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Archives of cardiovascular diseases
Volume 110, n° 2
pages 99-105 (février 2017)
Doi : 10.1016/j.acvd.2016.06.003
Received : 8 January 2016 ;  accepted : 16 June 2016
Absolute iron deficiency without anaemia in patients with chronic systolic heart failure is associated with poorer functional capacity
Insuffisance cardiaque avec dysfonction systolique : la carence martiale absolue est associée à une limitation fonctionnelle plus sévère

Joffrey Pozzo a, b, e, Pauline Fournier a, c, , Clément Delmas a, b, Paul-Louis Vervueren a, b, Jérôme Roncalli a, d, Meyer Elbaz a, b, Michel Galinier a, b, c, Olivier Lairez a, b, c, d
a Department of Cardiology, University Hospital of Rangueil, Toulouse, France 
b Rangueil Medical School, Paul Sabatier University, Toulouse, France 
c Cardiac Imaging Centre, Toulouse University Hospital, France 
d Purpan Medical School, Paul Sabatier University, Toulouse, France 
e Clinique Les Cèdres, Cornebarrieu, France 

Corresponding author at: Department of Cardiology, Toulouse University Hospital, 1, avenue Jean-Poulhès, TSA 50032, 31059 Toulouse Cedex 9, France.

Functional status is one of the main concerns in the management of heart failure (HF). Recently, the FAIR-HF and CONFIRM-HF trials showed that correcting anaemia using intravenous iron supplementation improved functional variables in patients with absolute or relative iron deficiency. Relative iron deficiency is supposed to be a marker of HF severity, as ferritin concentration increases with advanced stages of HF, but little is known about the impact of absolute iron deficiency (AID).


To study the impact of AID on functional variables and survival in patients with chronic systolic HF.


One hundred and thirty-eight non-anaemic patients with chronic systolic HF were included retrospectively. Patients were divided into two groups according to iron status: the AID group, defined by a ferritin concentration<100μg/L and the non-AID group, defined by a ferritin concentration100μg/L. Functional, morphological and biological variables were collected, and survival was assessed.


Patients in the AID group had a poorer 6-minute walking test (342 vs. 387m; P =0.03) and poorer peak exercise oxygen consumption (13.8 vs. 16.0mL/min/kg; P =0.01). By multivariable analysis, ferritin<100μg/L was associated with impaired capacity of effort, assessed by peak exercise oxygen consumption. By multivariable analysis, there was no difference in total mortality between groups, with a mean follow-up of 5.1±1.1 years.


The poorer functional evaluations in iron-deficient patients previously reported are not caused by the merging of two different populations (i.e. patients with absolute or relative iron deficiency). Our study has confirmed that non-anaemic HF patients with AID have poorer peak oxygen consumption. However, AID has no impact on the survival of these patients.

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Le statut fonctionnel du patient insuffisant cardiaque constitue un élément majeur de la qualité de vie et son amélioration un des buts du traitement. Récemment, les essais contrôlés FAIR-HF et CONFIRM-HF ont démontré que le fer intraveineux peut améliorer l’état fonctionnel des patients présentant une carence martiale absolue ou fonctionnelle. Cependant, à la différence d’une carence martiale absolue, une carence relative en fer ne pourrait être qu’un simple marqueur de la sévérité de l’insuffisance cardiaque, les taux de ferritine augmentant dans les stades avancés de l’insuffisance cardiaque en raison d’un état inflammatoire chronique.


Le but de cette étude est de déterminer si les patients insuffisants cardiaques non anémiques présentant une carence absolue en fer ont un statut fonctionnel et une survie différents des patients non carencés en fer.


Dans cette étude rétrospective, 138 patients insuffisants cardiaques avec altération de la fonction systolique ventriculaire gauche (FE<40 %) en stade 2 et 3 de la New York Heart Association, sans anémie, ont été inclus et séparés en 2 groupes en fonction de la valeur de la ferritinémie, inférieure ou supérieure à 100μg/L. Une évaluation fonctionnelle, morphologique et biologique a été effectuée. Une analyse de la survie en fonction de l’existence ou non d’une carence martiale absolue a été réalisée.


Les patients avec une carence martiale absolue (ferritinémie<100μg/L) présentaient une distance au test de marche de 6minutes (342 contre 387m ; p =0,03) et une consommation maximale d’oxygène à l’effort (13,8 contre 16,0mL/min/kg ; p =0,01) moindres que les patients sans carence absolue en fer (ferritinémie>100μg/L). En analyse multivariée, la ferritine inférieure à 100μg/L était associée à une altération de la capacité à l’effort, évaluée par VO2 max. En analyse univariée, aucune différence n’a été objectivée pour le risque de décès entre les deux groupes après un suivi moyen de 5.1±1.1 ans.


