title: Valve-Related Hemodynamics Mediate Human Bicuspid Aortopathy: Insights From Wall Shear Stress Mapping.
abstract: BACKGROUND
  Suspected genetic causes for extracellular matrix (ECM) dysregulation in the ascending aorta in patients with bicuspid aortic valves (BAV) have influenced strategies and thresholds for surgical resection of BAV aortopathy. Using 4-dimensional (4D) flow cardiac magnetic resonance imaging (CMR), we have documented increased regional wall shear stress (WSS) in the ascending aorta of BAV patients.
  
  
  OBJECTIVE
  This study assessed the relationship between WSS and regional aortic tissue remodeling in BAV patients to determine the influence of regional WSS on the expression of ECM dysregulation.
  
  
  METHODS
  BAV patients (n = 20) undergoing ascending aortic resection underwent pre-operative 4D flow CMR to regionally map WSS. Paired aortic wall samples (i.e., within-patient samples obtained from regions of elevated and normal WSS) were collected and compared for medial elastin degeneration by histology and ECM regulation by protein expression.
  
  
  RESULTS
  Regions of increased WSS showed greater medial elastin degradation compared to adjacent areas with normal WSS: decreased total elastin (p = 0.01) with thinner fibers (p = 0.00007) that were farther apart (p = 0.001). Multiplex protein analyses of ECM regulatory molecules revealed an increase in transforming growth factor β-1 (p = 0.04), matrix metalloproteinase (MMP)-1 (p = 0.03), MMP-2 (p = 0.06), MMP-3 (p = 0.02), and tissue inhibitor of metalloproteinase-1 (p = 0.04) in elevated WSS regions, indicating ECM dysregulation in regions of high WSS.
  
  
  CONCLUSIONS
  Regions of increased WSS correspond with ECM dysregulation and elastic fiber degeneration in the ascending aorta of BAV patients, implicating valve-related hemodynamics as a contributing factor in the development of aortopathy. Further study to validate the use of 4D flow CMR as a noninvasive biomarker of disease progression and its ability to individualize resection strategies is warranted.
authors: Department of Cardiac Sciences, Libin Cardiovascular Institute of Alberta, University of Calgary, Calgary, Canada.
authors: David G
authors: DG
authors: Guzzardi
authors: Department of Radiology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
authors: Alex J
authors: AJ
authors: Barker
authors: Department of Radiology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois; Department of Radiology, Academic Medical Center, Amsterdam, the Netherlands.
authors: Pim
authors: P
authors: van Ooij
authors: Division of Cardiac Surgery, Department of Surgery, Bluhm Cardiovascular Institute, Northwestern University, Chicago, Illinois.
authors: S Chris
authors: SC
authors: Malaisrie
authors: Division of Cardiology, Department of Medicine, Bluhm Cardiovascular Institute, Northwestern University, Chicago, Illinois.
authors: Jyothy J
authors: JJ
authors: Puthumana
authors: Department of Cardiac Sciences, Libin Cardiovascular Institute of Alberta, University of Calgary, Calgary, Canada.
authors: Darrell D
authors: DD
authors: Belke
authors: Department of Cardiac Sciences, Libin Cardiovascular Institute of Alberta, University of Calgary, Calgary, Canada.
authors: Holly E M
authors: HE
authors: Mewhort
authors: Department of Cardiac Sciences, Libin Cardiovascular Institute of Alberta, University of Calgary, Calgary, Canada.
authors: Daniyil A
authors: DA
authors: Svystonyuk
authors: Department of Cardiac Sciences, Libin Cardiovascular Institute of Alberta, University of Calgary, Calgary, Canada.
authors: Sean
authors: S
authors: Kang
authors: Division of Cardiac Surgery, Li Ka Shing Knowledge Institute of St. Michael's Hospital, University of Toronto, Toronto, Canada.
authors: Subodh
authors: S
authors: Verma
authors: Department of Radiology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
authors: Jeremy
authors: J
authors: Collins
authors: Department of Radiology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
authors: James
authors: J
authors: Carr
authors: Division of Cardiology, Department of Medicine, Bluhm Cardiovascular Institute, Northwestern University, Chicago, Illinois.
authors: Robert O
authors: RO
authors: Bonow
authors: Department of Radiology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois; Department of Biomedical Engineering, McCormick School of Engineering, Northwestern University, Chicago, Illinois.
authors: Michael
authors: M
authors: Markl
authors: Division of Cardiology, Department of Medicine, Bluhm Cardiovascular Institute, Northwestern University, Chicago, Illinois.
authors: James D
authors: JD
authors: Thomas
authors: Division of Cardiac Surgery, Department of Surgery, Bluhm Cardiovascular Institute, Northwestern University, Chicago, Illinois; Department of Biomedical Engineering, McCormick School of Engineering, Northwestern University, Chicago, Illinois.
authors: Patrick M
authors: PM
authors: McCarthy
authors: Department of Cardiac Sciences, Libin Cardiovascular Institute of Alberta, University of Calgary, Calgary, Canada; Division of Cardiac Surgery, Department of Surgery, Bluhm Cardiovascular Institute, Northwestern University, Chicago, Illinois. Electronic address: paul.fedak@gmail.com.
authors: Paul W M
authors: PW
authors: Fedak
mesh_terms: D000328:Adult; D001011:Aorta / Q000378:metabolism / Q000503:physiopathology*; D001021:Aortic Valve / Q000002:abnormalities* / Q000378:metabolism / Q000503:physiopathology; D000082882:Bicuspid Aortic Valve Disease; D016022:Case-Control Studies; D004549:Elastin / Q000378:metabolism; D005260:Female; D006349:Heart Valve Diseases / Q000378:metabolism / Q000503:physiopathology*; D006439:Hemodynamics; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism; D008875:Middle Aged; D013314:Stress, Mechanical; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism
chemical_list: D019714:Tissue Inhibitor of Metalloproteinases; D004549:Elastin; D020782:Matrix Metalloproteinases
keywords: aneurysm; imaging; remodeling