STABLE ISOTOPE STUDIES OF SYNTHESIS OF HUMAN LIPOPROTEIN[A] & OTHER P

心脏病是美国妇女死亡的主要原因。脂蛋白[a] （Lp[a]）已被确定为冠心病的独立危险因素，当血浆浓度大于30 mg/dl时，其在绝经后妇女中随着年龄的增长而增加，绝经后妇女的脂蛋白[a]通常高于年龄匹配的绝经前妇女。激素替代疗法可降低绝经后妇女的Lp[a]浓度，一些证据表明，在初始Lp[a]浓度较高的受试者中，雌激素降低Lp[a]的作用更大。与白人妇女相比，黑人妇女的Lp[a]浓度高出三倍，绝经后西班牙裔妇女的Lp[a]浓度比绝经后白人妇女低三分之一。此外，黑人妇女使用激素替代疗法降低Lp[a]的效果要大于白人妇女。因此，应该有可能区分黑人和白人女性之间、黑人和西班牙裔女性之间，以及白人和西班牙裔女性之间Lp[a]代谢的差异。本研究旨在确定绝经后妇女雌激素诱导的脂蛋白[a]浓度降低是否由于载脂蛋白[a]或载脂蛋白100合成率的改变，并确定雌激素降低脂蛋白[a]的效果是否取决于受试者的种族。同等数量的Lp[a]浓度大于30 mg/dl的黑人、白人和西班牙裔正常血脂绝经后妇女将被随机分配到两种治疗序列中的一种，这两种治疗序列都包括两个交替的3个月的活性和安慰剂激素替代治疗（结合雌激素1.25 mg/天，醋酸甲孕酮10 mg/天，10天/月），中间间隔3个月的洗脱期。载脂蛋白[a]表型将通过高分辨率琼脂糖电泳确定。ELISA法测定Lp[a]浓度。脂蛋白[a]中的载脂蛋白[a]和脂蛋白[a]中的载脂蛋白[a]、低密度脂蛋白、中密度脂蛋白和极低密度脂蛋白的体内合成速率将通过质谱定量计算这些蛋白质的[2H4]-赖氨酸富集率来计算；测量将在激素替代疗法前后进行。

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.