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Response to "Iron homeostasis in the OPTIMAAL study."
- Adriaan A. Voors, Stefan D. Anker (24 August 2009)
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Iron homeostasis in the OPTIMAAL study.
- P P Xaplanteris, Charalambos Vlachopoulos, Christodoulos Stefanadis (24 August 2009)
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Adriaan A. Voors, Cardiologist University Medical Center Groningen, Hanzeplein 1, 9713GZ Groningen, the Netherlands, Stefan D. Anker
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We agree with Xaplanteris et al (1) that hepcidin is an interesting research subject and needs more attention. Hepcidin is a The peptide hormone and plays a central role in iron homeostasis. Possibly hepcidin is highly relevant as a cause of iron defficiency in anaemia in CHF (2). Considering the assessment of hepcidin in blood samples, however, we think that Xaplanteris et al (1) somewhat overestimate the quality of hepcidin (non-HPLC) test kits currently available. Adlbrecht et al. (3) recently published pathophysiologic studies and states serum prohepcidin did not correlate with the presence of iron deficiency (0.102, P = 0.333). They used an ELISA test kit. Using the same methodolgy, our group was not able to find a significant difference in plasma levels of hepcidin when comparing CHF patients and healthy controls (unpublished). We think, these results are more likely due to poor quality of assessment methods available on the market, then due to a true 'no difference'. The reliable way of assessing hepcidin appears to be through HPLC, which is available in a limited number of laboratories and expensive. Unfortunately, we were not able to assess hepcidin in samples of OPTIMAAL. Interestingly, another recent study (4) reported that hepcidin is expressed in the heart and that its expression is upregulated in response to hypoxia and inflammation, suggesting a yet unexplored role of hepcidin in cardiac pathophysiology. All this discussion, however should not distract us from correcting anaemia and iron defficiency (5) which, we think, holds a lot of promise. The important biomarkers to assess absolute and functional iron defficiency remain ferritin and transferrin satturation besides hemoglobin (6) – a lot of work is still needed so that hepcidin may join the club. References 1. Letter of Xaplanteris et al to EHJ (to be completed by publisher) 2. Okonko DO, Anker SD. Anemia in chronic heart failure: pathogenetic mechanisms. J Card Fail. 2004;10(1 Suppl):S5-9. 3. Adlbrecht C, Kommata S, Hülsmann M, Szekeres T, Bieglmayer C, Strunk G, Karanikas G, Berger R, Mörtl D, Kletter K, Maurer G, Lang IM, Pacher R. Chronic heart failure leads to an expanded plasma volume and pseudoanaemia, but does not lead to a reduction in the body's red cell volume. Eur Heart J. 2008;29:2343-50. 4. Merle U, Fein E, Gehrke SG, Stremmel W, Kulaksiz H. The iron regulatory peptide hepcidin is expressed in the heart and regulated by hypoxia and inflammation. Endocrinology. 2007;148:2663-8. 5. Okonko DO, Grzeslo A, Witkowski T, Mandal AK, Slater RM, Roughton M, Foldes G, Thum T, Majda J, Banasiak W, Missouris CG, Poole-Wilson PA, Anker SD, Ponikowski P. Effect of intravenous iron sucrose on exercise tolerance in anemic and nonanemic patients with symptomatic chronic heart failure and iron deficiency FERRIC-HF: a randomized, controlled, observer- blinded trial. J Am Coll Cardiol. 2008;51:103-12. 6. Lainscak M, von Haehling S, Anker SD. Natriuretic peptides and other biomarkers in chronic heart failure: from BNP, NT-proBNP, and MR-proANP to routine biochemical markers. Int J Cardiol. 2009;132:303-11. Stefan D Anker, MD PhD Adriaan A Voors, MD PhD Conflict of Interest:None declared |
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P P Xaplanteris, PhD student Hippokrateion Hospital, Athens Medical School, 114 V.Sofias Av, 11527, Athens, Greece, Charalambos Vlachopoulos, Christodoulos Stefanadis
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We read with great interest the article by Anker et al. (1) addressing the prognostic value of anemia in acute myocardial infarction (AMI) survivors. The presented substudy of the main OPTIMAAL trial is of particular interest, as it sheds light on long-term iron homeostasis following AMI. The haematinics data show that abnormal iron levels were present in 80% of the 224 patients at baseline, thus suggesting that iron deficiency accounted for the majority of anaemics. Hepcidin, a hormone synthesized mainly in the liver, has recently emerged as the principle regulator of iron metabolism and erythropoiesis.(2) Hepcidin expression increases in an inflammatory millieu and has been proposed as a biomarker of anaemia of inflammation. Indeed, experimental data have demonstrated that hepcidin acts as an acute -phase protein in inflammatory states; lipopolysaccaride (LPS) and interleukin-6 (IL-6) upregulate its expression, thus blocking iron absorption from the duodenum. (3) Moreover, inflammation inhibits iron efflux from macrophages by down-regulating ferroportin 1, a protein that facilitates iron mobilization from macrophages.(4-6) The above-mentioned mechanisms lead to a decrease in iron availability for erythropoiesis. Preliminary data suggest an increase in hepcidin concentrations early in the course of AMI.(7) Moreover, expression of this hormone has been demonstrated in cardiomyocytes.(8) It would be of particular interest to determine its levels at baseline and follow-up in a subset of patients of the OPTIMAAL study. Such data regarding iron regulation and their correlation with inflammatory markers would provide valuable insights into the causes of anaemia in HF patients following AMI. References 1. Anker SD, Voors A, Okonko D, Clark AL, James MK, von Haehling S, Kjekshus J, Ponikowski P, Dickstein K, Investigators O. Prevalence, incidence, and prognostic value of anaemia in patients after an acute myocardial infarction: data from the OPTIMAAL trial. European Heart Journal 2009; 30(11):1331-1339. 2. Fleming RE, Bacon BR. Orchestration of iron homeostasis. N Engl J Med 2005; 352(17):1741-1744. 3. Kemna E, Pickkers P, Nemeth E, Van Der Hoeven H, Swinkels D. Time- course analysis of hepcidin, serum iron, and plasma cytokine levels in humans injected with LPS. Blood 2005; 106(5):1864. 4. Ludwiczek S, Aigner E, Theurl I, Weiss G. Cytokine-mediated regulation of iron transport in human monocytic cells. Blood 2003; 101(10):4148-4154. 5. Weiss G, Goodnough LT. Anemia of chronic disease. N Engl J Med 2005; 352(10):1011-1023. 6. Nemeth E, Rivera S, Gabayan V, Keller C, Taudorf S, Pedersen BK, Ganz T. IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. J Clin Invest 2004; 113(9):1271-1276. 7. Suzuki H, Toba K, Kato K, Ozawa T, Tomosugi N, Higuchi M, Kusuyama T, Iso Y, Kobayashi N, Yokoyama S, Fukuda N, Saitoh H, Akazawa K, Aizawa Y. Serum hepcidin-20 is elevated during the acute phase of myocardial infarction. Tohoku J Exp Med 2009; 218(2):93-98. 8. Merle U, Fein E, Gehrke SG, Stremmel W, Kulaksiz H. The iron regulatory peptide hepcidin is expressed in the heart and regulated by hypoxia and inflammation. Endocrinology 2007; 148(6):2663-2668. Conflict of Interest:None declared |
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