Abstract
BackgroundThe dilation of the aorta that occurs as a consequence of a congenitally bicuspid aortic valve (BAV) is associated with a risk of dissection, aneurysm or rupture. With progressive aortopathy, surgery is often recommended, but current patient selection strategies have limitations. A blood-based assay to identify those who would most benefit from prophylactic surgery would be an important medical advance. In a proof-of-concept study, we sought to identify aorta-specific differentially methylated regions (DMRs) detectable in plasma cell-free DNA (cfDNA) obtained from patients undergoing surgery for BAV-associated aortopathy.MethodsWe used bioinformatics and publicly available human methylomes to identify aorta-specific DMRs. We used data from 4D-flow cardiac magnetic resonance imaging to identify regions of elevated aortic wall shear stress (WSS) in patients with BAV-associated aortopathy undergoing surgery and correlated WSS regions with aortic tissue cell death assessed using TUNEL staining. Cell-free DNA was isolated from patient plasma, and levels of candidate DMRs were correlated with aortic diameter and aortic wall cell death.ResultsAortic wall cell death was not associated with maximal aortic diameter but was significantly associated with elevated WSS. We identified 24 candidate aorta-specific DMRs and selected 4 for further study. A DMR on chromosome 11 was specific for the aorta and correlated significantly with aortic wall cell death. Plasma levels of total and aorta-specific cfDNA did not correlate with aortic diameter.ConclusionsIn a cohort of patients undergoing surgery for BAV-associated aortopathy, elevated WSS created by abnormal flow hemodynamics was associated with increased aortic wall cell death which supports the use of aorta-specific cfDNA as a potential tool to identify aortopathy and stratify patient risk.
Highlights
The dilation of the aorta that occurs as a consequence of a congenitally bicuspid aortic valve (BAV) is associated with a risk of dissection, aneurysm or rupture
We identified novel and unique aortaspecific Differentially methylated region (DMR) that could be measured in human plasma cell-free DNA (cfDNA) obtained from patients with BAV-associated aortopathy who were undergoing surgery
Cell death is increased in aortic regions of elevated wall shear stress For all individual BAV patients, cell death, as assessed using terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and 4′,6-diamidino-2-phenylindole (DAPI) staining, was increased in regions of the ascending aorta that demonstrated elevated WSS compared to the regions of normal WSS as determined by cardiac magnetic resonance imaging (CMR) and this difference was significant for the paired comparisons and pooled data (Fig. 1)
Summary
The dilation of the aorta that occurs as a consequence of a congenitally bicuspid aortic valve (BAV) is associated with a risk of dissection, aneurysm or rupture. A blood-based assay to identify those who would most benefit from prophylactic surgery would be an important medical advance. In a proof-of-concept study, we sought to identify aorta-specific differentially methylated regions (DMRs) detectable in plasma cell-free DNA (cfDNA) obtained from patients undergoing surgery for BAV-associated aortopathy. The aortopathy that occurs as a consequence of a congenitally bicuspid aortic valve (BAV) is associated with a risk of dissection, aneurysm or rupture [1]. We hypothesize that aorta-specific DMRs detectable in cfDNA will allow the noninvasive assessment of disease and the prediction of important clinical events and enable precision medicine for optimal management of patients with aortopathy and highly variable individual risk
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