Development of Human-Like Advanced Coronary Plaques in Low-Density Lipoprotein Receptor Knockout Pigs and Justification for Statin Treatment Before Formation of Atherosclerotic Plaques.
Development of Human-Like Advanced Coronary Plaques in Low-Density Lipoprotein Receptor Knockout Pigs and Justification for Statin Treatment Before Formation of Atherosclerotic Plaques.
复制标题
DOI：
10.1161/jaha.115.002779
复制
发表时间：
2016-04-18
影响因子：
5.4
通讯作者：
Onishi A
中科院分区：
文献类型：
--
作者：
Li Y;Fuchimoto D;Sudo M;Haruta H;Lin QF;Takayama T;Morita S;Nochi T;Suzuki S;Sembon S;Nakai M;Kojima M;Iwamoto M;Hashimoto M;Yoda S;Kunimoto S;Hiro T;Matsumoto T;Mitsumata M;Sugitani M;Saito S;Hirayama A;Onishi A
虽然临床试验已经证明他汀类药物可以预防心血管事件，但他汀类药物对斑块形成的直接影响还不清楚。我们产生了低密度脂蛋白受体敲除（LDLR −/−）猪，以研究早期他汀类药物给药对动脉粥样硬化斑块（尤其是晚期斑块）发展的影响。 通过靶向缺失LDLR基因的外显子4产生LDLR −/−猪。给予标准饲料，LDLR −/−猪在6月龄时开始出现动脉粥样硬化病变。当3月龄LDLR −/−猪喂食高胆固醇、高脂肪（HCHF）饲料4个月（HCHF组）时，出现了类似人类的晚期冠状动脉斑块。我们还对3月龄LDLR −/−猪饲喂含匹伐他汀的HCHF饲料4个月（他汀类预防组）。尽管两组之间的血清胆固醇浓度无显著差异，但血管内超声显示他汀类药物治疗猪的斑块体积减少了52%。病理学检查显示，他汀类药物预防组的大多数病变（87%）为早期病变，而HCHF饮食组为45%（P<0.01）。HCHF饮食组中40%的斑块为薄帽纤维粥样硬化，而他汀类药物预防组为8%（P<0.01），斑块内出血为11%对1%（P<0.01），钙化为22%对1%（P<0.01）。我们的大型动物实验结果支持在动脉粥样硬化发生前预防他汀类药物。早期他汀类药物治疗似乎可以延缓冠状动脉粥样硬化的发展，并确保病变的稳定性。此外，我们开发的LDLR −/−猪代表了适合转化研究的类人晚期冠状动脉斑块的大型动物模型。
Although clinical trials have proved that statin can be used prophylactically against cardiovascular events, the direct effects of statin on plaque development are not well understood. We generated low‐density lipoprotein receptor knockout (LDLR −/−) pigs to study the effects of early statin administration on development of atherosclerotic plaques, especially advanced plaques. LDLR −/− pigs were generated by targeted deletion of exon 4 of the LDLR gene. Given a standard chow diet, LDLR −/− pigs showed atherosclerotic lesions starting at 6 months of age. When 3‐month‐old LDLR −/− pigs were fed a high‐cholesterol, high‐fat (HCHF) diet for 4 months (HCHF group), human‐like advanced coronary plaques developed. We also fed 3‐month‐old LDLR −/− pigs an HCHF diet with pitavastatin for 4 months (Statin Prophylaxis Group). Although serum cholesterol concentrations did not differ significantly between the 2 groups, intravascular ultrasound revealed 52% reduced plaque volume in statin‐treated pigs. Pathological examination revealed most lesions (87%) in the statin prophylaxis group were early‐stage lesions, versus 45% in the HCHF diet group (P<0.01). Thin‐cap fibroatheroma characterized 40% of the plaques in the HCHF diet group versus 8% in the statin prophylaxis group (P<0.01), intraplaque hemorrhage characterized 11% versus 1% (P<0.01), and calcification characterized 22% versus 1% (P<0.01). Results of our large animal experiment support statin prophylaxis before the occurrence of atherosclerosis. Early statin treatment appears to retard development of coronary artery atherosclerosis and ensure lesion stability. In addition, the LDLR −/− pigs we developed represent a large animal model of human‐like advanced coronary plaque suitable for translational research.