ANTIOXIDANTS AND PREVENTION OF EARLY ATHEROSCLEROSIS

背景 流行病学研究有证据表明， 一项未发表的试验表明，摄入更多的抗氧化维生素（AV） 与冠心病和中风风险降低有关。 动物的发现 模型表明，增加AV摄入可防止主动脉瓣狭窄的进展， 由致动脉粥样硬化饮食引起的脂肪条纹，但不是晚期损伤- 诱发病变。 这些观察结果表明， AV摄入可以防止早期动脉粥样硬化的进一步发展， 可能通过降低LDL对氧化修饰的敏感性， 随后的细胞毒性、趋化性、化学稳定性和不受调节的摄取 方面的影响. 一种新的自动化方法测定动脉内膜中层厚度（IMT）， 颈总动脉（CCA）使检测原发性 AV对早期动脉粥样硬化的预防作用。 两项试验的结果 我们的研究所证明低密度脂蛋白对CCA IMT的降低作用可以是 在小样本（少于30份）中快速检测（12至24个月内） （图）自动IMT。 实现了IMT进展延迟 在两项研究中，平均血管直径没有显著变化， 表明对早期病变有影响。 此外，一项研究发现， 血浆α-生育酚12个月变化之间的负相关 颈动脉IMT水平和变化。 这些发现意味着，如果有一个 补充α-生育酚对早期动脉粥样硬化影响， 在12至24个月内的小型研究中，可通过自动IMT检测到。 假说. 流行病学研究表明， 多年的维生素E补充。 据推测，相对 与安慰剂相比，维生素E补充剂（800 USP单位/天）可以延缓 CCA IMT在24个月内的进展率。 的假设 将在非裔美国人中进行测试，因为相对于白人， 65岁以下黑人的心血管死亡率急剧上升， 在横断面调查中发现他们增加了CCA IMT。 可行性。 该研究的可行性源于[1]最近 开发自动超声IMT测量， 重复性误差和所需的样本量; [2]便携性和低- 使得成像可以在移动的 货车; [3]补充573毫克/天的维生素E和 超声暴露; [4]受试者的可用性， 合作社区/学区正在参与正在进行的 研究;[15]相对于长期研究，依从性增加 在心脏病风险人群中。 设计 年龄在35-59岁之间的女性和男性非洲裔美国人将被 筛选 在学校或家中的颈动脉IMT（屏幕1）。 经过12 月，年龄和性别调整后的第66百分位数以上的受试者 屏幕I将被重新筛选（屏幕II）;那些显示最大 进展将被邀请参加一个磨合。 那些受试者 发现合作和依从（通过血浆α-生育酚水平） 将随机分配至维生素E（573 mg/天）和安慰剂组。 CCA 在12个月和24个月随访时观察IMT。 主要结局 将是平均CCA IMT的24个月变化率。

BACKGROUND. There is evidence from epidemiologic studies, and one unpublished trial, that greater intake of antioxidant vitamins (AV) is associated with reduced risk of CHD and stroke. Findings from an animal model indicate that increased intake of AV prevents progression of aortic fatty streaks induced by an atherogenic diet but not advanced injury- induced lesions. These observations suggest the hypothesis that increased AV intake may prevent further progression of early atherosclerosis, possible via reduced susceptibility of LDL to oxidative modification and consequent cytotoxic, chemotactic, chemostatic and unregulated uptake effects. A new automated method for determining intima-media thickness (IMT) of the common carotid artery (CCA) makes it feasible to test the primary prevention impact of AV on early atherosclerosis. Results of two trials at our institute demonstrate the LDL lowering effects on CCA IMT can be detected rapidly (within 12 to 24 months) in small samples (less than 30 per group) with automated IMT. Retardation of IMT progression was achieved in both studies without significant changes in average vessel diameter -- suggesting effects on early lesions. Furthermore, a Finish study found an inverse association between 12 month change in plasma alpha-tocopherol levels and change in carotid IMT. These findings imply that if there is an effect of alpha-tocopherol supplement on early atherosclerosis then it may be detectible with automated IMT in a small study within 12 to 24 months. HYPOTHESIS. Epidemiologic studies indicate cardiac protection after two years of vitamin E supplementation. It is thus hypothesized that, relative to placebo, vitamin E supplements (800 USP units/day) can retard the progression rate of CCA IMT over a period of 24 months. The hypothesis will be tested among African Americans since, relative to whites, cardiovascular mortality is sharply elevated in blacks under age 65, and they have been found to have increased CCA IMT in cross-sectional surveys. FEASIBILITY. The feasibility of the study stems from [1] recent development of an automated ultrasound IMT measure that reduces reproducibility error and required sample size; [2] portability and low- cost of the ultrasound system so that imaging can be conducted in a mobile van; [3] safety of both vitamin E supplementation at 573 mg/day and ultrasound exposure; [4] availability of subjects from a demonstrably cooperative community/school district that is participating in ongoing studies; and [15] increased compliance relative to longer term studies among persons at risk for cardiac events. DESIGN. Volunteering female and male African Americans aged 35-59 will be screened for carotid IMT at a school or at home (Screen 1). After 12 months, those subjects above the age and sex adjusted 66th percentile at Screen I will be rescreened (Screen II); those showing the greatest progression will be invited to participate in a run-in. Those subjects found to be cooperative and compliant (by plasma alpha-tocopherol level) will be randomized to vitamin E (573 mg/day) and placebo conditions. CCA IMT will be observed at 12 and 24 months follow ups. The primary outcome will be 24 month rate of change in average CCA IMT.