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(Circulation. 2005;111:1422-1430.)
© 2005 American Heart Association, Inc.

Valvular Heart Disease

Plaque Rupture After Short Periods of Fat Feeding in the Apolipoprotein E–Knockout Mouse

Model Characterization and Effects of Pravastatin Treatment

Jason Johnson, MSc^*; Kevin Carson, MB, ChB^*; Helen Williams, PhD; Sharada Karanam, PhD; Andrew Newby, PhD; Gianni Angelini, MD, MCh; Sarah George, PhD; Christopher Jackson, PhD

From the Bristol Heart Institute, University of Bristol, Bristol, United Kingdom.

Reprint requests to Dr Christopher Jackson, Bristol Heart Institute, University of Bristol, Level 7 Bristol Royal Infirmary, Bristol BS2 8HW, United Kingdom. E-mail chris.jackson{at}bristol.ac.uk

Received September 30, 2004; revision received November 12, 2004; accepted November 17, 2004.

Background— These studies examined the early time course of plaque development and destabilization in the brachiocephalic artery of the apolipoprotein E–knockout mouse, the effects of pravastatin thereon, and the effects of pravastatin on established unstable plaques.

Methods and Results— Male apolipoprotein E–knockout mice were fed a high-fat, cholesterol-enriched diet from the age of 8 weeks. Animals were euthanized at 1-week intervals between 4 and 9 weeks of fat feeding. Acutely ruptured plaques were observed in the brachiocephalic arteries of 3% of animals up to and including 7 weeks of fat feeding but in 62% of animals after 8 weeks, which suggests that there is a sharp increase in the number of plaque ruptures at 8 weeks. These acute plaque ruptures then appear to heal and form buried fibrous caps; after 9 weeks of fat feeding, mice had 1.05±0.15 buried fibrous caps at a single site in the brachiocephalic artery. Pravastatin (40 mg/kg of body weight per day for 9 weeks; resultant plasma concentration 16±4 nmol/L) had no effect on plasma cholesterol concentration in fat-fed apolipoprotein E–knockout mice but reduced the number of buried fibrous caps by 43% (P<0.0001). In longer-term experiments, the delay of pravastatin treatment until unstable plaques had developed reduced the incidence of acute plaque rupture by 36% (P<0.0001).

Conclusions— Plaque rupture occurs at high frequency in the brachiocephalic arteries of male apolipoprotein E–knockout mice after 8 weeks of fat feeding. Pravastatin treatment inhibits early plaque rupture and is also effective when begun after unstable plaques have developed.

Key Words: atherosclerosis • plaque • pathology • drugs

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