Weiss Robert M, Ohashi Masuo, Miller Jordan D, Young Stephen G, Heistad Donald D
Department of Internal Medicine, Room E317-A GH, University of Iowa College of Medicine, 200 Hawkins Dr, Iowa City, IA 52242, USA.
Circulation. 2006 Nov 7;114(19):2065-9. doi: 10.1161/CIRCULATIONAHA.106.634139. Epub 2006 Oct 30.
Hypercholesterolemia and old age are clinical risk factors for development of aortic valve stenosis, and hypercholesterolemia is a putative therapeutic target. We tested the hypothesis that calcification and aortic valve stenosis would develop in genetically hypercholesterolemic old mice.
Twenty-four low-density lipoprotein receptor-deficient apolipoprotein B-100-only (LDLr(-/-)ApoB(100/100)) mice were fed normal chow from weaning until age 20.1+/-0.5 months (mean+/-SE; range 17 to 22 months). Twenty-one age-matched (20.8+/-0.9 months, range 17 to 25 months) C57Bl/6 mice served as controls. Echocardiographic imaging was used to assess morphology and function of the aortic valve and left ventricle. A subset of 12 mice underwent invasive hemodynamic assessment of aortic valve function. Functionally significant aortic stenosis, with >75% reduction in valve area, occurred in 8 of 24 LDLr(-/-)ApoB(100/100) mice and in 0 of 21 controls (P=0.01). In the subset that underwent catheterization, mice with echocardiographic evidence of aortic stenosis had a systolic transvalvular gradient of 57+/-6 mm Hg. In the group of all LDLr(-/-)ApoB(100/100) mice with aortic stenosis, left ventricular mass was increased by 67% (P=0.001) and ejection fraction was decreased by 30% (P=0.004) compared with LDLr(-/-)ApoB(100/100) without aortic stenosis. Von Kossa staining of the aortic valve demonstrated abundant mineralization in LDLr(-/-)ApoB(100/100) mice but not in control mice. Superoxide (oxyethidium fluorescence) was present in valve tissue from all 3 groups of mice and was more abundant in mice with aortic stenosis.
Hypercholesterolemic LDLr(-/-)ApoB(100/100) mice are prone to develop calcification and oxidative stress in the aortic valve, with functional valvular heart disease, mimicking the clinical syndrome. This discovery holds promise for elucidation of the pathophysiology of aortic valve disease mechanisms and for the design of effective nonsurgical treatment.
高胆固醇血症和老年是主动脉瓣狭窄发生的临床风险因素，高胆固醇血症是一个假定的治疗靶点。我们检验了基因性高胆固醇血症老年小鼠会发生钙化和主动脉瓣狭窄的假说。
24只低密度脂蛋白受体缺陷型仅载脂蛋白B-100（LDLr(-/-)ApoB(100/100)）小鼠从断奶后至20.1±0.5个月（平均±标准误；范围17至22个月）喂食正常食物。21只年龄匹配（20.8±0.9个月，范围17至25个月）的C57Bl/6小鼠作为对照。超声心动图成像用于评估主动脉瓣和左心室的形态及功能。12只小鼠的一个亚组接受了主动脉瓣功能的有创血流动力学评估。24只LDLr(-/-)ApoB(100/100)小鼠中有8只出现功能上显著的主动脉狭窄，瓣膜面积减少>75%，而21只对照小鼠中无一只出现（P=0.01）。在接受导管插入术的亚组中，有超声心动图证据显示主动脉狭窄的小鼠收缩期跨瓣膜梯度为57±6 mmHg。在所有有主动脉狭窄的LDLr(-/-)ApoB(100/100)小鼠组中，与无主动脉狭窄的LDLr(-/-)ApoB(100/100)小鼠相比，左心室质量增加67%（P=0.001），射血分数降低30%（P=0.004）。主动脉瓣的冯·科萨染色显示LDLr(-/-)ApoB(100/100)小鼠有大量矿化，而对照小鼠无。超氧化物（氧化乙锭荧光）在所有3组小鼠的瓣膜组织中均存在，且在有主动脉狭窄的小鼠中更丰富。
高胆固醇血症的LDLr(-/-)ApoB(100/100)小鼠主动脉瓣易于发生钙化和氧化应激，并伴有功能性瓣膜性心脏病，模拟临床综合征。这一发现有望阐明主动脉瓣疾病机制的病理生理学，并为设计有效的非手术治疗方法提供依据。
