Advanced Study of Aortic Pathology (ASAP). Homo sapiens

BACKGROUND: The vast majority of thoracic aortic aneurysms (TAAs) are observed either together with a bicuspid aortic valve (BAV), a common congenital disorder, or in idiopathic cases such as patients with a normal tricuspid aortic valve (TAV). The main objective of our study was to identify shared and unique gene expression properties underlying the aortic dilation of BAV and TAV patients. METHODS AND RESULTS: Tissue biopsies for RNA and histological analyses were obtained from aorta of non-dilated (45mm) aorta of BAV and TAV patients (in total 131 patients). Additional controls were from mammary artery of the same patients (n=88) and aorta from transplant donors (n=13). Gene expression profiles generated using Affymetrix Exon arrays were analyzed from controls and from aorta intima-media and adventitia of patients (in total 345 samples). 606 genes in aortic intima-media were found to be differentially expressed with dilation. Of these, only few (<4%) were differentially expressed in both BAV and TAV patients. Gene set enrichment analysis identified cell adhesion and extracellular region gene ontology sets as common features of TAA in BAV and TAV patients. The set of immune response genes was observed to be particularly overexpressed in aortic media of dilated TAV samples. CONCLUSION: The divergent gene expression profiles indicate fundamental differences in TAA etiology of BAV and TAV patients. Immune response activation solely in the aorta media of TAV patients suggests that inflammation is a causal factor of TAA in this patient group. Overall design: Biobank of patient material. Each tissue sample is from a different patient as indicated by patient ID.

研究背景：绝大多数胸主动脉瘤（thoracic aortic aneurysms, TAAs）要么合并二叶主动脉瓣（bicuspid aortic valve, BAV，一种常见先天性疾病），要么见于特发性病例，例如携带正常三叶主动脉瓣（tricuspid aortic valve, TAV）的患者。本研究的核心目标是鉴定二叶主动脉瓣与三叶主动脉瓣患者主动脉扩张过程中共有的及独有的基因表达特征。
方法与结果：用于RNA分析与组织学检测的组织活检样本，取自131例二叶主动脉瓣及三叶主动脉瓣患者的非扩张主动脉（以45mm作为扩张判定阈值）。额外的对照样本取自同批次患者的乳内动脉（共88例）以及移植供体的主动脉组织（共13例）。使用Affymetrix外显子芯片生成的基因表达谱，对对照样本以及患者主动脉内膜-中层与外膜组织的样本（共计345份）进行了分析。在主动脉内膜-中层组织中，共鉴定出606个随主动脉扩张发生差异表达的基因；其中仅不到4%的基因在二叶主动脉瓣与三叶主动脉瓣患者中均呈现差异表达。基因集富集分析显示，细胞黏附与细胞外区域相关的基因本体（gene ontology, GO）集，是两类患者相关胸主动脉瘤的共同特征。免疫应答相关基因集在扩张型三叶主动脉瓣患者的主动脉中层组织中呈现显著高表达。
结论：二叶主动脉瓣与三叶主动脉瓣患者的基因表达谱存在显著差异，提示两类患者的胸主动脉瘤病因学存在本质区别。仅在三叶主动脉瓣患者的主动脉中层组织中观察到的免疫应答激活现象，表明炎症反应是该类患者罹患胸主动脉瘤的致病因素。
实验整体设计：患者样本生物样本库。每份组织样本均来自不同患者，样本以患者ID进行标识。