David G Guzzardi1, Alex J Barker2, Pim van Ooij3, S Chris Malaisrie4, Jyothy J Puthumana5, Darrell D Belke1, Holly E M Mewhort1, Daniyil A Svystonyuk1, Sean Kang1, Subodh Verma6, Jeremy Collins2, James Carr2, Robert O Bonow5, Michael Markl7, James D Thomas5, Patrick M McCarthy8, Paul W M Fedak9. 1. Department of Cardiac Sciences, Libin Cardiovascular Institute of Alberta, University of Calgary, Calgary, Canada. 2. Department of Radiology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois. 3. Department of Radiology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois; Department of Radiology, Academic Medical Center, Amsterdam, the Netherlands. 4. Division of Cardiac Surgery, Department of Surgery, Bluhm Cardiovascular Institute, Northwestern University, Chicago, Illinois. 5. Division of Cardiology, Department of Medicine, Bluhm Cardiovascular Institute, Northwestern University, Chicago, Illinois. 6. Division of Cardiac Surgery, Li Ka Shing Knowledge Institute of St. Michael's Hospital, University of Toronto, Toronto, Canada. 7. Department of Radiology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois; Department of Biomedical Engineering, McCormick School of Engineering, Northwestern University, Chicago, Illinois. 8. 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. 9. 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.
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. OBJECTIVES: 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.
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. OBJECTIVES: 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.
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