A novel swine model of abdominal aortic aneurysm

J. Michael Cullen, Guanyi Lu, Alexander H. Shannon, Gang Su, Ashish Sharma, Morgan Salmon, Anna Z. Fashandi, Michael D. Spinosa, William G. Montgomery, W. Forrest Johnston, Gorav Ailawadi, Gilbert R. Upchurch

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

Abstract

Objective: Few large-animal models exist for the study of aortic aneurysms. β-Aminopropionitrile (BAPN) is a compound known to cause aortic aneurysms by inhibiting lysyl oxidase, a collagen cross-linking enzyme. It is hypothesized that BAPN plus aneurysm induction surgery would result in significant aneurysm formation in swine with biologic properties similar to human disease. Methods: Initial experiments were performed in uncastrated male swine not treated with BAPN (surgery alone). Subsequently, uncastrated male swine were fed BAPN (0.15 g/kg) for 7 days before undergoing surgery; the infrarenal aorta was circumferentially dissected and measured, balloon dilated, and perfused with elastase (500 units) and type I collagenase (8000 units), with extraluminal elastase application. In the BAPN groups, daily BAPN feedings continued until swine harvest at postoperative days 7, 14, and 28. Results: Swine undergoing surgery alone (n = 12) had significantly less dilation at 28 days compared with BAPN + surgery swine (51.9% ± 29.2% [0%-100%] vs 113.5% ± 30.2% [52.9%-146.2%]; P < .0003). Mean aortic dilation in animals undergoing treatment with surgery and BAPN was 86.9% ± 47.4% (range, 55.6%-157.1%), 105.4% ± 58.1% (50%-133.3%), and 113.5% ± 30.2% (52.9%-146.2%) at 7, 14, and 28 days, respectively. In the BAPN + surgery group, significant elastolysis was present at all time points, whereas aortic wall collagen content was not significantly different. Smooth muscle cells were significantly depleted at 14 and 28 days, and M1 macrophages were increased at 14 and 28 days (P < .05, all). Matrix metalloproteinase 2 was elevated at 7 days (P < .05). Multiple proinflammatory cytokines were elevated within the aortic wall of BAPN + surgery swine. Conclusions: BAPN plus surgery resulted in significantly larger aortic aneurysms than surgery alone and was critical to aneurysm formation in this novel swine model. Hallmarks of human disease, such as elastin fragmentation, smooth muscle cell depletion, macrophage infiltration, matrix metalloproteinase activation, and proinflammatory cytokine expression, were observed in BAPN-treated swine. This model better parallels many of the characteristics of human AAAs and may be suitable for prehuman drug trials. Clinical Relevance: Translation of abdominal aortic aneurysm (AAA) models from small animals to large animals is critical for device development and further elucidation of AAA pathogenesis mechanisms. We have developed a reproducible large-animal model of AAA disease with >100% dilation in swine. The swine AAA have a histology and inflammatory milieu similar to human, and it is hoped that further work using this model will expand our understanding of this disease.

Original languageEnglish (US)
Pages (from-to)252-260.e2
JournalJournal of vascular surgery
Volume70
Issue number1
DOIs
StatePublished - Jul 2019
Externally publishedYes

Keywords

  • Aortic aneurysm
  • Cardiovascular diseases
  • Cytokines
  • Immunohistochemistry
  • Inflammation
  • Macrophages

ASJC Scopus subject areas

  • Surgery
  • Cardiology and Cardiovascular Medicine

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