Experimental Studies
Pravastatin Has Cholesterol-Lowering Independent Effects on the Artery Wall of Atherosclerotic Monkeys

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Abstract

Objectives. This study examined the direct effects of pravastatin on the artery wall of atherosclerotic monkeys after dietary lipid lowering.

Background. Clinical trials suggest that hepatic hydroxymethylglutaryl coenzyme A reductase inhibitors may reduce the risk of coronary heart disease out of proportion to their effect on angiographically assessed lumen stenosis.

Methods. Thirty-two cynomolgus monkeys were fed an atherogenic diet for 2 years (progression phase) and then fed a lipid-lowering diet either containing (n = 14) or not containing (n = 18) pravastatin in the diet for an additional 2 years (treatment phase). As designed, total plasma cholesterol and high density lipoprotein concentrations did not differ between groups at the beginning of or during the treatment phase of the experiment (p > 0.05).

Results. Quantitative angiography revealed that coronary arteries of the pravastatin-treated monkeys dilated 10 ± 3%, whereas those from untreated control monkeys constricted −2 ± 2% in response to acetylcholine (p < 0.05). There were no treatment effects on plaque size of coronary arteries measured at the end of the treatment phase of the study (0.110 ± 0.048 mm2[untreated] vs. 0.125 ± 0.051 mm2[pravastatin]; p > 0.05) or on the amount of reduction in plaque size in common iliac arteries during the treatment phase of the study (48 ± 5% [untreated] vs. 45 ± 6% [pravastatin]; p > 0.05). However, histochemical analysis of the atherosclerotic lesions indicated that the arteries from pravastatin-treated monkeys had significantly fewer macrophages in the intima and media, less calcification and less neovascularization in the intima (p < 0.05).

Conclusions. We conclude that compared with control monkeys, the arteries of pravastatin-treated monkeys had better dilator function and plaque characteristics more consistent with plaque stability than those of monkeys not receiving pravastatin. These beneficial arterial effects of pravastatin occurred independently of plasma lipoprotein concentrations and despite similar changes in plaque size between the groups.

Abbreviations

ANOVA
analysis of variance
HDL
high density lipoprotein
HMG-CoA
hydroxymethylglutaryl coenzyme A
LDL
low density lipoprotein
QCA
quantitative coronary angiography
TPC
total plasma cholesterol
VLDL
very low density lipoprotein

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This study was supported in part by an unrestricted gift from Bristol-Myers Squibb Company and by Grants HL45666 and HL48743 from the National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland.