Division of Cardiothoracic Surgery, Department of Surgery, Medical University of South Carolina, Charleston, SC 29425, USA.
J Thorac Cardiovasc Surg. 2013 May;145(5):1326-33. doi: 10.1016/j.jtcvs.2012.12.027. Epub 2013 Jan 11.
Thoracic aortic aneurysms (TAAs) develop through an asymptomatic process resulting in gross dilation that progresses to rupture if left undetected and untreated. If detected, patients with TAA are followed over time until the risk of rupture outweighs the risk of surgical repair. Current methodologies for tracking TAA size are limited to expensive computed tomography or magnetic resonance imaging because no acceptable population screening tools are currently available. Previous studies from this laboratory and others have identified differential protein profiles for the matrix metalloproteinases (MMPs) and their endogenous tissue inhibitors (TIMPs), in ascending TAA tissue from patients with bicuspid aortic valves (BAVs), versus patients with idiopathic degenerative disease and a tricuspid aortic valve (TAV). In addition, altered microRNA (miR) expression levels have also been reported in TAAs compared with normal aortic tissue. The objective of our study was to identify circulating factors within plasma that could serve as potential biomarkers for distinguishing etiologic subtypes of aneurysm disease.
Ascending TAA tissue and plasma specimens were obtained from patients with BAV (n = 21) and TAV (n = 21) at the time of surgical resection. The protein abundance of key MMPs (1, 2, 3, 8, and 9), TIMPs (1, 2, 3, and 4), and miRs (1, 21, 29a, 133a, 143, and 145) was examined using a multianalyte protein profiling system or by quantitative polymerase chain reaction, respectively. Results were compared with normal aortic tissue and plasma obtained from patients without aortic disease (n = 10).
Significant (P < .05) differences in standardized miR-1 and miR-21 abundance between BAV and TAV aortic tissue samples and different tissue and plasma profiles of analyte differences from normal aorta where observed between the BAV and TAV groups. Linear regression analysis revealed significant linear relationships in plasma and tissue measurements only for MMP-8 and TIMP-1, TIMP-3, and TIMP-4 (P < .05). Receiver operator curve analysis revealed specific cassettes of analytes predictive of TAA disease. Relative to normal aorta, BAV proteolytic balance was significantly increased for MMP-1, MMP-2, and MMP-7, and for decreased MMP-8 and MMP-9. In contrast, TAV proteolytic balance relative to normal aorta was significantly increased only for MMP-1 and decreased for MMP-8 and MMP-9.
Taken together, these unique data demonstrate differential plasma profiles of MMPs, TIMPs, and miRs in ascending TAA specimens from patients with BAV and TAV. These results suggest that circulating biomarkers may form the foundation for a broader platform of biomarkers capable of detecting the presence of TAA using a simple blood test and may also be useful in personalized strategies to distinguish between etiologic subtypes of TAAs in patients with aneurysm disease.
胸主动脉瘤（TAAs）通过无症状的过程发展，导致严重扩张，如果未被发现和治疗，就会进展为破裂。如果被发现，TAA 患者会随着时间的推移进行随访，直到破裂的风险超过手术修复的风险。目前用于跟踪 TAA 大小的方法仅限于昂贵的计算机断层扫描或磁共振成像，因为目前没有可接受的人群筛查工具。本实验室和其他实验室之前的研究已经确定了在升主动脉瘤组织中，与特发性退行性疾病和三尖瓣主动脉瓣（TAV）患者相比，二叶式主动脉瓣（BAV）患者的基质金属蛋白酶（MMPs）及其内源性组织抑制剂（TIMPs）的差异蛋白谱。此外，与正常主动脉组织相比，TAAs 中的微小 RNA（miR）表达水平也发生了改变。本研究的目的是确定血浆中循环因子是否可以作为区分动脉瘤疾病病因亚型的潜在生物标志物。
在手术切除时，从 BAV（n=21）和 TAV（n=21）患者的升主动脉瘤组织和血浆标本中提取关键 MMPs（1、2、3、8 和 9）、TIMPs（1、2、3 和 4）和 miRs（1、21、29a、133a、143 和 145）的蛋白丰度，分别使用多分析物蛋白谱分析系统或定量聚合酶链反应进行检测。将结果与无主动脉疾病患者的正常主动脉组织和血浆（n=10）进行比较。
BAV 和 TAV 主动脉组织样本中 miR-1 和 miR-21 的标准化丰度存在显著差异（P<.05），BAV 和 TAV 组之间的不同组织和血浆分析物差异存在显著差异。线性回归分析显示，仅 MMP-8 和 TIMP-1、TIMP-3 和 TIMP-4 在血浆和组织测量中存在显著线性关系（P<.05）。接受者操作特征曲线分析显示，特定的分析物组合具有预测 TAA 疾病的能力。与正常主动脉相比，BAV 的蛋白水解平衡显著增加，MMP-1、MMP-2 和 MMP-7 增加，而 MMP-8 和 MMP-9 减少。相比之下，TAV 相对于正常主动脉的蛋白水解平衡仅增加 MMP-1，而 MMP-8 和 MMP-9 减少。
综上所述，这些独特的数据表明 BAV 和 TAV 患者升主动脉瘤标本中 MMPs、TIMPs 和 miRs 的血浆谱存在差异。这些结果表明，循环生物标志物可能成为使用简单血液检测检测 TAA 存在的更广泛生物标志物平台的基础，并且可能在区分动脉瘤疾病患者病因亚型的个体化策略中也很有用。
