Acquired Mechanisms of Bicuspid Aortic Valve-Associated Aortopathy

Guzzardi, David G.

Acquired Mechanisms of Bicuspid Aortic Valve-Associated Aortopathy

dc.contributor.advisor	Fedak, Paul
dc.contributor.author	Guzzardi, David G.
dc.contributor.committeemember	O'Brien, Edward
dc.contributor.committeemember	Di Martino, Elena S.
dc.date	2018-11
dc.date.accessioned	2018-07-09T14:42:40Z
dc.date.available	2018-07-09T14:42:40Z
dc.date.issued	2018-07-05
dc.description.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.	en_US
dc.identifier.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	en_US
dc.identifier.doi	http://dx.doi.org/10.11575/PRISM/32321
dc.identifier.uri	http://hdl.handle.net/1880/107099
dc.language.iso	eng
dc.publisher.faculty	Cumming School of Medicine
dc.publisher.faculty	Graduate Studies
dc.publisher.institution	University of Calgary	en
dc.publisher.place	Calgary	en
dc.rights	University of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission.
dc.subject	bicuspid aortic valve
dc.subject	aortopathy
dc.subject	fluoroquinolone
dc.subject	extracellular matrix
dc.subject	wall shear stress
dc.subject.classification	Medicine and Surgery	en_US
dc.title	Acquired Mechanisms of Bicuspid Aortic Valve-Associated Aortopathy
dc.type	doctoral thesis
thesis.degree.discipline	Cardiovascular & Respiratory Sciences
thesis.degree.grantor	University of Calgary
thesis.degree.name	Doctor of Philosophy (PhD)
ucalgary.item.requestcopy	true