Rebuttal
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.
Authors' response
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).
In comparison with iron status parameters, iron homeostasis markers, such as serum soluble Transferrin Receptor, could help better assess HF patients in which intravenous iron therapy is indicated. Iron homeostasis markers may be also useful during follow-up in order to prevent iron overload and show ID improvement as well.
Regarding the clinical benefit of intravenous iron therapy, using the Ganzoni formula (described above), encouraging randomised papers in HF patients have been done (6,7). Although we agree we need to be cautious regarding the theoretical harmful effects of this therapy, mostly since we lack long-term studies, available data point out it could have true benefit. However, further studies showing usefulness of iron homeostasis markers for adjusting intravenous iron dosage (and prevent iron overload) are needed.
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