第一部分：二叶主动脉瓣类型、主动脉瓣功能不全类型及胸主动脉扩张类型之间关系的研究

目的：探究二叶主动脉瓣（Bicuspid Aortic Valve, BAV）类型、主动脉瓣功能不全类型及胸主动脉扩张类型之间的关系

方法：我们回顾性研究了自2011年2月至2016年1月，407例行胸主动脉计算机断层扫描血管造影检查及胸主动脉手术（主动脉根部置换和/或升主动脉置换和/或主动脉弓部近端置换）的患者。研究中分析了BAV类型、主动脉瓣功能不全类型二者之间的关系，以及主动脉瓣病损类型（由BAV类型和主动脉瓣功能不全类型两两组合而成）和胸主动脉扩张类型之间的关系。

结果：BAV类型与主动脉瓣功能不全类型密切相关(p<0.01)。Type-1 LR型BAV患者发生主动脉瓣关闭不全（Aortic Valve Regurgitation, AR）的倾向性较高，Type-0 LAT型更易发生主动脉瓣狭窄（Aortic Valve Stenosis，AS）。Type-1 RN 型BAV患者易发生AS+AR。主动脉瓣病损类型与主动脉扩张类型密切相关(p<0.01)。Type-1 LR 合并AS的患者更容易发生单独的升主动脉扩张。Type-1 LR 合并AR的患者倾向于发生主动脉根部合并升主动脉扩张。Type-0 LAT合并AS的患者易发生升主动脉合并主动脉弓部近端扩张。

结论：Type-1 LR合并AS的BAV患者发生升主动脉扩张的倾向性较高，Type-0 LAT合并AS的BAV患者发生升主动脉合并主动脉弓部近端扩张的倾向性较高，在这两类人群中升主动脉及主动脉弓部近端扩张的发生可能与升主动脉内的异常血流有关。Type-1 LR合并AR的患者更易发生主动脉根部合并升主动脉的扩张，提示其主动脉扩张的发生可能与遗传因素有关。

第二部分：Type-0 LAT型二叶主动脉瓣合并主动脉瓣狭窄患者主动脉弓部近端扩张的随访研究

目的：通过随访探究Type-0 LAT型BAV合并AS的患者如果合并升主动脉及主动脉弓部近端扩张行wheat’s手术（主动脉瓣置换合并升主动脉置换）而主动脉弓部近端扩张在手术中旷置，旷置的主动脉弓部近端是否会在术后继续发生扩张。

方法：10例患者在术前及随访过程中均行主动脉CTA检查，主动脉CTA经三维重建后测量主动脉弓部近端直径，比较随访过程中主动脉弓部近端直径和术前主动脉弓部近端直径的差异。

结果：入组患者平均随访时间17.50±5.89月。术前的主动脉弓部近端直径平均值为44.33±3.25 mm，术后随访主动脉弓部近端直径平均值为39.42±2.41 mm。术前和术后随访主动脉直径比较有显著性差异(p < 0.001)，Type-0 LAT合并AS的患者wheat’s术后随访期间的主动脉弓部近端直径与术前相比明显减小。

结论：Type-0 LAT 合并AS的BAV患者在wheat’s术后主动脉弓部近端不会发生持续性的扩张，其主动脉弓部近端的扩张可能与升主动脉内血流动力学异常密切相关。对于该类患者在手术中可不必积极行主动脉弓部近端的人工血管置换。

第三部分：瓣膜相关性异常血流导致二叶主动脉瓣相关升主动脉扩张的发生

目的：探究瓣膜相关性异常血流导致的高壁面剪切力(Wall Shear Stress, WSS)与主动脉壁组织损伤之间的关系及其损伤调控机制。

方法：研究中入选了12例BAV（Type-1 LR、Type-0 LAT）合并AS的患者，通过四维血流心脏核磁共振观察患者胸主动脉内的血流模式，测量主动脉壁WSS。根据主动脉壁WSS分布及大小分别在WSS最大区域和最小区域获取主动脉壁组织并进行范-格吉森染色观察主动脉壁损伤以及应用蛋白免疫印迹杂交法测定主动脉壁组织匀浆中基质金属蛋白酶(Matrix Metalloproteinases,MMPs)及基质金属蛋白酶组织抑制剂-1 (Tissue Inhibitor of MatrixMetalloproteinase-1, TIMP-1)的表达情况。比较两个区域主动脉壁组织损伤的差异以及MMPs及TIMP-1表达的差异。

结果：在所有入组患者中均可见主动脉壁中层弹力纤维的降解、缺失以及主动脉中层结构的改变。WSS最大区域平均弹力纤维层厚度（3.40±0.69μm）与最小区域（5.52±0.85μm）相比明显变薄（p＜0.001），WSS最大区域平均弹力纤维层间距（32.12±5.83μm）与最小区域（23.33±3.81μm）相比明显增宽（p＜0.001）。主动脉壁组织匀浆中MMP-1（p<0.01）、MMP-3（p=0.037）在WSS最大区域的表达明显低于WSS最小区域, MMP-2（p=0.066）、TIMP-1（p=0.986）蛋白表达量在两个区域未见显著差异。

结论：主动脉壁局部WSS增高可导致相应部位主动脉壁组织损伤。瓣膜相关性异常血流在Type-1 LR和Type-0 LAT型BAV合并AS患者的升主动脉扩张的发生中起着重要作用。

PartⅠAssociation Between Bicuspid Aortic Valve Phenotype, Type of Valvular Dysfunction and Aortic Configuration

Objective:To investigate the association between bicuspid aortic valve (BAV) phenotype, type of valvular dysfunction and aortic configuration. 

