Porras Ana M, Shanmuganayagam Dhanansayan, Meudt Jennifer J, Krueger Christian G, Hacker Timothy A, Rahko Peter S, Reed Jess D, Masters Kristyn S
Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI (A.M.P., K.S.M.).
Department of Animal Sciences, University of Wisconsin-Madison, Madison, WI (D.S., J.J.M., C.G.K., J.D.R.).
J Am Heart Assoc. 2015 Oct 27;4(10):e002254. doi: 10.1161/JAHA.115.002254.
Familial hypercholesterolemia (FH) is a prevalent hereditary disease associated with increased atherosclerosis and calcific aortic valve disease (CAVD). However, in both FH and non-FH individuals, the role of hypercholesterolemia in the development of CAVD is poorly understood. This study used Rapacz FH (RFH) swine, an established model of human FH, to investigate the role of hypercholesterolemia alone in the initiation and progression of CAVD. The valves of RFH swine have not previously been examined.
Aortic valve leaflets were isolated from wild-type (0.25- and 1-year-old) and RFH (0.25-, 1-, 2-, and 3-year-old) swine. Adult RFH animals exhibited numerous hallmarks of early CAVD. Significant leaflet thickening was found in adult RFH swine, accompanied by extensive extracellular matrix remodeling, including proteoglycan enrichment, collagen disorganization, and elastin fragmentation. Increased lipid oxidation and infiltration of macrophages were also evident in adult RFH swine. Intracardiac echocardiography revealed mild aortic valve sclerosis in some of the adult RFH animals, but unimpaired valve function. Microarray analysis of valves from adult versus juvenile RFH animals revealed significant upregulation of inflammation-related genes, as well as several commonalities with atherosclerosis and overlap with human CAVD.
Adult RFH swine exhibited several hallmarks of early human CAVD, suggesting potential for these animals to help elucidate CAVD etiology in both FH and non-FH individuals. The development of advanced atherosclerotic lesions, but only early-stage CAVD, in RFH swine supports the hypothesis of an initial shared disease process, with additional stimulation necessary for further progression of CAVD.
家族性高胆固醇血症（FH）是一种常见的遗传性疾病，与动脉粥样硬化和钙化性主动脉瓣疾病（CAVD）的发生风险增加相关。然而，在FH患者和非FH个体中，高胆固醇血症在CAVD发生发展中的作用仍未完全明确。本研究使用Rapacz FH（RFH）猪这一已确立的人类FH模型，来探究单纯高胆固醇血症在CAVD起始和进展中的作用。此前尚未对RFH猪的瓣膜进行过检查。
从野生型（0.25岁和1岁）和RFH（0.25岁、1岁、2岁和3岁）猪中分离出主动脉瓣叶。成年RFH动物表现出早期CAVD的诸多特征。在成年RFH猪中发现瓣膜叶显著增厚，同时伴有广泛的细胞外基质重塑，包括蛋白聚糖富集、胶原蛋白紊乱和弹性蛋白断裂。成年RFH猪中脂质氧化增加和巨噬细胞浸润也很明显。心脏内超声心动图显示部分成年RFH动物存在轻度主动脉瓣硬化，但瓣膜功能未受影响。对成年与幼年RFH动物的瓣膜进行微阵列分析，结果显示炎症相关基因显著上调，同时与动脉粥样硬化有一些共同特征，且与人类CAVD存在重叠。
成年RFH猪表现出早期人类CAVD的若干特征，表明这些动物有潜力帮助阐明FH患者和非FH个体中CAVD的病因。RFH猪出现了晚期动脉粥样硬化病变，但仅出现了早期CAVD，这支持了最初存在共同疾病过程的假说，即CAVD进一步进展还需要额外的刺激因素。
