Do Hemochromatosis Mutations Protect Against Iron-Mediated Atherogenesis?
Do Hemochromatosis Mutations Protect Against Iron-Mediated Atherogenesis?
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DOI：
10.1161/circgenetics.109.906230
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发表时间：
2009-12-01
影响因子：
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通讯作者：
Sullivan, Jerome L.
中科院分区：
文献类型：
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作者：
Sullivan, Jerome L.
有人提出，适度的铁储存水平，远远低于传统的铁超载，会促进心血管疾病，而持续的铁枯竭可以预防心血管疾病。1-6这个所谓的“铁假说”最初是为了解释心血管疾病的性别差异和绝经后疾病的增加。尽管这一想法持续争论了25年，但作为一种可信和可验证的假说，它已经获得了一定的地位。7-18目前还没有发表对这一假说的最终检验。最近报道了第一个部分解决这一假说的随机临床试验。7第一个随机临床试验7作为对这一想法的一般测试有两个关键限制：(1)这是一项二级预防试验，(2)铁减少方案远远不能实现充分的铁消耗。Zacharski等人报道，如果在60岁之前就开始减少铁，那么减少铁储存可以显著提高有症状但稳定的外周动脉疾病患者的存活率。第一个随机临床试验为一项新的试验提供了令人信服的支持，该试验旨在全面检验最初的假设。多项流行病学研究使用身体铁负荷的各种可变参数调查了各种动脉粥样硬化事件的对照结果，呈现了一幅关于铁假设的令人困惑的图景。19当发现患有纯合子血色素沉着症的患者患有严重的终生铁超载时，他们的动脉粥样硬化没有增加，甚至可能受到保护，从而造成了完全的混淆。在对这一假说的辩论中，纯合血色沉着症的疾病模式被认为是反对这一假说的最有说服力的证据。20这种“血色素沉着症悖论”被认为是一种反常现象，使得这一假设对一些观察家来说是站不住脚的。当遗传铁超载中储存的大量铁似乎不会引发动脉粥样硬化加剧时，正常储存的铁水平怎么会对血管系统有害呢？
It has been proposed that modest levels of stored iron, far less than conventional iron overload, promote cardiovascular disease and that sustained iron depletion is protective against it. 1–6 This so-called “iron hypothesis” was initially presented as an explanation for the sex difference in cardiovascular disease and the increase in disease after menopause. The idea, although continually debated for 25 years, has achieved some standing as a plausible and testable hypothesis. 7–18 No definitive test of the hypothesis has yet been published. A first randomized clinical trial to partially address the hypothesis was recently reported. 7 The first randomized clinical trial7 had 2 key limitations as a general test of the idea:(1) it was a trial of secondary prevention and (2) the iron reduction protocol fell far short of achieving full iron depletion. Zacharski et al7 reported that reducing iron stores significantly improves survival for patients with symptomatic but stable peripheral arterial disease, if iron reduction begins before the age of 60 years. The first randomized clinical trial provides compelling support for a new trial designed to fully test the original hypothesis.Controversial results from multiple epidemiological studies investigating a variety of atherosclerotic events using all kinds of variable parameters of body iron load have presented a confusing picture regarding the iron hypothesis. 19 Confusion became complete when it appeared that patients with homozygous hemochromatosis who were afflicted with serious life-long iron overload had no increase in atherosclerosis and might even be protected against atherosclerosis. In the debate on the hypothesis, the disease pattern in homozygous hemochromatosis has been perceived as perhaps the most persuasive evidence against the hypothesis. 20 This “hemochromatosis paradox” is seen as an anomaly that makes the hypothesis untenable for some observers. How can normal stored iron levels be bad for the vascular system, when massive amounts of stored iron in genetic iron overload do not seem to provoke increased atherosclerosis?