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. 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. 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. 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.

中文翻译：

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二叶式主动脉瓣相关主动脉病患者游离 DNA 中主动脉特异性 DNA 甲基化模式

先天性二叶式主动脉瓣 (BAV) 导致的主动脉扩张与夹层、动脉瘤或破裂的风险相关。对于进行性主动脉病，通常建议进行手术，但目前的患者选择策略存在局限性。通过基于血液的检测来识别那些最能从预防性手术中受益的人将是一项重要的医学进步。在一项概念验证研究中，我们试图鉴定在接受 BAV 相关主动脉病手术的患者的血浆游离 DNA (cfDNA) 中可检测到的主动脉特异性差异甲基化区域 (DMR)。我们使用生物信息学和公开的人类甲基化组来识别主动脉特异性 DMR。我们使用 4D 流心脏磁共振成像的数据来识别接受手术的 BAV 相关主动脉病患者的主动脉壁剪切应力 (WSS) 升高的区域，并将 WSS 区域与使用 TUNEL 染色评估的主动脉组织细胞死亡相关联。从患者血浆中分离出无细胞 DNA，候选 DMR 的水平与主动脉直径和主动脉壁细胞死亡相关。主动脉壁细胞死亡与最大主动脉直径无关，但与 WSS 升高显着相关。我们确定了 24 个候选主动脉特异性 DMR，并选择了 4 个进行进一步研究。11 号染色体上的 DMR 对主动脉具有特异性，并且与主动脉壁细胞死亡显着相关。总 cfDNA 和主动脉特异性 cfDNA 的血浆水平与主动脉直径不相关。在接受 BAV 相关主动脉病手术的一组患者中，血流动力学异常导致的 WSS 升高与主动脉壁细胞死亡增加相关，这支持使用主动脉特异性 cfDNA 作为识别主动脉病和分层患者风险的潜在工具。