Sex differences in cardiovascular ageing

Allison A Merz; Susan Cheng

doi:10.1136/heartjnl-2015-308769

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Sex differences in cardiovascular ageing

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Regarding sex differences in cardiovascular ageing: let's not forget iron
Mark R. Goldstein
Published on: 12 May 2016
Author Reply: Sex Differences in Cardiovascular Ageing
Susan Cheng
Published on: 12 May 2016

Published on: 12 May 2016
Regarding sex differences in cardiovascular ageing: let's not forget iron
- Mark R. Goldstein, Physician
- Other Contributors:
  Luca Mascitelli, Comando Brigata Alpina "Julia"/Multinational Land Force, Medical Service, 8 Via S. Agostino, Udine, 33100, Italy. and Leo R. Zacharski, Research Service, Veterans Affairs Medical Center, White River Junction, VT, USA; Department of Medici
The interesting paper of Merz and Cheng did not mention iron as a plausible non-hormonal factor, which might in part explain the sex differences in cardiovascular aging [1].
Mounting evidence suggests that the metabolic derangements and detrimental cardiovascular effects usually attributed to menopause represent only a mere consequence of the older age of menopausal women, rather than related to the loss of ov...
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The interesting paper of Merz and Cheng did not mention iron as a plausible non-hormonal factor, which might in part explain the sex differences in cardiovascular aging [1].
Mounting evidence suggests that the metabolic derangements and detrimental cardiovascular effects usually attributed to menopause represent only a mere consequence of the older age of menopausal women, rather than related to the loss of ovarian function. In fact, heart protection by premenopausal levels of female hormones, that is the oestrogen hypothesis, is not consistent with epidemiological findings that premenopausal hysterectomy essentially cancels the protection even in patients with preservation of functioning ovaries [2]. On the contrary, these data [2] suggest that an intact uterus has an important role in the protection of premenopausal women, and this is likely related to the beneficial effect of iron depletion in menstruating women (i.e. the iron hypothesis suggested since 1981 by Sullivan [3]).
A protective effect of iron depletion may be related to the decreased availability of redox-active iron within atherosclerotic lesions. Serum ferritin concentrations, commonly used as a surrogate for iron stores, are significantly lower in premenopausal menstruating women (25-50 ng/mL) compared to men (140-150 ng/mL) of similar age, but slowly increase after menopause. Interestingly, average menstrual blood loss each year (780 mL) approximates blood loss from donating approximately two 500 mL units of whole blood [4]. It is noteworthy that phlebotomy of one unit of whole blood twice a year among predominantly white middle-aged and elderly men with peripheral arterial disease, resulted in a significant decrease in overall mortality, myocardial infarction and stroke over a several year period, compared to the control group not phlebotomized [4]. Not surprisingly, during the trial, the average serum ferritin concentration in the iron reduction group was approximately 60 ng/mL compared to 110 ng/mL in the control group [4]. On the contrary, it has become evident that supplemental iron use among elderly woman may be significantly and dose dependently associated with increased total mortality [5].
In conclusion, higher vascular wall iron, contained in macrophages, might in part explain the sex difference in cardiovascular ageing. Moreover, donating blood twice a year by men and possibly postmenopausal women might decrease CVD morbidity and mortality. Furthermore, unnecessary iron supplements should be avoided and iron fortification of our food supply should be questioned. Finally, randomized trials of iron depletion for the primary and secondary prevention of vascular disease need to be done.
1. Merz AA, Cheng S. Sex differences in cardiovascular ageing. Heart 2016 Feb [Epub ahead of print]. 2. Kannel WB, Levy D. Menopause, hormones, and cardiovascular vulnerability in women. Arch Intern Med 2004;164:479-81. 3. Sullivan JL. Iron and the sex difference in heart disease risk. Lancet 1981;1:1293-4. 4. Zacharski LR, Shamayeva G, Chow BK. Effect of controlled reduction of body iron stores on clinical outcomes in peripheral arterial disease. Am Heart J 2011;162:949-957.e1. 5. Mursu J, Robien K, Harnack LJ. Dietary supplements and mortality rate in older women: the Iowa Woman's Health Study. Arch Intern Med 2011;171:1625-1633.
