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Mr Ivan J. Nunez-Gil
Mr Juan Roberto Peraira-Moral
Mr Marcin Kruszewski
Mr Przemyslaw Leszek
Recent studies show that in areas such as oncology and nephrology, intravenous iron alone or combined with erythropoietin-stimulating agents (ESA) do not increase survival. However, iron alone or combined with ESA may be helpful with regard to the fact that in heart failure, myocardial iron load at the cellular level is reduced. Nevertheless, intravenous iron may lead to elevation of a toxic cellular labile iron pool. Additionally, our studies show that iron homeostasis can be optimally assessed on the basis of 1) serum transferin, its receptor TfR1; 2) ferritin concentration and 3) TfR1/logFR ratio rather than only ferritin or transferin saturation.
Basic science emphasises the deleterious effects of oxidative stress and iron overload for cardiomyocytes. The purpose of the Garzoni formula however, is to avoid iron overload. Iron homeostasis markers may be useful during follow-up in order to prevent iron overload and show ID improvement.
We read with interest Vol 10 N°16 in the e-journal of the ESC Council for Cardiology Practice “Anemia in heart failure: intravenous iron therapy” by Peraira-Moral J. Roberto and Núñez-Gil Ivan J. Authors present diagnostic testing, prognostic implications and management options for intravenous iron supplementation in anemic and non-anemic iron-deficient heart failure patients. Whether a result of true or functional iron deficiency, - iron deficiency anemia or anaemia of chronic disease or disorders- anemia is a common complication of cancer or cancer treatment, as well as chronic kidney disease and heart failure. Early clinical trials in oncology and nephrology, as well as in heart failure - as your article reports, had suggested that correction of anaemia using intravenous iron and erythropoietin- stimulating agents (ESA) might improve survival and quality of life of those treated. However, more recent blinded clinical trials in these areas do not support this data (1, 2). Additionally, there is concern in chronic kidney disease, that tailoring iron/ESA treatment to achieve higher Hb levels actually leads to higher mortality (3). In heart failure, lack of data regarding impact of iron/ESA supplementation on metabolism of iron in heart cells and long-term effect on cardiac function renders long-term outcome of patients difficult to predict. Nevertheless, as recommended in advanced heart failure(4), iron supplementation seems important in that myocardial iron load at the cellular level is reduced in the failing heart, as we have recently reported (5) and as done also by Maeder et al. (6) Furthermore, in heart failure patients, an increase in the main protein responsible for iron acquisition, myocardial transferrin receptor, (while iron deficient patients also have significantly reduced iron storage capacity due to decreased content of myocardial ferritin (M-FR) – the main iron storage protein), were shown (5). However, intravenous iron supplementation leads to increased plasma nontransferrin bound iron (NTBI) which might contain a potentially toxic form of iron that could exert a harmful effect related to the increase of a toxic cellular labile iron pool (7) (LIP - is defined as a weakly chelated iron that rapidly passes through the cell and probably consists of both forms of ionic iron (Fe2+ and Fe3+) associated with a variety of ligands with low affinity for iron ions). Although LIP accounts for a fraction of total cellular iron (3–5%), it may have deleterious effects on living cells (8). It was recently shown in animal models that downregulation of M-FR (heavy chain) increases LIP, oxidative stress and cell death in cardiomyocytes of the failing heart (9). Additionally, oxidative stress associated with inflammatory conditions frequently observed in HF accompanied by increase in NTBI may lead to an increase in the LIP via both transferring dependent and independent pathways and formation of highly reactive oxygen species, causing an increased myocyte loss, alteration of myocyte function by affecting several excitation–contraction coupling proteins, and interstitial fibrosis as well (10). Regarding serum iron homeostasis markers, traditionally preferred clinical serum markers for body iron stores are serum iron, transferrin saturation and ferritin of which, the last two are usually used as the main criterion for identifying an iron-deficient population. However, it was shown that transferrin saturation and ferritin only hardly reflect iron status (11). Rather, iron homeostasis can be better assessed on the basis of 1) serum transferin, its receptor TfR1, 2) ferritin concentration and 3) TfR1/logFR ratio. We also demonstrated that these markers reflected myocardial iron load and expression of heart proteins related to its metabolism (12). Finally we would like to reiterate the cautious final comment of authors: Intravenous iron has emerged as a well tolerated and effective therapy to improve symptoms and quality of life in both anaemic and non-anaemic HF patients with iron deficiency, however larger-scale and longer-term studies are necessary to confirm the safety and efficacy of this therapy in HF patients, especially in those without anaemia.
We read with interest the letter by Drs Leszek and Kruszewski in response to our review of anaemia in heart failure, Vol10 N°16. Authors make an elegant description of iron homeostasis and biochemical consequences of iron supplementation. We would like to comment some of the issues put forward. As we described previously in the e-journal of Cardiology Practice (1), iron deficiency (ID) is one of the most important causes of anaemia in heart failure (HF) patients. ID is defined using body iron status criteria: low serum iron concentration, transferrin saturation <10-15% and ferritin <100ng/ml (or 100-300 ng/ml and transferrin saturation < 20%). Classically, total iron dose required is calculated using the Ganzoni formula (2) (body weight (kg) x 2.4 x (15 – patient's haemoglobin (g/dl)) + 500 mg for stores).
