To the Editor In a systematic review, Muka et al1 found a higher risk of cardiovascular disease mortality and a higher overall mortality in women who experience premature or early-onset menopause. We suggest that the substantial increase in serum ferritin levels at menopause signals a dramatic alteration in iron metabolism possibly associated with enhanced inflammatory responses. We ask the authors to consider that the observed and significant increase in risk of cardiovascular disease in women is associated with altered iron homeostasis and the possible increase in body iron stores after menstrual blood flow cessation.2
The 1976 Framingham Study3 provided groundbreaking evidence that menopause is associated with a highly significant, 2-fold increase in the incidence of heart disease. Cardiovascular protection diminished after surgical menopause, regardless of whether oophorectomy had been performed. Muka et al1 emphasize the striking association between menopause and coronary risk without comment on the significant alteration in iron metabolism accompanying menstrual cessation.
The hypothesis that increased cardiovascular disease following menopause results from oxidative stress catalyzed by excess iron accumulation was tested in the Veterans Affairs Cooperative Study Trial 410, The Iron and Atherosclerosis Study. Phlebotomy effects on clinical outcomes were tested in patients with peripheral arterial disease with iron store reduction, estimated by serum ferritin levels, to levels approaching 25 ng/mL, which occur in healthy menstruating women.4 Data from this prospective study demonstrated that lower ferritin levels (eg, 76-78 ng/mL) predicted improved outcomes in younger men with peripheral arterial disease (later in smokers) on removal of an amount of iron represented by approximately a liter of blood. Lower ferritin levels strongly predicted improved clinical outcomes, regardless of randomization group, with a threshold for benefit below 76-78 ng/mL.
We suggest that iron in catalytic form stimulates inflammatory responses and leukocyte activity and associates with elevation of interleukin 6 and other inflammatory biomarkers. We have reported direct associations5 between elevated ferritin levels and inflammatory biomarkers, predominantly interleukin 6, and mortality.
Data from multiple sources support a clear need for additional studies testing the relationship between increased cardiovascular disease risk associated with changing iron homeostasis in women during and after menopause. We recommend sequential measurements of ferritin levels, along with levels of iron, hepcidin, and inflammatory biomarkers in premenopausal and postmenopausal women to assess the effects of these biomarkers as risk factors for cardiovascular mortality.2 Provision of a biological basis for the effect of early menopause on cardiovascular disease requires further investigation of the crucial role of iron metabolism.
Corresponding Author: Virginia Mary Hayes, MS, Ambulatory Care, VA Sierra Nevada Health Care System, 975 Kirman Ave, Reno, NV 89521 (firstname.lastname@example.org).
Published Online: January 4, 2017. doi:10.1001/jamacardio.2016.5082
Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.
Hayes VM, DePalma RG, Zacharski LR. Effect of Iron Levels on Women After Premature or Early-Onset Menopause. JAMA Cardiol. Published online January 04, 2017. doi:10.1001/jamacardio.2016.5082