对患有和未患有糖尿病的患者钙化主动脉瓣钙化和炎症的组织病理学评估。
Histopathological assessment of calcification and inflammation of calcific aortic valves from patients with and without diabetes mellitus.
作者信息
Mosch Josephin, Gleissner Christian A, Body Simon, Aikawa Elena
机构信息
Center of Excellence in Vascular Biology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, USA.
Department of Cardiology, University Hospital, Heidelberg, Germany.
出版信息
Histol Histopathol. 2017 Mar;32(3):293-306. doi: 10.14670/HH-11-797. Epub 2016 Jun 29.
BACKGROUND
Calcific aortic valve disease (CAVD) is the most common valvular heart disease and likely evolves from inflammatory pre-conditions in the valve. Type II diabetes mellitus (DMII) has been associated with pathogenesis of CAVD, however, the mechanism initiating CAVD in DMII is not well understood and the human valve pathology in DMII has not been described. We therefore performed quantitative histological analyses of aortic valves of CAVD patients with and without DMII.
METHODS
CAVD human aortic valves (n=45) obtained after surgical valve replacement were examined macroscopically with gross measurements of calcified areas. Inflammation and calcification were assessed by immunohistochemistry and immunofluorescence staining.
RESULTS
Calcification was increased in diabetic patients according to gross measurements (p<0.01) and alizarin red staining (p=0.05). Early calcification markers, including Runx2 (p=0.02) and alkaline phosphatase (ALP, p=0.03) were significantly elevated in diabetic patients. Furthermore, in diabetic patients we found significantly increased expression of annexin II (p=0.04) and annexin V (p=0.04), both of which are thought to play a role in microcalcification formation via apoptosis or extracellular vesicle release. Macrophage numbers were comparable in both groups (p=0.41), while the expression of the pro-inflammatory protein S100A9 (p<0.01) was significantly decreased in diabetic individuals. Evaluation of lymphocytes revealed similar CD8 (p=0.45) and CD4 (p=0.92) T cell counts in diabetic and non-diabetic aortic valves.
CONCLUSION
Aortic valves from diabetic patients show more calcification, while inflammation is similar in both patient populations. Considering the generally accepted theory of an inflammation-dependent mechanism of calcification, these data suggest that in patients with CAVD requiring valve replacement, diabetic patients could be molecularly in a more advanced disease stage with a higher grade of mineralization than non-diabetic patients.
背景
钙化性主动脉瓣疾病（CAVD）是最常见的心脏瓣膜病，可能由瓣膜的炎症前期病变发展而来。II型糖尿病（DMII）与CAVD的发病机制有关，然而，DMII中引发CAVD的机制尚未完全明确，且DMII患者的人体瓣膜病理学特征也未得到描述。因此，我们对患有和未患有DMII的CAVD患者的主动脉瓣进行了定量组织学分析。
方法
对手术换瓣后获取的45例CAVD患者的人主动脉瓣进行大体检查，测量钙化区域。通过免疫组织化学和免疫荧光染色评估炎症和钙化情况。
结果
根据大体测量（p<0.01）和茜素红染色（p=0.05），糖尿病患者的钙化程度增加。糖尿病患者中早期钙化标志物，包括Runx2（p=0.02）和碱性磷酸酶（ALP，p=0.03）显著升高。此外，在糖尿病患者中，我们发现膜联蛋白II（p=0.04）和膜联蛋白V（p=0.04）的表达显著增加，这两种蛋白都被认为通过凋亡或细胞外囊泡释放参与微钙化形成。两组巨噬细胞数量相当（p=0.41），而糖尿病个体中促炎蛋白S100A9的表达显著降低（p<0.01）。淋巴细胞评估显示，糖尿病和非糖尿病主动脉瓣中的CD8（p=0.45）和CD4（p=0.92）T细胞计数相似。
结论
糖尿病患者的主动脉瓣钙化更严重，而两组患者的炎症情况相似。考虑到普遍接受的钙化炎症依赖性机制理论，这些数据表明，在需要换瓣的CAVD患者中，糖尿病患者在分子水平上可能处于比非糖尿病患者更晚期的疾病阶段，矿化程度更高。
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