DOES ATHEROSCLEROSIS REGRESS WITH THERAPY FOR LOW HDLC?

低 HDLC 治疗可使动脉粥样硬化消退吗？

基本信息

批准号：
6223424
负责人：
BRUCE G BROWN
金额：
$ 32.56万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
1994
资助国家：
美国
起止时间：
1994-09-30 至 2001-02-28
项目状态：
已结题

项目摘要

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.

超过三分之一的冠状动脉疾病患者（CAD）“低” HDL胆固醇（HDLC）水平（小于35 mg/dl；美国20％）和“正常” LDLC（少于145；美国平均），当前为此治疗指南不是基于临床试验数据。低HDLC 水平是强大的心血管疾病（CV）疾病的独立预测指标和简历死亡率的风险，男女同样。它是提出的这种高的CAD风险是由于交付之间的不平衡胆固醇通过LDL进入动脉内膜，并被HDL清除。同样，由于HDL用作抗氧化剂和细胞保护剂，因此 HDL的作用可能是防止LDL氧化，从而限制巨噬细胞 - 介导的内膜脂质积累或预防血管细胞毒性。最近的流行病学，实验和临床试验证据表明 HDL胆固醇升高15 mg/dL会降低CAD的发生率和死亡率为30-70％，抗氧化维生素E，C和β-胡萝卜素可能会减少CAD事件和动脉粥样硬化。潜在的绝对在现有CAD的人中，收益要大得多。也一直表明HDLC响应运动，戒烟，体重而增加还原和单不饱和脂肪。我们的目标是测试HDLC正常LDLC低的患者，CAD，两个这些观察结果提出的假设：1）减少药理学和卫生手段的LDLC-HDLC不平衡（比率）将停止或扭转动脉粥样硬化的进展，2）维生素 E，C和β-胡萝卜素将独立降低动脉粥样硬化，从而增强LDL-HDL治疗效果。因此，我们建议将160个这样的人随机化（少于62 Y.O.）和妇女（小于67 Y.O.）进行双盲疗法，分配给阶乘设计：1）中剂量烟酸（500 mg Qid），加上辛伐他汀（20 mg QD）; 2）抗氧化剂鸡尾酒（维生素C（500 mg bid），E（400 IU）出价）和β-胡萝卜素（12.5 mg QD））; 3）上述两个组合；或4）双安慰剂。所有这些患者将采用卫生手段提高HDLC。这将通过专业咨询来完成饮食，戒烟和结构化锻炼计划。主要这些研究中的终点将是CAD的进展，如完全评估通过串行定量动脉造影进行盲目分析。次要终点包括心血管事件的频率（死亡，梗塞和血运重建）以及内膜疾病的变化在研究子集中通过血管内超声评估。机制利益将根据疾病变化的相关性评估或临床事件发生率随着治疗引起的脂蛋白变化（ldl，hdl，hdl2，idl）或apoproteins {b，ai，aii，e and e and（a）}或in 饮食变量或抗氧化维生素的血浆水平，或在LDL对氧化的抗性中。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利益的大小和机制。它解决了大约三分之一患者的有效治疗问题谁CAD似乎主要与低HDLC相关联，其中不是指导临床或血管造影试验，其中当前有争议的适当疗法是有争议的。因此，它很棒潜在的公共卫生影响。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Lipid altering or antioxidant vitamins for patients with coronary disease and very low HDL cholesterol? The HDL-Atherosclerosis Treatment Study Design.

对于患有冠心病和高密度脂蛋白胆固醇极低的患者，可以使用调脂维生素或抗氧化维生素吗？

DOI：
发表时间：
1998
期刊：
The Canadian journal of cardiology
影响因子：
0
作者：
Brown,BG;Zhao,XQ;Chait,A;Frohlich,J;Cheung,M;Heise,N;Dowdy,A;DeAngelis,D;Fisher,LD;Albers,J
通讯作者：
Albers,J

What benefit can be derived from treating normocholesterolemic patients with coronary artery disease?

治疗患有冠状动脉疾病的胆固醇正常的患者可以获得什么益处？