1) Locatelli F, Becker H. Update on anemia management in nephrology, including current guidelines on the use of erythropoiesis-stimulating agents and implications of the introduction of "biosimilars", Oncologist 2009;14 Suppl 1:16-21.
2) Locatelli F, Gascón P. Is nephrology more at ease than oncology with erythropoiesis-stimulating agents? Treatment guidelines and an update on benefits and risks. Oncologist. 2009;14 Suppl 1:57-62. 3) Singh AK, Szczech L, Tang KL, Barnhart H, Sapp S, Wolfson M, Reddan D; CHOIR Investigators. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med. 2006 Nov 16;355(20):2085-98. 4) Silverberg DA, WexlerD, Iaina A, Schwartz D; The role of correction of anaemia in patients with congestive heart failure: a short review. Eur J Heart Fail. 2008 10: 819–823 5) Leszek P, Sochanowicz B, Szperl M, Kolsut P, Brzóska K, Piotrowski W, Rywik TM, Danko B, Polkowska-Motrenko H, Rózanski JM, Kruszewski M. Myocardial iron homeostasis in advanced chronic heart failure patients. Int J Cardiol. 2011 Sep 5 (Epub ahead of print) doi 10.1016/j.ijcard.2011.08.006 6) Maeder MT, Khammy O, dos Remedios C, Kaye DM. Myocardial and systemic iron depletion in heart failure implications for anemia accompanying heart failure. J Am Coll Cardiol. 2011 Jul 26;58(5):474-80. 7) Kruszewski M, Iwanenko T. Labile iron pool correlates with iron content in the nucleus and the formation of oxidative DNA damage in mouse lymphoma L5178Y cell lines. Acta Biochim Pol. 2003;50(1):211-5. 8) Kruszewski M. Labile iron pool: the main determinant of cellular response to oxidative stress. Mutat Res. 2003 Oct 29;531(1-2):81-92. Review. 9) Omiya S, Hikoso S, Imanishi Y, Saito A, Yamaguchi O, Takeda T, Mizote I, Oka T, Taneike M, Nakano Y, Matsumura Y, Nishida K, Sawa Y, Hori M, Otsu KJ. Downregulation of ferritin heavy chain increases labile iron pool, oxidative stress and cell death in cardiomyocytes. J Mol Cell Cardiol. 2009 Jan;46(1):59-66. Epub 2008 Oct 19. 10) Oudit GY, Trivieri MG, Khaper N, Liu PP, Backx PH. Role of L-type Ca2+ channels in iron transport and iron-overload cardiomyopathy. J Mol Med (Berl). 2006 May; 84(5): 349-64. Epub 2006 Apr 8. 11) Wish JB. Assessing Iron Status: Beyond Serum Ferritin and Transferrin Saturation. Clin J Am Soc Nephrol 2006 1: S4-S8 12) Leszek P, Sochanowicz B, Kolsut P, Brzoska K, Szperl M, Piotrowski W, Rywik T, Danko B, Rozanski J, Kruszewski. Serum transferrin receptor and its ratio to serum ferritin as the powerful markers in the proper characterization of myocardial iron load and homeostasis. Eur Heart J 2011; 32(suppl 1): 1119-1194
1) Peraira R, Núñez-Gil IJ. Anemia in heart failure: intravenous iron therapy. E-journal of Cardiology Practice, 2012. Vol 10 Nº 16. 2) Ganzoni AM. Intravenous iron-dextran: Therapeutic and experimental possibilities. Schweiz Med Wochenschr. 1970;100:301–3. 3) Tsushima RG, Wickenden AD, Bouchard RA, Oudit GY, Liu PP, Backx PH. Modulation of Iron Uptake in Heart by L-Type Ca2+ Channel Modifiers. Possible Implications in Iron Overload. Circ Res 1999;84:1302-1309 4) Oudit GY, Trivieri MG, Khaper N, Liu PP, Backx PH. Role of L-type Ca2+ channels in iron transport and iron-overload cardiomyopathy. J Mol Med (Berl). 2006 May; 84(5): 349-64. Epub 2006 Apr 8.
5) Leszek P, Sochanowicz B, Szperl M et al. Myocardial iron homeostasis in advanced chronic heart failure patients. Int J Cardiol (2011), doi:10.1016/j.ijcard.2011.08.006 6) Okonko DO, Grzeslo A, Witkowski T, et al. 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, 51:103-112. 7) Anker SD, Comin Colet J, Filippatos G, et al. Ferric Carboxymaltose in Patients with Heart Failure and Iron Deficiency. N Engl J Med 2009;361:2436-2448
Przemyslaw Leszek MD, PhD Heart Failure and Transplantology Dept., Institute of Cardiology, ul. Alpejska 42, 04-628 Warszawa, Poland Marcin Kruszewski MsC, PhD Center of Radiobiology and Biological Dosimetry, Institute of Nuclear Chemistry and Technology, ul. Dorodna 16, 03–195 Warszawa, Poland Independent Laboratory of Molecular Biology, Institute of Agricultural Medicine, ul. Jaczewskiego 2, 20-950 Lublin, Poland
Juan Roberto Peraira-Moral, MD, PhD Heart Failure Unit. Cardiology Department Instituto de Cardiología. Madrid, Spain Iván J Núñez-Gil, MD, PhD, FESC Coronary Care Unit. Cardiovascular Institute Hospital Clínico San Carlos, Madrid, Spain All Authors' Disclosures: None Declared.
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