Heart disease is the leading cause of death in American women. Lipoprotein[a] (Lp[a]), which has been established as an independent risk factor for coronary heart disease at plasma concentrations greater than 30 mg/dl, increases with age in postmenopausal women and is generally higher in postmenopausal women than in age-matched premenopausal women. Hormone replacement therapy decreases Lp[a] concentration in postmenopausal women, and some evidence suggests that the Lp[a]-lowering effect of estrogen is greater in subjects with higher initial Lp[a] concentrations. Compared with white women, black women have three times higher Lp[a] concentrations, and postmenopausal Hispanic women have one third lower Lp[a] concentrations than postmenopausal white women. In addition, Lp[a] lowering with hormone replacement therapy is greater in black women than in white women. Therefore, it should be possible to distinguish differences in Lp[a] metabolism between black and white women, between black and Hispanic women, and possibly between white and Hispanic women. This study is designed to determine if estrogen-induced lowering of Lp[a] concentrations in postmenopausal women is due to altered rates of apo[a] or apoB100 synthesis and to determine if the efficacy of Lp[a] lowering by estrogen depends on the ethnicity of the subject. Equal numbers of black, white, and Hispanic normolipidemic postmenopausal women with Lp[a] concentration greater than 30 mg/dl will be randomized to one of two treatment sequences, both of which will include two alternating 3-month periods of active and placebo hormone replacement therapy (1.25 mg/day of conjugated estrogen and 10 mg/day for 10 days/month of medroxyprogesterone acetate) separated by a 3-month washout period. Apo[a] phenotypes will be determined by high-resolution agarose electrophoresis. Lp[a] concentrations will be measured by ELISA. The rates of synthesis in vivo of apo[a] in Lp[a] and of apoB100 in Lp[a], low-density lipoprotein, intermediate-density lipoprotein, and very-low-density lipoprotein will be computed from mass spectrometric quantification of [2H4]-lysine enrichment rates for these proteins; measurements will be performed before and after hormone replacement therapy.
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