DOES ATHEROSCLEROSIS REGRESS WITH THERAPY FOR LOW HDLC?

超过三分之一的冠心病（CAD）患者有“低” HDL胆固醇（HDLc）水平（低于35 mg/dl;美国第20百分位数） 和“正常”LDLc（小于145;美国平均值），这是一组目前 治疗指南并非基于临床试验数据。 低HDL c 水平是心血管（CV）疾病的强有力的独立预测因子 和CV死亡风险，男性和女性同样如此。 拟 这种高CAD风险是由于 胆固醇通过LDL进入动脉内膜并通过HDL清除。 此外，由于HDL作为抗氧化剂和细胞保护剂， HDL的作用可能是防止LDL氧化，从而限制巨噬细胞- 介导的内膜脂质积聚或防止血管细胞毒性。 最近的流行病学、实验和临床试验证据表明， 高密度脂蛋白胆固醇升高15 mg/dl会降低冠心病发病率， 死亡率降低30-70%，抗氧化剂维生素E、C和β-胡萝卜素 可能减少CAD事件和动脉粥样硬化形成。 潜在的绝对 对于那些有CAD的人来说，好处更大。 还已经 HDLc会随着运动、戒烟、体重增加而升高， 减少和单不饱和脂肪。 我们的目标是在低HDLc正常LDLc和CAD患者中检测两种 从这些观察中产生的假设：1）减少 通过药理学和卫生学方法测定的LDLc-HDLc失衡（比率）将 停止或逆转动脉粥样硬化的进展，以及2）维生素 维生素E、维生素C和β-胡萝卜素将独立地减少动脉粥样硬化的发生， 增强LDL-HDL治疗效果。 因此，我们建议随机选择160名这样的男性（小于62岁）。和 女性（67岁以下）双盲治疗，分配到 析因设计：1）中等剂量烟酸（500 mg qid）+辛伐他汀（20 mg qd）; 2）抗氧化剂鸡尾酒（维生素C（500 mg bid）、E（400 IU bid）和β-胡萝卜素（12.5mg qd）; 3）上述两种药物的组合; 或4）双重安慰剂。 所有这些病人将采取卫生措施， 升高HDL c。 这将通过专业咨询来完成， 节食、戒烟和有组织的锻炼计划。 主 这些研究的终点将是在一个全面的 通过连续定量动脉造影进行盲法分析。 二次 终点包括心血管事件的频率（死亡， 梗死和血运重建）以及内膜疾病变化 通过血管内超声在研究亚组中进行评估。 机制 将根据疾病变化的相关性评估获益 或治疗诱导的脂蛋白变化的临床事件发生率 (LDL HDL、HDL 2、IDL）或脱辅基蛋白{B、AI、AII、E和（a）}或 饮食变量，或抗氧化维生素的血浆水平，或 LDL对氧化的抵抗力。 这项为期5年的安慰剂对照研究采用了最先进的技术 评估受益的程度和机制。 它解决了 对大约三分之一的患者进行有效治疗的问题 CAD似乎主要与低HDLc相关，其中， 尚未进行定向临床或血管造影试验， 适当的治疗目前是有争议的。 因此，它具有很大的 潜在的公共卫生影响。

More than one-third of patients with coronary disease (CAD) have "low" HDL cholesterol (HDLc) levels (less than 35 mg/dl; U.S. 20th percentile) and "normal" LDLc (less than 145; U.S. mean), a group for whom current treatment guidelines are not based on clinical trial data. Low HDLc levels are strong, independent predictors of cardiovascular (CV) disease and CV mortality risk, equally so for both men and women. It is proposed that this high CAD risk is due to an imbalance between delivery of cholesterol into the arterial intima by LDL and its removal by HDL. Also, since HDL serve as antioxidants and cytoprotectants, an important HDL role may be to prevent LDL oxidation and thus limit macrophage- mediated intimal lipid accumulation or to prevent vascular cell toxicity. Recent epidemiologic, experimental, and clinical trial evidence suggests that a 15 mg/dl rise in HDL cholesterol would reduce CAD incidence and mortality by 30-70% and that antioxidant vitamins E, C, and Beta-carotene might reduce CAD events and atherogenesis. The potential absolute benefit is much greater in those with existing CAD. It has also been shown that HDLc rises in response to exercise, smoking cessation, weight reduction and monounsaturated fats. Our goal is to test, in patients with low HDLc normal LDLc, and CAD, two hypotheses that spring from these observations: 1) that reducing the LDLc-HDLc imbalance (ratio) by pharmacological and hygienic means will halt or reverse the progression of atherosclerosis, and 2) that vitamins E, C and Beta-carotene will independently reduce atherogenesis and thus enhance the LDL-HDL treatment effect. Therefore, we propose to randomize 160 such men (less than 62 y.o.) and women (less than 67 y.o.) to double-blinded therapy, assigned in a factorial design: 1) mid-dose niacin (500 mg qid), plus simvastatin (20 mg qd); 2) an antioxidant cocktail (vitamin C (500 mg bid), E (400 IU bid), and Beta-carotene (12.5 mg qd)); 3) a combination of the above two; or 4) double placebo. All these patients will adopt hygienic means for raising HDLc. This will be accomplished by professional counseling in diet, smoking cessation, and a structured exercise program. The primary endpoint in these studies will be CAD progression as assessed in a fully blinded analysis by serial quantitative arteriography. Secondary endpoints include the frequency of cardiovascular events (death, infarction, and revascularization) as well as intimal disease change assessed in a study subset by intravascular ultrasound. Mechanisms of benefit will be assessed in terms of the correlation of disease change or clinical event rate with the therapy-induced changes in lipoproteins (LDL, HDL, HDL2, IDL) or in apoproteins {B, AI, AII, E and (a)} or in dietary variables, or in the plasma levels of antioxidant vitamins, or in the resistance of LDL to oxidation. This 5-year placebo-controlled study employs state-of-the-art techniques to assess both the magnitude and mechanisms of benefit. It addresses the question of effective therapy for the roughly one-third of patients for whom CAD appears associated principally with low HDLc, among whom there has not been a directed clinical or angiographic trial, and among whom appropriate therapy is currently controversial. As such, it has great potential public health impact.