The iron hypothesis:does iron play a role in atherosclerosis?

Atherosclerotic cardiovascular disease (CVD) is the single largest killer in western societies, accounting for 48 percent of all deaths.1 Currently, in the United States, more than 10 million individuals have symptomatic CVD, while an even greater number have asymptomatic CVD.1,2 This results in approximately 1.5 million myocardial infarctions (MIs) and 975,000 deaths annually, with an economic burden of $120 billion, which is equivalent to 3 percent of the Gross Domestic Product. There are several risk factors whose association with atherosclerosis is well established, including age, gender, lipid disorders, smoking, hypertension, diabetes mellitus, obesity, and sedentary lifestyle.3,4 Yet, about 25 percent of CVD deaths in men and 15 percent in women occur in persons with multivariate Framingham Study risk scores in the lowest two quintiles, according to standard risk factors.5 It has been suggested that about half of atherosclerosis cases cannot be attributed to standard risk factors.6 This fact has recently stimulated a call for investigation of new risk factors.7,8 Gender is unquestionably an important risk factor. Women experience less than half the incidence of and mortality due to coronary heart disease (CHD) as age-matched men experience.9 An approximate 10-year difference in age-specific rates between the genders persists throughout the lifespan. Protection from CHD persists in women even in the presence of severe hyperlipidemia.10 It appears that ageadjusted CHD rates in women markedly increase after menopause and may then approach those of men.11 The lower incidence of CHD in women has never been adequately explained. It has been suggested that estrogenassociated changes—perhaps of lipids, endothelial function, or vasoreactivity—may be protective before menopause (when they are lost).12-14 Observations from the Framingham Study cohort as early as 1976 suggested that the risk of CHD in women is increased by simple hysterectomy in the presence of functioning ovaries.11 If this observation is correct, then estrogen may not be the only factor involved in women’s resistance to CHD. More recently, the failure of postmenopausal estrogen replacement to prevent recurrent coronary events in the Heart and Estrogen/Progestin Replacement Study (HERS) trial raises a similar question.15 In 1981, Sullivan first proposed the so-called “iron hypothesis,” suggesting that the regular menstrual loss of iron, rather than other effects of estrogen, protects women against CHD.16 Iron is an essential catalyst in the oxidation process. Oxidative modification of low-density lipoprotein (LDL) cholesterol appears to be one of the pivotal steps in atherogenesis.17,18 Thus, iron depletion through menstrual loss, or through the donation of whole blood, would beneficially affect atherogenesis.19