Otto C M, Kuusisto J, Reichenbach D D, Gown A M, O'Brien K D
Department of Medicine, University of Washington, Seattle 98195.
Circulation. 1994 Aug;90(2):844-53. doi: 10.1161/01.cir.90.2.844.
Nonrheumatic stenosis of trileaflet aortic valves, often termed senile or calcific valvular aortic stenosis, is considered a "degenerative" process, but little is known about the cellular or molecular factors that mediate its development.
To characterize the developing aortic valvular lesion, we performed histological and immunohistochemical studies on Formalin-fixed and methanol-Carnoy's-fixed paraffin-embedded aortic valve leaflets or on frozen sections obtained at autopsy from 27 adults (age, 46 to 82 years) with normal leaflets (n = 6), mild macroscopic leaflet thickening (n = 15), or clinical aortic stenosis (n = 6). Focal areas of thickening ("early lesions") were characterized by (1) subendothelial thickening on the aortic side of the leaflet, between the basement membrane (PAS-positive) and elastic lamina (Verhoeff-van Gieson), (2) the presence of large amounts of intracellular and extracellular neutral lipids (oil red O) and fine, stippled mineralization (von Kossa), and (3) disruption of the basement membrane overlying the lesion. Regions of the fibrosa adjacent to these lesions were characterized by thickening and by protein, lipid, and calcium accumulation. Control valves showed none of these abnormalities. Immunohistochemical studies were performed using monoclonal antibodies directed against macrophages (anti-CD68 or HAM-56), and contractile proteins of smooth muscle cells or myofibroblasts (anti-alpha-actin and HHF-35) or rabbit polyclonal antiserum against T lymphocytes (anti-CD3). In normal valves, scattered macrophages were present in the fibrosa and ventricularis, and occasional muscle actin-positive cells were detected in the proximal portion of the ventricularis near the leaflet base, but no T lymphocytes were found. In contrast, early lesions were characterized by the presence of an inflammatory infiltrate composed of non-foam cell and foam cell macrophages, occasional T cells, and rare alpha-actin-positive cells. In stenotic aortic valves, a similar but more advanced lesion was seen.
The early lesion of "degenerative" aortic stenosis is an active inflammatory process with some similarities (lipid deposition, macrophage and T-cell infiltration, and basement membrane disruption) and some dissimilarities (presence of prominent mineralization and small numbers of smooth muscle cells) to atherosclerosis.
三叶主动脉瓣的非风湿性狭窄，通常称为老年性或钙化性主动脉瓣狭窄，被认为是一个“退行性”过程，但对于介导其发展的细胞或分子因素知之甚少。
为了描述主动脉瓣病变的发展过程，我们对27例成人（年龄46至82岁）尸检获得的福尔马林固定、甲醇 - 卡诺固定石蜡包埋的主动脉瓣叶或冰冻切片进行了组织学和免疫组织化学研究，这些成人的瓣膜分别为正常瓣叶（n = 6）、轻度宏观瓣叶增厚（n = 15）或临床主动脉狭窄（n = 6）。增厚的局灶区域（“早期病变”）具有以下特征：（1）在瓣叶主动脉侧的基底膜（PAS阳性）和弹性膜（Verhoeff - van Gieson）之间的内皮下增厚；（2）存在大量细胞内和细胞外中性脂质（油红O）以及细小的点状矿化（von Kossa）；（3）病变上方基底膜的破坏。与这些病变相邻的纤维层区域表现为增厚以及蛋白质、脂质和钙的积聚。对照瓣膜未显示这些异常。使用针对巨噬细胞（抗CD68或HAM - 56）、平滑肌细胞或肌成纤维细胞的收缩蛋白（抗α - 肌动蛋白和HHF - 35）的单克隆抗体或针对T淋巴细胞的兔多克隆抗血清（抗CD3）进行免疫组织化学研究。在正常瓣膜中，纤维层和心室层存在散在的巨噬细胞，在靠近瓣叶基部的心室层近端偶尔检测到肌动蛋白阳性细胞，但未发现T淋巴细胞。相比之下，早期病变的特征是存在由非泡沫细胞和泡沫细胞巨噬细胞、偶尔的T细胞以及罕见的α - 肌动蛋白阳性细胞组成的炎性浸润。在狭窄的主动脉瓣中，可见类似但更严重的病变。
“退行性”主动脉狭窄的早期病变是一个活跃的炎症过程，与动脉粥样硬化有一些相似之处（脂质沉积、巨噬细胞和T细胞浸润以及基底膜破坏），也有一些不同之处（显著矿化的存在和平滑肌细胞数量少）。
