Graduate Student Seminar Series
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Presentation Title: Echocardiogram-Based Detection of Congenital Valvular Malformations
Bicuspid aortic valve disease (BAVD) is a congenital abnormality that impacts over 2% of the global population. The condition involves the fusion of two of the three leaflets of the aortic valve, leading to aberrant blood flow into the aorta. Disturbed hemodynamics is associated with increased risk of aortopathies, such as ascending aortic dilatation (AAD), which can lead to fatal aortic dissection or rupture.
We hypothesize that the elevated risk of developing AAD in BAVD is a result of disruptions local cell function and signaling caused by changes in hemodynamics. To test this hypothesis, we will leverage a novel mouse model with a mutation in natriuretic peptide 2 receptor (Npr2): ~10% of Npr2+/- mice develop BAVD, whereas the remaining 90% have normal tricuspid aortic valves (TAV), enabling the effects of BAVD-associated hemodynamics to be decoupled from the underlying genetic mutation.
We first established echocardiography-based criteria to identify normal tricuspid vs. congenitally abnormal (bicuspid) aortic valves in neonatal Npr2+/- mice. Approximately 10-15% of neonatal mice exhibited echocardiographic features associated with valve malformations and disrupted flow, including: i) regurgitation and recirculation by color Doppler; ii) peak systolic velocities >1300 mm/sec by pulse Doppler; and iii) putative fusion of leaflets along commissures by electrocardiogram-gated kilohertz visualization. Valves with these echographic features were confirmed by gross anatomy visualization to have stenotic and thickened leaflets, with partial to full bicuspid fusions. Movat’s pentachrome staining confirmed a range of fusions in BAVs, mimicking the gradient of malformations observed in human BAVD.
This study establishes a robust method to classify and characterize valve morphologies in neonatal mice as an essential first step to studying the role of BAV-associated hemodynamics in AAD. On-going work will determine focal transcriptional and proteomic perturbations in the ascending aorta specifically associated with BAV-associated hemodynamics.
Supervisor Name: Craig Simmons
Year of Study: 2
Program of Study: PhD
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