Do hemochromatosis mutations protect against iron-mediated atherogenesis

It has been proposed that modest levels of stored iron, farless than conventional iron overload, promote cardio-vascular 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 deple-tion. 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 stud-ies 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 Confu-sion became complete when it appeared that patients with homozygous hemochromatosis who were afflicted with seri-ous 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 “hemo-chromatosis 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