Open AccessDevelopment of Human‐Like Advanced Coronary Plaques in Low‐Density Lipoprotein Receptor Knockout Pigs and Justification for Statin Treatment Before Formation of Atherosclerotic Plaques
Author(s) -
Li Yuxin,
Fuchimoto Daiichiro,
Sudo Mitsumasa,
Haruta Hironori,
Lin QingFei,
Takayama Tadateru,
Morita Shotaro,
Nochi Tomonori,
Suzuki Shunichi,
Sembon Shoichiro,
Nakai Michiko,
Kojima Misaki,
Iwamoto Masaki,
Hashimoto Michiko,
Yoda Shunichi,
Kunimoto Satoshi,
Hiro Takafumi,
Matsumoto Taro,
Mitsumata Masako,
Sugitani Masahiko,
Saito Satoshi,
Hirayama Atsushi,
Onishi Akira
Publication year - 2016
Publication title -
journal of the american heart association
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.494
H-Index - 85
ISSN - 2047-9980
DOI - 10.1161/jaha.115.002779
Subject(s) - medicine , statin , ldl receptor , fibrous cap , intravascular ultrasound , atorvastatin , cardiology , coronary artery disease , pcsk9 , cholesterol , lipoprotein , pathology
Background 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. Methods and Results 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). Conclusions 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.