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Does ciprofloxacin increase susceptibility to aortic dissection and rupture in mice?
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.
Ciprofloxacin should be used with caution in patients with aortic dilatation, as well as in those at high risk for aortic aneurysm and dissection.
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.
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.
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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Accepted for Publication: April 22, 2018.
Corresponding Author: Scott A. LeMaire, MD (firstname.lastname@example.org), and Ying H. Shen, MD, PhD (email@example.com), Department of Surgery, Baylor College of Medicine, One Baylor Plaza, BCM 390, Houston, TX 77030.
Published Online: July 25, 2018. doi:10.1001/jamasurg.2018.1804
Author Contributions: Drs LeMaire and Shen had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: LeMaire, Coselli, Shen.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: LeMaire, Shen.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: LeMaire, L. Zhang, Ren, Shen.
Obtained funding: LeMaire, Shen.
Administrative, technical, or material support: All authors.
Supervision: LeMaire, Coselli, Shen.
Conflict of Interest Disclosures: None reported.
Funding/Support: This study was supported by the Roderick D. MacDonald Research Fund at Baylor St Luke’s Medical Center (grant 17RDM004) and the National Institutes of Health (grant R01HL131980). Dr LeMaire’s work is supported in part by the Jimmy and Roberta Howell Professorship in Cardiovascular Surgery at Baylor College of Medicine.
Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Additional Contributions: We gratefully acknowledge Nicole Stancel, PhD, ELS, Scientific Publications at the Texas Heart Institute, for editorial support; Scott Weldon, MA, Division of Cardiothoracic Surgery, Baylor College of Medicine, for preparation of the promotional image; and Nicholas S. Zhang, Division of Cardiothoracic Surgery, Baylor College of Medicine, for technical support. Dr Stancel and Mr Weldon are employed by these institutions. Mr Zhang was not compensated.
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