Myocardial iron homeostasis in advanced chronic heart failure patients☆
Introduction
Chronic heart failure (HF) is commonly accompanied by iron deficiency and/or anemia that seem to be an important contributors to HF worsening, increased mortality, hospitalization and morbidity rates [1], [2]. Several open label studies have shown that the correction of anemia with iron together with erythropoietic agents might be beneficial in an adequately selected group of patients [3], [4], [5], [6], [7]. Recently, it was shown also that the correction of iron deficiency with the use of iv iron supplementation in patients with HF even without anemia may result in their short-term clinical improvement, however the long-term outcome is unpredictable [2], [8], [9]. Studies on inclusion criteria and qualification for iron replenishment therapy were based only on serum iron markers, such as transferrin saturation and ferritin level.
Anemia is also commonly seen in patients with chronic kidney disease, however, since the recent studies showed an increased risk of primary composite end point (components: hospitalization for HF, myocardial infarction, stroke, death) and hospitalization for cardiovascular causes in the high-hemoglobin group [10], [11] the Anemia Guideline Committee of the Dialysis Outcomes Quality Initiative restrictively updated its guidelines.
Yet little is known about myocardial iron load in the failing heart, a proper characterization of iron homeostasis in HF seems important, as the additional iron supplementation could potentially exert a harmful effect related to production of intracellular reactive oxygen species (ROS) [12], [13], [14]. In addition iron-induced oxidative damage can not only alter myocyte function affecting directly the function of several excitation-contraction coupling proteins but also increase myocyte loss and interstitial fibrosis [15]. Moreover elevated iron may also affect the function of endothelial and smooth muscle cells, which can additionally affect myocardial perfusion and function [16], [17].
Thus, the purpose of our study was to assess the myocardium iron load (M-Iron) and the alteration in the level of ferritin (M-FR) and soluble transferrin receptor (M-sTfR) in the failing myocardium with regard to well established serum iron markers. M-FR is the main iron storage protein, whereas M-sTfR takes part in iron acquisition.
Section snippets
Study population
The study group comprised of 33 consecutive patients referred to heart transplantation (OHT). Myocardial studies were performed in failing ventricular myocardium (FH) obtained during transplantation. Before transplantation all patients with chronic renal insufficiency, hematological, thyroid diseases or known disease that caused gastrointestinal bleeding, were excluded from the study.
Myocardium from 10 non-failing hearts (NFH) of male subjects aged 22–47 years who had died from head trauma and
Study group
The study group consisted of 33 consecutive patients (25 males, 8 females), mean age 48 years, with chronic advanced HF due to idiopathic (n = 10), ischemic (n = 21), hypertrophic (n = 1) or restrictive (n = 1) cardiomiopathy (Table 1).
Despite optimal pharmacological therapy, consisting of angiotensin-converting enzyme inhibitors, aldosterone antagonists, β-blockers and diuretics, the patients remained symptomatic and were referred to heart transplantation. All participants had HF symptoms, classified
Discussion
Iron participates in crucial biological events, including processing of dioxygen, a prerequisite of aerobic metabolism. As a component of many enzymes (including oxidative and respiratory chains) it plays an important role in catalysis and energy production. The same redox properties that allow iron to be a functional enzymatic cofactor also make this metal a key participant in oxygen-mediated toxicity as the trace amounts of unshielded iron ions can give rise to the highly toxic hydroxyl
Acknowledgement
The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology [32].
References (32)
- et al.
The use of subcutaneous erythropoietin and intravenous iron for the treatment of the anemia of severe, resistant congestive heart failure improves cardiac and renal function and functional cardiac class, and markedly reduces hospitalizations
J Am Coll Cardiol
(2000) - et al.
Effect of darbepoetin alfa on exercise tolerance in anemic patients with symptomatic chronic heart failure: a randomized, double-blind, placebo-controlled trial
J Am Coll Cardiol
(2007) - et al.
Mortality and target haemoglobin concentrations in anaemic patients with chronic kidney disease treated with erythropoietin: a meta-analysis
Lancet
(2007) - et al.
Labile plasma iron in iron overload: redox activity and susceptibility to chelation
Blood
(2003) Labile iron pool: the main determinant of cellular response to oxidative stress
Mutat Res
(2003)- et al.
Downregulation of ferritin heavy chain increases labile iron pool, oxidative stress and cell death in cardiomyocytes
J Mol Cell Cardiol
(2009) Anemia in heart failure time to rethink its etiology and treatment?
J Am Coll Cardiol
(2006)- 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) - et al.
Etiology of anemia in patients with advanced heart failure
J Am Coll Cardiol
(2006) - et al.
Is anemia in chronic heart failure caused by iron deficiency?
J Am Coll Cardiol
(2007)
Assessment of iron status
Clin Biochem
Ethics in the authorship and publishing of scientific articles
Int J Cardiol
Anemia is common in heart failure and is associated with poor outcomes: insights from a cohort of 12 065 patients with new-onset heart failure
Circulation
The impact of new onset anaemia on morbidity and mortality in chronic heart failure: results from COMET
Eur Heart J
The safety and tolerability of darbepoetin alfa in patients with anaemia and symptomatic heart failure
Eur J Heart Fail
Randomized, double-blind, placebo-controlled study to evaluate the effect of two dosing regimens of darbepoetin alfa in patients with heart failure and anaemia
Eur Heart J
Cited by (72)
Relationship between iron deficiency and expression of genes involved in iron metabolism in human myocardium and skeletal muscle
2023, International Journal of CardiologyTriad role of hepcidin, ferroportin, and Nrf2 in cardiac iron metabolism: From health to disease
2022, Journal of Trace Elements in Medicine and BiologyCitation Excerpt :Clinical trials including that of Myocardial-IRON, which has 53-participants, and of AFFIRM-AHF, an extended trial with 1132 participants, has shown that correcting the iron deficiency through intravenous (IV) ferric carboxymaltose improves the rate of hospitalization for HF and cardiac structure and function [191–193]. The serum-soluble transferrin receptor (sTfR) has been proposed as an accurate marker of iron status/erythropoiesis since it is unaffected by inflammation [194,195], unlike HEP, FPN or FT [196–198]. Interestingly, a recent large cohort study (AtheroGene) detected that iron deficiency mediated an increase in sTfR levels, which is strongly associated with prospect myocardial infarction or cardiovascular death [199,200].
Systemic iron deficiency does not affect the cardiac iron content and progression of heart failure
2021, Journal of Molecular and Cellular CardiologyBenefits of intravenous iron supplementation in heart failure
2024, Global Cardiology Science and PracticeIron Dyshomeostasis and Mitochondrial Function in the Failing Heart: A Review of the Literature
2024, American Journal of Cardiovascular Drugs
- ☆
The study was supported by the Polish Ministry of Science Grant (5038/B/P01/2011/40).