A new study finds that patients taking fluoroquinolone antibiotics may be at higher risk of aortopathy in part because of human aortic myofibroblast–mediated extracellular matrix (ECM) dysregulation.
“Emerging evidence supports pharmacologic-associated aortopathy in patients receiving fluoroquinolone [FQ] antibiotics,” said first author, and his colleagues, citing previous research showing that, “compared with patients receiving amoxicillin antibiotics, those receiving FQ have a 66% higher risk of aneurysm or dissection within a 2-month period after commencing FQ use.”
Based upon such data, the Food and Drug Administration issued aabout the increased risk of ruptures or tears in the aorta with fluoroquinolone antibiotics in certain patients, updating their regarding “disabling and potentially permanent side effects of the tendons, muscles, joints, nerves, and central nervous system that can occur together in the same patient,” upon exposure to this class of antibiotics. Earlier in 2018, the FDA had about serious and potentially fatal low blood sugar levels and mental health side effects with fluoroquinolone antibiotics.
Dr. Guzzardi and his colleagues at the University of Calgary (Alta.) performed a study to attempt to determine the possible cellular mechanisms for the observed aortopathy. In their study published in the, Dr. Guzzardi and his colleagues isolated human aortic myofibroblasts from nine patients with aortopathy who were undergoing elective ascending aortic resection.
Following exposure of cells to FQ, the researchers assessed secreted matrix metalloproteinases relative to tissue inhibitors of matrix metalloproteinases (TIMPs). In addition, they examined ECM degradation by using a three-dimensional gelatin-fluorescein isothiocyanate fluorescence microgel assay. Aortic cellular collagen type I expression following FQ exposure was determined by immunoblotting and immunofluorescent staining. Dr. Guzzardi and his colleagues also looked at cell apoptosis, necrosis, and metabolic viability using two versions of vital staining.
They found that FQ exposure significantly decreased aortic cell TIMP-1 (P less than .004) and TIMP-2 (P less than .0004) protein expression, compared with controls, and the ratio of matrix metalloproteinase 9/TIMP-2 was increased (P less than .01). This suggests an increased capacity for ECM degradation after FQ exposure, according to the researchers.
In addition, FQ exposure attenuated collagen type I expression as assessed by immunoblotting (P less than .002) and immunofluorescence (P less than .02).
“FQ induces human aortic myofibroblast–mediated ECM dysregulation by decreasing TIMP expression and preventing compensatory collagen deposition. These data provide novel insights into the mechanisms that may underlie the clinical association of FQ exposure and increased risk of acute aortic events in the community. Our data suggest cautious use of FQ in selected patient populations with preexistent aortopathy and connective tissue disorders,” the researchers concluded.
In an accompanying, while warning that these are preliminary observations based upon a small number of patients with aortopathy, , of Tampere (Finland) University, wrote that, “for the first time, the wild theory of fluoroquinolone-associated aortopathy has a molecular hint that is based on collagen degeneration and progression of aortic disease. ... This theory is in line with previous observations revealing antifibrotic activity and decreased collagen-1 protein expression with fluoroquinolones. The enigmatic puzzle of the progression of some aortic events may alarmingly be iatrogenic, and the clinician may wisely consider a prudent use of fluoroquinolones in patients with aortic dilatation.”
The authors and commentators reported that they had no commercial conflicts to disclose.
SOURCE: Guzzardi DG et al.