TY - JOUR
T1 - Development of human-like advanced coronary plaques in low-density lipoprotein receptor knockout pigs and justification for statin treatment before formation of atherosclerotic plaques
AU - Li, Yuxin
AU - Fuchimoto, Daiichiro
AU - Sudo, Mitsumasa
AU - Haruta, Hironori
AU - Lin, Qing Fei
AU - Takayama, Tadateru
AU - Morita, Shotaro
AU - Nochi, Tomonori
AU - Suzuki, Shunichi
AU - Sembon, Shoichiro
AU - Nakai, Michiko
AU - Kojima, Misaki
AU - Iwamoto, Masaki
AU - Hashimoto, Michiko
AU - Yoda, Shunichi
AU - Kunimoto, Satoshi
AU - Hiro, Takafumi
AU - Matsumoto, Taro
AU - Mitsumata, Masako
AU - Sugitani, Masahiko
AU - Saito, Satoshi
AU - Hirayama, Atsushi
AU - Onishi, Akira
N1 - Publisher Copyright:
© 2016 The Authors.
PY - 2016/4/1
Y1 - 2016/4/1
N2 - 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 highcholesterol, 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 (Plt;0.01), intraplaque hemorrhage characterized 11% versus 1% (Plt;0.01), and calcification characterized 22% versus 1% (Plt;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.
AB - 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 highcholesterol, 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 (Plt;0.01), intraplaque hemorrhage characterized 11% versus 1% (Plt;0.01), and calcification characterized 22% versus 1% (Plt;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.
KW - Atherosclerosis
KW - Cholesterol
KW - Coronary disease
KW - Plaque
KW - Statins
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U2 - 10.1161/JAHA.115.002779
DO - 10.1161/JAHA.115.002779
M3 - Article
C2 - 27091180
AN - SCOPUS:84992435989
VL - 5
JO - Journal of the American Heart Association
JF - Journal of the American Heart Association
SN - 2047-9980
IS - 4
M1 - e002779
ER -