Acquired Mechanisms of Bicuspid Aortic Valve-Associated Aortopathy
Date
2018-07-05
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Abstract
Bicuspid aortic valve (BAV)-associated aortopathy is characterized by progressive aortic extracellular matrix (ECM) remodeling leading to aneurysm, dissection or rupture. The cause of this aortopathy is unclear; a genetically-driven basis has been favoured, but recent studies implicating an acquired valve-mediated hemodynamic mechanism have challenged this long-standing view despite no clear link between aortic hemodynamics and ECM remodeling having been delineated. We hypothesized that aortopathy in human BAV patients is influenced by valve-mediated wall shear stress (WSS) in a regionally-dependent manner. Aortic tissue specimens from BAV patients that received pre-operative 3-dimensional time-resolved phase-contrast magnetic resonance imaging (4D flow MRI) to compute regional WSS were assessed quantitatively for their expression of aortopathy. Compared to aortic tissue subjected to normal WSS, adjacent tissue from the same BAV aortas subjected to regionally-elevated WSS exhibited demonstrably worse elastic fiber histopathology, increased protease expression and elevated levels of transforming growth factor β-1 (TGFβ-1) consistent with maladaptive aortic ECM remodeling. We also observed that incremental increases in aortic WSS in the human BAV aorta correlate with increased severity of elastic fiber histopathology, and that this association is most strongly observed in BAV patients with primary stenosis and in mildly-dilated (< 4.5 cm) aortas in the earlier stages of disease. These novel data support a critical role for valve-mediated hemodynamics in coordinating the expression of BAV-associated aortopathy and dispute the assumption that aortic pathology in these patients is primarily driven by genetics. Fluoroquinolone (FQ) antibiotic use constitutes another acquired mechanism of aortopathy that may place BAV patients with pre-existing aortic pathology at risk of disease exacerbation. However, no cellular mechanism has been provided underlying this association. We hypothesized that in aortic myofibroblast cells from BAV-associated aortopathy patients, FQ exposure would alter the proteolytic profile favouring ECM dysregulation and modulate collagen expression. We observed that FQ exposure generates a functional increase in ECM degradation driven by reduced tissue inhibitors of matrix metalloproteinases (TIMPs) alongside impaired compensatory collagen-1 expression. These findings may explain the increased incidence of acquired FQ-associated aortopathy and encourage judicious use of FQ in BAV patients with pre-existing aortic pathology.
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Keywords
bicuspid aortic valve, aortopathy, fluoroquinolone, extracellular matrix, wall shear stress
Citation
Guzzardi, D. G. (2018). Acquired Mechanisms of Bicuspid Aortic Valve-Associated Aortopathy (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca. doi:10.11575/PRISM/32321