Is increased tissue ferritin a risk factor for atherosclerosis and ischaemic heart disease?

COMMENTARY Is increased tissue ferritin a risk factor for atherosclerosis and ischaemic heart disease? In 1981 Sullivan postulated a link between tissue iron stores and the risk of heart disease' because both the incidence of ischaemic heart disease (IHD) and the serum concentration of ferritin are much lower in pre-menopausal women than in men of the same age, whereas in men and women over 45 they are similar. There have been several recent challenges to this claim.24 Iron in a chemically unreactive form is stored intracel-lularly as ferritin and the concentration of serum ferritin reflects the level of iron in the tissues. Sullivan's hypothesis was supported by a study in Finnish men which showed that high serum ferritin concentrations were associated with an excess risk of myocardial infarction and that the incidence of myocardial infarction and the serum ferritin concentration correlated with the dietary intake of iron, most of which was consumed as haem.5 Others used the serum transferrin concentration as a measure of iron stores. This was inappropriate because the transferrin concentration reflects the availability of iron to the tissues and varies diurnally and from day to day.6 When Magnusson et al measured the total iron binding capacity (transferrin) and ferritin concentrations they did not find a correlation with myocardial infarction.3 Nor did Ascherio et al find a significant association between total iron intake and risk of coronary heart disease.4 This is not surprising because, except for haem, the absorption of iron by the gut is well controlled. Men with an intake of haem iron in the top quintile had a higher incidence of fatal coronary disease or non-fatal myocardial infarction than men with an intake in the lowest quintile, although this variable did not show a significant association with the risk of coronary heart disease.4 So the extent of any association with a higher risk of heart disease remains uncertain. The distinction between cardiovascular disease and myocardial infarction is important78 but epidemiological evidence is not sufficiently sophisticated to determine whether a detrimental effect of high iron stores operates on the myocardium or on the coronary arteries themselves. Iron promotes the modification of low density lipoproteins (LDL) in vitro and theoretically could enhance atherogenesis. But such modification of LDL is unlikely in the circulation, where any free iron will be captured by transferrin. If it occurs at all, such modification is more likely in the interstitium. Haem iron too …