 ), and here we used it on rats. Previously we reported that carotid jugular AVFs created in NOS3 overexpression mice had bigger CSA and flow than AVFs created in NOS3 knockout mice and wild-type mice ( Pike et al, 2019 ; Falzon et al, 2020 ), but AVFs in three mouse strains had similar anastomosis angle, tortuosity, and nonplanarity angle ( Falzon et al, 2020 ).…”

“…Geometrical analysis was performed as previously described for mouse and human ( Falzon et al, 2020 ; He et al, 2021 ) with modifications for rat. First, Amira (Thermo Fisher Scientific, Waltham, Mass) was used to reconstruct the lumen from the 2D black-blood MRI sequence.…”

“…The centerlines and STL of the reconstruction were used in MATLAB (MATLAB, Natick, Mass) to calculate the CSA at 0.1 mm intervals along the centerline ( He et al, 2013 ). The x, y, and z coordinates of the centerlines and anastomosis origin were used to calculate the geometric parameters of A-V distance, anastomosis angle, tortuosity, and nonplanarity angle, as previously described for human and mouse, with modifications for rat ( Figure 3 ; Eqs 1 – 4 ) ( Falzon et al, 2020 ; He et al, 2021 ).…”

“…These parameters may give us further insights into the mechanics of AVF remodeling. These analyses have been performed by us to AVFs in patients ( Yang et al, 2020 ; He et al, 2021 ) and a mouse model ( Falzon et al, 2020 ). Here we modified these protocols for rats.…”