High Dose Alpha Tocopherol and Carotid Atherosclerosis

高剂量α-生育酚和颈动脉粥样硬化

• 批准号: 6743146
• 负责人: Ishwarlal Jialal
• 金额: $ 15.15万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-30 至 2006-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6743146
• 关键词: alternative medicine; angina pectoris; angiocardioultrasonography; antiinflammatory agents; antioxidants; atherosclerosis; biomarker; blood tests; carotid artery; clinical research; dosage; human subject; human therapy evaluation; inflammation; longitudinal human study; myocardial infarction; oxidative stress; patient oriented research; tocopherols; vitamin therapy

DESCRIPTION (provided by applicant): Cardiovascular disease is the leading cause of morbidity and mortality in Westernized populations. Both oxidative stress and inflammation appear to be crucial in atherogenesis. The most consistent data with respect to micronutrient antioxidants and atherosclerosis appears to relate to alpha tocopherol (AT). Studies to date have shown that AT supplementation results in both an antioxidant and anti-inflammatory effect, especially at higher doses (>-800 IU/day). The aim of the present study (RO1AT00005) is to test the effect of supplementation with 1200 IU/day of RRR-AT in a placebo-controlled, randomized double blind trial over 2 years on the progression of carotid atherosclerosis in patients with stable coronary artery disease (angina pectoris or previous myocardial infarction). Subjects (n = 120), as determined by our power calculations, will have to be on the AHA Phase II diet and have an LDL cholesterol <125 mg/dL on diet alone or diet and hypolipidemic drug therapy on at least 2 visits at least 4 weeks apart during the lead in phase. Intimal-medial thickness (IMT) of both carotids, including the common carotid, the bulb and the proximal internal carotid will be determined by high-resolution B-mode sonography. At six month intervals blood samples will be obtained for liver function, creatinine, complete blood count, lipid profile, antioxidants and fatty acid levels, LDL oxidation, plasma soluble cell adhesion molecules (CAMs), C-reactive protein (CRP) and monocyte activity. Also, a 24-hour urine sample will be obtained for F2 -isoprostanes, a measure of in-vivo oxidative stress. IMT will be determined at baseline, 1, 1.5 and 2 years. The mean change in IMT and the rate of progression will be compared between the AT and placebo groups. Isolated LDL will be subjected to copper catalyzed oxidation and the kinetics studied. Isolated monocytes will be activated with lipopolysaccharide and the following activities assayed: superoxide anion release, interleukin-1 beta, TNF-alpha and interleukin-6 release and adhesion to human endothelium. Soluble CAMs will be quantitated by ELISA and CRP will be assayed by a high sensitive assay. AT levels and the parameters of oxidative stress and inflammation will be correlated with changes in IMT. This study has the additional novelty of correlating biomarkers of oxidative stress and inflammation with a cardiovascular endpoint and will establish whether high dose AT decreases atherosclerosis progression.

描述（由申请人提供）：心血管疾病是西方化人群发病和死亡的主要原因。 氧化应激和炎症似乎在动脉粥样硬化形成中至关重要。 关于微量营养素抗氧化剂和动脉粥样硬化的最一致的数据似乎与α生育酚（AT）有关。 迄今为止的研究表明，AT 补充剂具有抗氧化和抗炎作用，特别是在较高剂量（>-800 IU/天）时。 本研究 (RO1AT00005) 的目的是在一项为期 2 年的安慰剂对照、随机双盲试验中测试每天补充 1200 IU RRR-AT 对稳定冠状动脉患者颈动脉粥样硬化进展的影响疾病（心绞痛或既往心肌梗塞）。 根据我们的功效计算确定，受试者 (n = 120) 必须采用 AHA II 期饮食，并且仅饮食或饮食和降血脂药物治疗至少 2 次访视时 LDL 胆固醇 <125 mg/dL导入阶段期间相隔 4 周。 两个颈动脉（包括颈总动脉、球部和近端颈内动脉）的内膜内侧厚度 (IMT) 将通过高分辨率 B 型超声检查确定。 每隔六个月采集一次血样，用于检测肝功能、肌酐、全血细胞计数、血脂谱、抗氧化剂和脂肪酸水平、低密度脂蛋白氧化、血浆可溶性细胞粘附分子 (CAM)、C 反应蛋白 (CRP) 和单核细胞活性。 此外，还将获取 24 小时尿液样本中的 F2-异前列烷，这是体内氧化应激的衡量标准。 IMT 将在基线、1 年、1.5 年和 2 年确定。 将比较 AT 组和安慰剂组之间 IMT 的平均变化和进展率。 分离的 LDL 将进行铜催化氧化并研究动力学。 分离的单核细胞将用脂多糖激活并测定以下活性：超氧阴离子释放、白细胞介素1β、TNF-α和白细胞介素6释放以及对人内皮的粘附。 可溶性 CAM 将通过 ELISA 进行定量，CRP 将通过高灵敏度测定进行测定。 AT水平以及氧化应激和炎症参数将与IMT的变化相关。 这项研究的另一个新颖之处是将氧化应激和炎症的生物标志物与心血管终点相关联，并将确定高剂量 AT 是否会减缓动脉粥样硬化的进展。