Ciprofloxacin Exposure Promotes Aortic Dissection and Arterial Rupture in a Mouse Model of Vascular Ehlers-Danlos Syndrome.

OBJECTIVE

We tested the hypothesis that ciprofloxacin exposure increases the incidence of aortic dissection and arterial rupture in vascular Ehlers-Danlos (vEDS) mice.

BACKGROUND

While data support that fluoroquinolones exacerbate lethal sequela in some types of aortic pathology, the potential danger of these drugs has not been studied in the context of vEDS.

METHODS

Eight-week-old male and female vEDS mice ( Col3a1[G209S/WT] ) and wild-type littermates ( Col3a1[WT/WT] ) were randomly assigned to receive either ciprofloxacin (n=25) or vehicle control (n=24) through daily gavage for 2 weeks and were monitored for 4 weeks. We compared groups based on survival, aortic dissection and rupture incidence, and aortic tissue levels of collagen, lysyl oxidase (LOX), matrix metalloproteinases (MMP), macrophages, and apoptosis.

RESULTS

All vEDS mice that received vehicle and all littermate controls survived the 4-week study period. In contrast, 44% of vEDS mice that received ciprofloxacin died ( P <0.001) due to aortic or arterial rupture manifesting as hemopericardium or hemothorax, most within 7 days of exposure. Findings were similar in male and female vEDS mice. Compared with aortic tissue from vehicle-treated vEDS mice, tissue from ciprofloxacin-treated vEDS mice exhibited decreased collagen content, decreased LOX, increased MMP2 and 9 levels, increased macrophage infiltration, and increased apoptosis (all P <0.001).

CONCLUSIONS

In a mouse model of vEDS, ciprofloxacin exposure resulted in aortic inflammation, collagen disruption, cell death, reduced LOX, and increased risk of fatal dissection and rupture of the aorta and branch arteries. These novel translational findings strongly support recommendations to avoid fluoroquinolones in patients with vEDS.