Iron and the role of Chlamydia pneumoniae in heart disease.

To the Editor: Chronic infection of the coronary arteries by Chlamydia pneumoniae has been proposed as a heart disease risk factor (1). One reason for this proposal is the organism's association with one or more other risk factors for heart disease (2). However, an independent pathogenic role for C. pneumoniae in heart disease is unlikely if its presence is only a marker for another risk factor. In the Helsinki Heart Study (3), markers of chronic C. pneumoniae infection were a significant risk factor for a cardiac event, independent of most traditional risk factors; however, some association with known risk factors was seen, including a positive association with smoking and an unexpected negative association with spare-time physical activity.

We postulate a key role for iron, a proposed risk factor for heart disease (4-6), in promoting the growth of C. pneumoniae in coronary arteries. Iron is an essential growth factor for nearly all pathogenic microorganisms (7). In particular, the growth of C. pneumoniae in a human lung cell line and in Hep-2 cells is strongly inhibited by iron restriction or by use of the iron chelator deferoxamine (8, P. Saikku, pers. comm.). Excess iron is present in atherosclerotic lesions. Seven times more iron is present in atherosclerotic than in healthy arteries (9).

Among proposed risk factors for heart disease, iron provides the most conceptually straightforward explanation for the presence of C. pneumoniae in coronary vessels. We propose that chronic infection of coronary arteries by C. pneumoniae occurs only if excess iron is present in vivo. Excess iron is defined as stored iron or iron in excess of the amount needed to maximize hematocrit. This implies that C. pneumoniae can establish infection in the coronary arteries only if a threshold level of available iron is present. Confirmation of the hypothesis could explain an association of C. pneumoniae with coronary atherosclerosis and, more generally, with ischemic heart disease and would be consistent with the greater susceptibility of men than women to C. pneumoniae infection (2) and myocardial infarction. Moreover, confirmation of the hypothesis would leave open the question of whether C. pneumoniae is directly atherogenic or merely finds fertile ground for growth in arteries because of the presence of iron above some threshold level.

Until age 20, men and women show few differences in prevalence of antibody titers against C. pneumoniae. After age 20, the prevalence of markers diverges sharply, with men showing a much steeper rise than women. This is similar to the patterns observed for both stored iron levels and rate of myocardial infarction in men and women, especially between the ages of 20 and 50 years (4,5). In later years, prevalence rates for C. pneumoniae markers do not rise as steeply for women as the curves for stored iron level or myocardial infarction rates (2). These patterns are compatible with associations between stored iron, myocardial infarction rate, and markers for infection with C. pneumoniae. Another relevant observation is the negative association of markers with spare-time physical activity (2). Such activity is associated with lower stored iron levels (10), which may decrease vulnerability to C. pneumoniae.

The presence of excess iron in regulating susceptibility to C. pneumoniae does not readily explain the geographic gradient in the frequency of antibodies (2). C. pneumoniae infection seems to be more prevalent near the equator. In general, acquisition of stored iron is more problematic among impoverished persons, many of whom live near the equator. Parasitic infections that cause chronic iron loss from bleeding in the gut and bladder, along with limited availability of easily absorbed heme iron in meat, tend to minimize iron acquisition in these areas. C. pneumoniae may be endemic in populations near the equator, especially among children in tropical urban slums, because of other factors that eliminate any differential effects on the basis of iron levels. In these areas chlamydial antibodies may be a good marker for invasion but not necessarily for disease.

We suggest that, above a modest threshold level of stored iron in vivo, C. pneumoniae acquires the ability to colonize coronary arteries. Invasion and colonization by the organism in vivo probably require a concentration of available iron similar to that needed for growth in cell culture. Even in a state of total iron depletion, iron is still present in the body in abundance. However, in iron depletion virtually all iron in the body is functional iron. Functional iron, i.e., iron in hemoglobin, may not be readily accessible to the organism. Our hypothesis implies that stored iron can be mobilized by C. pneumoniae for growth. An approach to testing the hypothesis would involve comparing the ability of C. pneumoniae to colonize macrophages from stored iron-replete persons with those from persons without stored iron. If the hypothesis is confirmed, maintenance of an iron-depleted state under medical supervision could be recommended as a preventive strategy against recolonization after a course of antibiotic therapy.

Acknowledgment

We thank Jane E. Raulston for review of the manuscript and for useful suggestions.

References

(1.) Saikku P, Mattila K, Nieminen MS, Huttunen JL, Leinonen M, Ekman M-R, et al. Serological evidence of an association of a novel Chlamydia, TWAR, with chronic coronary heart disease and acute myocardial infarction. Lancet 1988;ii:983-5.

(2.) Saikku P. The epidemiology and significance of Chlamydia pneumoniae. J Infect 1992;25 Suppl I:27-34.

(3.) Saikku P, Leinonen M, Tenkanen L, Linnanmaki E, Ekman MR, Manninen V, et al. Chronic Chlamydia pneumoniae infection as a risk factor for coronary heart disease in the Helsinki Heart Study. Ann Intern Med 1992;15;116:273-8.

(4.) Sullivan JL. Iron and the sex difference in heart disease risk. Lancet 1981;1:1293-4.

(5.) Sullivan JL. Iron versus cholesterol--perspectives on the iron and heart disease debate. J Clin Epidemiol 1996;49:1345-52.

(6.) Salonen JT, Nyyssonen K, Korpela H, Tuomilehto J, Seppanen R, Salonen R. High stored iron levels are associated with excess risk of myocardial infarction in eastern Finnish men. Circulation 1992;86:803-11.

(7.) Weinberg ED. Patho-ecologic implications of microbial acquisition of host iron. Reviews in Medical Microbiology 1998;9:171-8.

(8.) Freidank HM, Billing H. Influence of iron restriction on the growth of Chlamydia pneumoniae TWAR and Chlamydia trachomatis. Clinical Microbiology and Infection 1997;3 Suppl 2:193.

(9.) Thong PSP, Selley M, Watt F. Elemental changes in atherosclerotic lesions using nuclear microscopy. Cell Mol Biol 1996;42:103-10.

(10.) Lakka TA, Nyyssonen K, Salonen JT. Higher levels of conditioning leisure time physical activity are associated with reduced levels of stored iron in Finnish men. Am J Epidemiol 1994;140:148-60.

Jerome L. Sullivan(*) and Eugene D. Weinberg([dagger])

(*) University of Florida College of Medicine, Gainesville, Florida, USA; and ([dagger]) Indiana University, Bloomington, Indiana, USA