Aorta-specific DNA methylation patterns in cell-free DNA from patients with bicuspid aortic valve-associated aortopathy.

BACKGROUND: 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. 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. METHODS: We 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. RESULTS: Aortic 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. CONCLUSIONS: In 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.

Bicuspid aortic valve-associated aortopathy: update on biomarkers.

PURPOSE OF REVIEW: Bicuspid aortic valve (BAV)-associated aortopathy is common and its progression for individual patients is difficult to predict. The present review aims to identify recent developments using biomarkers for the determination of risk and progression of disease in patients with BAV aortopathy. RECENT FINDINGS: Novel rare genetic variants and epigenetic methylation signatures affecting non-cytosine phosphate guanine (non-CpG) and CpG sites, nicotinamide phosphoribosyltransferase and Sod expression may lead to improved prediction of the aortopathy phenotype. Circulating transforming growth factor ß-1/endoglin and miRNA signatures are found to be indicative of aortic dilation. Aortic miRNA, sphingomyelin and oxidative stress levels are linked to aortopathy progression and aortic dilation. Further evidence is shown that the pattern of cusp fusion in BAV may influence the location and extent of aortopathy. SUMMARY: The clinical phenotypic variability seen in BAV patients suggests complex interactions between genetic variants, epigenetic regulation modifications and the variable effect of valve-mediated hemodynamic flow disturbances on the aorta and its secreted markers. Emerging biomarkers may serve along with advanced noninvasive imaging modalities to precisely identify risk of aortic complications and identify those patients who are in need of surgical intervention.