Tamoxifen Inhibits Arterial Accumulation of LDL Degradation Products and Progression of Coronary Artery Atherosclerosis in Monkeys

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Abstract
Estrogen replacement therapy reduces the risk of coronary heart disease in postmenopausal women and inhibits progression of coronary artery atherosclerosis in monkeys. Tamoxifen is a nonsteroidal compound with mixed estrogen agonist and antagonist properties. Its antagonist activity is useful in chemotherapy of breast cancer and may have protective effects on plasma lipid concentrations, but its effects on atherogenesis have not been defined. The goal of this study was to examine the effect of tamoxifen on plasma lipids, arterial and hepatic LDL metabolism, and progression of coronary artery atherosclerosis in surgically postmenopausal female monkeys. Thirty-five monkeys were fed an atherogenic diet containing 1.3 mg·kg −1 ·d −1 tamoxifen (equivalent to the usual dose of 20 mg/d given to women). Thirty-one monkeys were fed the same atherogenic diet with no tamoxifen. Ten monkeys from each treatment group were fed the test diets for 12 weeks to examine the short-term effects of tamoxifen on arterial LDL metabolism. The rest of the monkeys were fed the test diets for 3 years to study the long-term effects of tamoxifen on development of atherosclerosis. In the short term, tamoxifen inhibited the rate of arterial accumulation of LDL degradation products overall ( P =.03) and decreased hepatic cholesterol content ( P =.003). In the long term, tamoxifen increased plasma concentrations of triglycerides (0.60±0.67 versus 0.23±0.02 mmol/L, P =.001) and reduced average LDL molecular weight (5.3±0.2 versus 4.8±0.1 g/μmol, P =.004) but had no effects on plasma total, LDL, or HDL cholesterol concentrations. Coronary artery atherosclerosis (intimal area, mean±SEM) was 0.25±0.06 mm 2 in control monkeys and 0.12±0.03 mm 2 in tamoxifen-treated monkeys ( P =.057). We conclude that tamoxifen has antiatherogenic effects that may be modulated in part through direct effects on arterial LDL metabolism.