title: Concomitant coiling reduces metalloproteinase levels in flow diverter-treated aneurysms but anti-inflammatory treatment has no effect.
abstract: OBJECTIVE
  Flow diverters (FD) can cause rare but devastating delayed aneurysm ruptures in which matrix metalloproteinases (MMPs) have been potentially implicated. Concomitant coiling or anti-inflammatory medications have been proposed to prevent the risk of delayed ruptures. The aim of this study was to evaluate concomitant coiling and ciclosporin in regulating the expression of MMPs in FD-treated aneurysms.
  
  
  METHODS
  Elastase-induced aneurysms were created in 20 rabbits. Aneurysms were treated with (1) FD alone; (2) FD with concomitant coiling; (3) FD+ ciclosporin; or (4) left untreated as controls. At sacrifice, MMP levels were analyzed by zymography. Kruskal-Wallis one-way non-parametric ANOVA was performed for each enzyme. If significant results were observed for the Kruskal-Wallis test, pairwise group comparisons were performed using Dunn's test with Bonferroni multiple-testing correction.
  
  
  RESULTS
  Significant differences were observed among groups for pro-MMP9 (p=0.0337). Pairwise comparison demonstrated higher levels of pro-MMP9 with concomitant coiling compared with untreated aneurysms (p=0.012), with higher though not significantly different levels of pro-MMP9 in FD with concomitant coiling versus FD alone. While not statistically significant, trends were noted regarding differences in active-MMP9 across groups, with a lower level of active-MMP9 with concomitant coiling compared with the other FD groups. No significant differences were observed for pro- or active-MMP2 across groups, or for FD + ciclosporin compared with FD alone.
  
  
  CONCLUSIONS
  FD implantation increases the level of pro-MMP9 expression in aneurysms. Provocative trends regarding modulation of active-MMP9 expression with concomitant coiling suggest the need for larger confirmatory preclinical studies. Anti-inflammatory treatment with ciclosporin appears to have a minimal biological effect.
  
  
  BACKGROUND
  R01NS076491.
authors.affiliation: Applied Neuroradiology Laboratory, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Evan
authors.identifier: http://orcid.org/0000-0002-4453-0244
authors.initials: E
authors.lastname: Thielen
authors.affiliation: Applied Neuroradiology Laboratory, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Megan
authors.identifier: http://orcid.org/0000-0002-2289-7985
authors.initials: M
authors.lastname: McClure
authors.affiliation: Applied Neuroradiology Laboratory, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Aymeric
authors.initials: A
authors.lastname: Rouchaud
authors.affiliation: Applied Neuroradiology Laboratory, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Yong-Hong
authors.initials: YH
authors.lastname: Ding
authors.affiliation: Applied Neuroradiology Laboratory, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Daying
authors.initials: D
authors.lastname: Dai
authors.affiliation: Applied Neuroradiology Laboratory, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Dana
authors.identifier: http://orcid.org/0000-0002-9676-232X
authors.initials: D
authors.lastname: Schroeder
authors.affiliation: George Mason University, Bioengineering, Fairfax, Virginia, USA.
authors.forename: Juan
authors.initials: J
authors.lastname: Cebral
authors.affiliation: Applied Neuroradiology Laboratory, Mayo Clinic, Rochester, Minnesota, USA.|Department of Radiology, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: David F
authors.initials: DF
authors.lastname: Kallmes
authors.affiliation: Applied Neuroradiology Laboratory, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Ramanathan
authors.initials: R
authors.lastname: Kadirvel
mesh_terms: D017542:Aneurysm, Ruptured / Q000201:enzymology / Q000628:therapy; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage*; D016572:Cyclosporine / Q000008:administration & dosage*; D057510:Endovascular Procedures / Q000379:methods*; D002532:Intracranial Aneurysm / Q000201:enzymology / Q000628:therapy*; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis*; D011817:Rabbits; D015607:Stents; D016896:Treatment Outcome
chemical_list: D000893:Anti-Inflammatory Agents; D016572:Cyclosporine; D020780:Matrix Metalloproteinase 9
keywords: Aneurysm; Coil; Flow Diverter; Inflammation