Conflict of Interest:
None declared
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Conflict of Interest:
None declared.
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Published on: 12 May 2016
Author Reply: Sex Differences in Cardiovascular Ageing
- Susan Cheng
- Other Contributors:
  Allison A Merz
We thank Dr. Goldstein for bringing to our attention the iron hypothesis as a potential non-hormonal factor contributing to sex differences in cardiovascular aging. We also find intriguing the possibility that iron depletion in menstruating women may be cardio- protective. We had previously been aware of the potential role of iron as a byproduct of heme-oxygenase activity in mediating cardiometabolic risk,[1] with a numb...
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We thank Dr. Goldstein for bringing to our attention the iron hypothesis as a potential non-hormonal factor contributing to sex differences in cardiovascular aging. We also find intriguing the possibility that iron depletion in menstruating women may be cardio- protective. We had previously been aware of the potential role of iron as a byproduct of heme-oxygenase activity in mediating cardiometabolic risk,[1] with a number of community studies having reported equivocal findings when examining the relation between either iron or ferritin with respect to outcomes.[2-5] It is our impression that heterogeneity in prior study results may be related to differences in participant sampling methods, the iron measures used (ferritin, total iron binding capacity, transferrin saturation, serum iron, and dietary iron intake), and presence of potential confounding variables that could influence both iron levels and a given outcome of interest (e.g. inflammation, genetic variants). Given that iron accumulation patterns have been observed to vary by age and race as well as sex,[6] we agree that further studies investigating the role of iron as a potential contributor to cardiovascular risk are warranted. In particular, interventional studies could evaluate sex-based differences and also account for variables that could influence both iron levels and a given outcome of interest (e.g. blood donation and/or phlebotomy patterns, supplemental intake of iron, dietary patterns including heme vs. non-heme iron intake, and factors that might elevate ferritin as part of the acute phase response). We look forward to learning more about the potential contribution of iron depletion to sex differences in cardiovascular disease, in particular, as additional evidence emerges from this understudied field.
References
1. Fredenburgh LE, Merz AA, Cheng S. Haeme oxygenase signalling pathway: implications for cardiovascular disease. Eur Heart J. 2015 Jun 21;36(24):1512-8. doi: 10.1093/eurheartj/ehv114. Epub 2015 Mar 31. Review. PubMed PMID: 25827602; PubMed Central PMCID: PMC4475572.
2. Salonen JT, Nyyssonen K, Korpela H, Tuomilehto J, Sepp?nen R, Salonen R. High stored iron levels are associated with excess risk of myocardial infarction in eastern Finnish men. Circulation. 1992 Sep;86(3):803-11. PubMed PMID: 1516192.
3. Baer DM, Tekawa IS, Hurley LB. Iron stores are not associated with acute myocardial infarction. Circulation. 1994 Jun;89(6):2915-8. PubMed PMID: 8205708.
4. Mu?oz-Bravo C, Guti?rrez-Bedmar M, G?mez-Aracena J, Garc?a- Rodr?guez A, Navajas JF. Iron: protector or risk factor for cardiovascular disease? Still controversial. Nutrients. 2013 Jul 1;5(7):2384-404. doi: 10.3390/nu5072384. Review. PubMed PMID: 23857219; PubMed Central PMCID: PMC3738979.
5. Basuli D, Stevens RG, Torti FM, Torti SV. Epidemiological associations between iron and cardiovascular disease and diabetes. Front Pharmacol. 2014 May 20;5:117. doi: 10.3389/fphar.2014.00117. eCollection 2014. Review. PubMed PMID: 24904420; PubMed Central PMCID: PMC4033158.
6. Zacharski LR, Ornstein DL, Woloshin S, Schwartz LM. Association of age, sex, and race with body iron stores in adults: analysis of NHANES III data. Am Heart J. 2000 Jul;140(1):98-104. PubMed PMID: 10874269.
Conflict of Interest:
None declared
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Conflict of Interest:
None declared.
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