title: Development of Human-Like Advanced Coronary Plaques in Low-Density Lipoprotein Receptor Knockout Pigs and Justification for Statin Treatment Before Formation of Atherosclerotic Plaques.
abstract: 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.
  
  
  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.
authors.affiliation: Department of Advanced Cardiovascular Imaging, Nihon University School of Medicine, Itabashi-ku, Tokyo, Japan.
authors.forename: Yuxin
authors.initials: Y
authors.lastname: Li
authors.affiliation: Transgenic Pig Research Unit, National Institute of Agrobiological Sciences, Tsukuba, Ibaraki, Japan.
authors.forename: Daiichiro
authors.initials: D
authors.lastname: Fuchimoto
authors.affiliation: Division of Cardiology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo, Japan.
authors.forename: Mitsumasa
authors.initials: M
authors.lastname: Sudo
authors.affiliation: Division of Cardiology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo, Japan.
authors.forename: Hironori
authors.initials: H
authors.lastname: Haruta
authors.affiliation: Division of Cardiology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo, Japan.
authors.forename: Qing-Fei
authors.initials: QF
authors.lastname: Lin
authors.affiliation: Department of Advanced Cardiovascular Imaging, Nihon University School of Medicine, Itabashi-ku, Tokyo, Japan Division of Cardiology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo, Japan.
authors.forename: Tadateru
authors.initials: T
authors.lastname: Takayama
authors.affiliation: Laboratory of Mucosal Immunology, Graduate School of Agricultural Science, Tohoku University, Sendai, Miyagi, Japan.
authors.forename: Shotaro
authors.initials: S
authors.lastname: Morita
authors.affiliation: Department of Pathology, Nihon University School of Medicine, Itabashi-ku, Tokyo, Japan Laboratory of Mucosal Immunology, Graduate School of Agricultural Science, Tohoku University, Sendai, Miyagi, Japan.
authors.forename: Tomonori
authors.initials: T
authors.lastname: Nochi
authors.affiliation: Transgenic Pig Research Unit, National Institute of Agrobiological Sciences, Tsukuba, Ibaraki, Japan.
authors.forename: Shunichi
authors.initials: S
authors.lastname: Suzuki
authors.affiliation: Transgenic Pig Research Unit, National Institute of Agrobiological Sciences, Tsukuba, Ibaraki, Japan.
authors.forename: Shoichiro
authors.initials: S
authors.lastname: Sembon
authors.affiliation: Transgenic Pig Research Unit, National Institute of Agrobiological Sciences, Tsukuba, Ibaraki, Japan.
authors.forename: Michiko
authors.initials: M
authors.lastname: Nakai
authors.affiliation: Animal Genome Research Unit, National Institute of Agrobiological Sciences, Tsukuba, Ibaraki, Japan.
authors.forename: Misaki
authors.initials: M
authors.lastname: Kojima
authors.affiliation: Prime Tech Ltd, Tsuchiura, Ibaraki, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Iwamoto
authors.affiliation: Prime Tech Ltd, Tsuchiura, Ibaraki, Japan.
authors.forename: Michiko
authors.initials: M
authors.lastname: Hashimoto
authors.affiliation: Division of Cardiology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo, Japan.
authors.forename: Shunichi
authors.initials: S
authors.lastname: Yoda
authors.affiliation: Division of Cardiology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kunimoto
authors.affiliation: Department of Advanced Cardiovascular Imaging, Nihon University School of Medicine, Itabashi-ku, Tokyo, Japan Division of Cardiology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo, Japan.
authors.forename: Takafumi
authors.initials: T
authors.lastname: Hiro
authors.affiliation: Division of Cell Regeneration and Transplantation, Department of Functional Morphology, Nihon University School of Medicine, Itabashi-ku, Tokyo, Japan.
authors.forename: Taro
authors.initials: T
authors.lastname: Matsumoto
authors.affiliation: Division of Cardiology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo, Japan.
authors.forename: Masako
authors.initials: M
authors.lastname: Mitsumata
authors.affiliation: Department of Pathology, Nihon University School of Medicine, Itabashi-ku, Tokyo, Japan.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Sugitani
authors.affiliation: Department of Advanced Cardiovascular Imaging, Nihon University School of Medicine, Itabashi-ku, Tokyo, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Saito
authors.affiliation: Department of Advanced Cardiovascular Imaging, Nihon University School of Medicine, Itabashi-ku, Tokyo, Japan Division of Cardiology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo, Japan hirayama.atsushi@nihon-u.ac.jp onishi.akira@nihon-u.ac.jp.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Hirayama
authors.affiliation: Transgenic Pig Research Unit, National Institute of Agrobiological Sciences, Tsukuba, Ibaraki, Japan Department of Animal Science and Resources, College of Bioresource Sciences, Nihon University, Fujisawa, Kanagawa, Japan hirayama.atsushi@nihon-u.ac.jp onishi.akira@nihon-u.ac.jp.
authors.forename: Akira
authors.initials: A
authors.lastname: Onishi
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D003324:Coronary Artery Disease / Q000209:etiology* / Q000517:prevention & control; D004036:Diet, Atherogenic / Q000009:adverse effects; D004195:Disease Models, Animal; D005260:Female; D055786:Gene Knockout Techniques; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D008297:Male; D058226:Plaque, Atherosclerotic / Q000209:etiology* / Q000517:prevention & control; D011973:Receptors, LDL / Q000235:genetics / Q000502:physiology*; D013552:Swine
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011973:Receptors, LDL
keywords: atherosclerosis; cholesterol; coronary disease; plaque; statins