Methods: We retrospectively reviewed 407 patients of BAV with thoracic computed tomography angiography (CTA), who had undergone aortic surgeries from February 2011 to January 2016.BAV phenotypes, aortic valve lesion types (combining BAV phenotypes and the types of valvular dysfunction), and clusters of aortic configuration were categorized separately.Then, the association between BAV phenotypes and types of valvular dysfunction, as well as the association between types of aortic valve lesion and aortic configurationswere evaluated.

Results: There was close association between BAV phenotypes and the types of valvular dysfunction (p<0.01). Valvular regurgitation was more frequently in Type-1 LR, whereas valvular stenosis in Type-0 LAT. For Type-1 RN, more patients who suffered from aortic valve stenosis combined with regurgitation were observed.After that, the significant association between aortic valve lesion types and the clusters of aortic configuration were revealed (p<0.01). In Type-1 LR, valvular stenosis tended to exhibit ascending aorta (AAo) dilation alone, but regurgitation more frequently showed as aortic root dilation (AoR) and AAo dilation. Patients of Type-0 LAT with stenosis were more frequently presented with aortic dilation with AAo and proximal aortic arch.

Conclusions: In BAVs (Type-1 LR and Type-0 LAT) with valvular stenosis, aortic dilation was more localized to AAo/AAo+PArc, indicating the hemodynamic turbulence theory. Insufficient BAV (Type-1 LR) were associated with a more extensive aortic dilation (AoR + AAo), supporting a more aggressive inherent-disposed aortopathy.

PartⅡ The Follow-up Study on Proximal Aortic Arch Dilation in Patients with Stenotic Bicuspid Type-0 LAT

Objective: In this study, we followed patients with stenotic BAV (Type-0 LAT) who had undergone wheat’s operationwithout hemiarch repair, in order to investigate whether PArc dilation continued after surgery.

Methods: All of the patients had undergone thoracic CTA examination before and after surgery. 3-dimensional reconstruction of CTA was used to measure the diameters of aorta. The diameters of PArc in follow-up were compared with those pre-operation.

Results: The late follow-up period was between 6 and 26 months (mean, 17.50±5.89months). The mean pre-operative diameter of PArc was 44.33±3.25mm, and the mean diameter in follow-up was 39.42±2.41mm. Significant difference (p<0.001) was found in the diameter of PArc between pre-operation and follow-up. The diameter of PArc in follow-up is significantly less than those pre-operation.

Conclusions: For stenotic BAV patients (Type-0 LAT) with dilation of AAo+PArc, there is no continuous expansion of PArc after wheat’s operation. Hemodynamics may mediate the dilation of PArc in these patients. If the patients of stenotic bicuspid Type-0 LAT occurred with aortic dilation of AAo+PArc, we should less aggressively replace the dilation of PArc. 

Part ⅢValve-Related Hemodynamics Mediate Ascending Aorta Dilation in Patients with Bicuspid Aortic Valve

Objective: This study investigated the relationship between wall shear stress (WSS) and regional aortic tissue remodeling in stenotic BAVs (Type-1 LR and Type-0 LAT), and determined the impact of elevated WSS on the expression of matrix metalloproteinases (MMPs) and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1).

Methods：Twelve patients underwent 4-dimensional flow cardiac magnetic resonance imaging (4-D Flow CMR) to evaluate aortic WSS before surgery. Paired aortic wall samples (regions of maximal and minimal WSS) were collected from all cohort patients during wheat’s operation. Aortic medial elastin degeneration was quantified by histology image analysis and extracellular matrix regulation by matrix-related protein expression.

Results: Histological analysis ofaortic tissue demonstrated significantly decreased elastin content and architecture consistent with aortopathy in all patients. The mean thickness of elastin fibers was found significantly decreased in aortic wall (p＜0.001) that exposed to maximal WSS (3.40±0.69μm) compared with aortic wall from the region of minimal WSS (5.52±0.85μm). The mean distance between elastin fibers was significantly greater (p＜0.001) in regions of maximal WSS (32.12±5.83μm) than in those of minimal WSS (23.33±3.81μm). The analyses of extracellular matrix regulatory molecules showed that aortic wall subjected to minimal WSS demonstrated significantly increased protein expression of MMP-1 (p<0.01) and MMP-3 (p=0.037). However, we did not find the association between WSS and the expression of MMP-2 (p=0.066) and TIMP-1 (p=0.986) in paired aortic wall.

Conclusions: Regions of elevated WSS correspond with aortic medial tissue remodeling. Valve-related hemodynamics may play an important role in the development of ascending aorta dilation in stenotic BAVs (Type-1 LR and Type-0 LAT).