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Original Investigation
July 25, 2018

Effect of Ciprofloxacin on Susceptibility to Aortic Dissection and Rupture in Mice

Author Affiliations
  • 1Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas
  • 2Department of Cardiovascular Surgery, Texas Heart Institute, Houston
  • 3Cardiovascular Research Institute, Baylor College of Medicine, Houston, Texas
  • 4Stem Cell Research, Texas Heart Institute, Houston
JAMA Surg. Published online July 25, 2018. doi:10.1001/jamasurg.2018.1804
Key Points

Question  Does ciprofloxacin increase susceptibility to aortic dissection and rupture in mice?

Findings  This study showed that ciprofloxacin significantly increased the incidence of aortic dissection and rupture in a mouse model of moderate, sporadic aortic aneurysm and dissection. In these mice, ciprofloxacin decreased lysyl oxidase expression and activity, increased MMP levels and activity, and increased elastic fiber fragmentation and cell injury, which may contribute to increased susceptibility to stress-induced aortic destruction.

Meaning  Ciprofloxacin should be used with caution in patients with aortic dilatation, as well as in those at high risk for aortic aneurysm and dissection.

Abstract

Importance  Fluoroquinolones are among the most commonly prescribed antibiotics. Recent clinical studies indicated an association between fluoroquinolone use and increased risk of aortic aneurysm and dissection (AAD). This alarming association has raised concern, especially in patients with AAD with risk of rupture and in individuals at risk for developing AAD.

Objective  To examine the effect of ciprofloxacin on AAD development in mice.

Design, Setting, and Participants  In a mouse model of moderate, sporadic AAD, 4-week-old male and female C57BL/6J mice were challenged with a high-fat diet and low-dose angiotensin infusion (1000 ng/min/kg). Control unchallenged mice were fed a normal diet and infused with saline. After randomization, challenged and unchallenged mice received ciprofloxacin (100 mg/kg/d) or vehicle through daily gavage during angiotensin or saline infusion. Aortic aneurysm and dissection development and aortic destruction were compared between mice. The direct effects of ciprofloxacin on aortic smooth muscle cells were examined in cultured cells.

Results  No notable aortic destruction was observed in unchallenged mice that received ciprofloxacin alone. Aortic challenge induced moderate aortic destruction with development of AAD in 17 of 38 mice (45%) and severe AAD in 9 (24%) but no rupture or death. However, challenged mice that received ciprofloxacin had severe aortic destruction and a significantly increased incidence of AAD (38 of 48 [79%]; P = .001; χ2 = 10.9), severe AAD (32 of 48 [67%]; P < .001; χ2 = 15.7), and rupture and premature death (7 of 48 [15%]; P = .01; χ2 = 6.0). The increased AAD incidence was observed in different aortic segments and was similar between male and female mice. Compared with aortic tissues from challenged control mice, those from challenged mice that received ciprofloxacin showed decreased expression of lysyl oxidase, an enzyme that is critical in the assembly and stabilization of elastic fibers and collagen. These aortas also showed increased matrix metalloproteinase levels and activity, elastic fiber fragmentation, and aortic cell injury. In cultured smooth muscle cells, ciprofloxacin treatment significantly reduced lysyl oxidase expression and activity, increased matrix metalloproteinase expression and activity, suppressed cell proliferation, and induced cell death. Furthermore, ciprofloxacin—a DNA topoisomerase inhibitor—caused nuclear and mitochondrial DNA damage and the release of DNA into the cytosol, subsequently inducing mitochondrial dysfunction, reactive oxygen species production, and activation of the cytosolic DNA sensor STING, which we further showed was involved in the suppression of lysyl oxidase expression and induction of matrix metalloproteinase expression.

Conclusions and Relevance  Ciprofloxacin increases susceptibility to aortic dissection and rupture in a mouse model of moderate, sporadic AAD. Ciprofloxacin should be used with caution in patients with aortic dilatation, as well as in those at high risk for AAD.

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