La diminution des performances fonctionnelles précédemment observée chez les patients carencés en fer n’est pas liée à la superposition de deux populations différentes : les patients présentant une carence martiale absolue ou fonctionnelle. Ces données confirment que les patients insuffisants cardiaques avec une carence martiale absolue ont une capacité maximale de consommation d’oxygène plus faible. Cependant, l’existence d’une carence martiale absolue n’influence pas la survie de ces patients.

The full text of this article is available in PDF format.

Keywords : Heart failure, Iron deficiency, Functional evaluation

Mots clés : Insuffisance cardiaque, Ferritinémie, Évaluation fonctionnelle

Abbreviations : AID, BNP, HF, LVEF, NYHA, peak VO2 , TSR


Improvement of dyspnoea and functional status still remains one of the main concerns in the treatment of heart failure (HF). It is now known that anaemia is a strong worsening factor for both functional status and survival in HF [1, 2, 3, 4]; its prevalence in HF ranges from 23% to 57% [5, 6]. Paradoxically, correction of anaemia by erythropoietin did not improve the prognosis of patients with HF in the RED-HF trial [7]. Although anaemia in HF can be multifactorial, iron deficiency remains the main cause and was shown recently to be a strong predictive factor for death and morbidity in a population that included anaemic and non-anaemic patients [8]. Numerous studies have demonstrated that correcting anaemia using intravenous iron administration leads to an improvement in functional variables (such as the Minnesota Living with Heart Failure Questionnaire, New York Heart Association [NYHA] stage or 6-minute walking test), renal function, B-type natriuretic peptide (BNP) concentration and left ventricular ejection fraction (LVEF) [9, 10, 11, 12, 13]. The recent FAIR-HF [14] and CONFIRM-HF [15] trials showed that intravenous iron supplementation by ferric carboxymaltose led to an improvement in functional variables in patients with iron deficiency, independent of anaemia. These results suggest that prognosis and functional status in HF are linked more to the iron deficiency than to the anaemia itself. Diagnosis of iron deficiency usually considers two different populations: patients with an absolute iron deficiency (AID), defined by a low ferritin concentration, indicating low iron reserve; and patients with a relative iron deficiency, defined by a normal or high ferritin concentration, but a low transferrin saturation rate (TSR). In this last group, low TSR is the result of iron sequestration secondary to an increase in haptoglobin, and despite a high production of ferritin induced by inflammation. Consequently, because ferritin concentration increases with inflammation in patients with advanced HF [16], we can suppose that the poorer functional status and survival of patients with relative iron deficiency are the result of a more advanced disease. The physiopathology of AID is very different and results from a decrease in iron stores.

The aim of our study was to investigate the impact of AID, independent of anaemia, on the functional status and survival of patients with chronic systolic HF.


Patients referred to our tertiary centre for HF at the University Hospital of Toulouse for optimisation of their therapy, implantation of a cardioverter defibrillator, multisite pacing, or evaluation of heart transplantation or assistance device indication were included retrospectively between January 2007 and December 2008. All patients had undergone coronary angiography within the past 2 years, and the diagnosis of ischaemic cardiomyopathy was retained when there was>50% stenosis of at least one principal coronary artery. Patients with decompensated HF, defined by the exacerbation of typical symptoms of HF within the last month, or anaemia, defined by a haemoglobin concentration<13.0g/dL in men or<12.0g/dL in women, were excluded from the study. Patients without anaemia were separated into two groups: patients with AID, defined by a ferritin concentration<100μg/L and patients without AID, defined by a ferritin concentration100μg/L.

Clinical testing

Functional variables (including NYHA stage, 6-minute walking test and peak oxygen consumption [peak VO2 ]), LVEF and BNP were compared between groups. Peak VO2 was assessed with a cycling ergometer; the protocol started at 20W, with an increase of 10W each minute, and consisted of measuring the maximal oxygen uptake in last 30seconds of a maximal effort. The 6-minute walking test consisted of measuring the maximal distance covered by the patient in 6minutes. LVEF was determined by transthoracic echocardiography, using the conventional apical two- and four-chamber views and the modified Simpson's biplane method.


Clinical follow-up was done by a telephone interview with the patient's general practitioner or cardiologist, with the patient or with their family. The outcome event examined was all-cause mortality. Patients who underwent cardiac transplantation during follow-up were considered as dead at the date of intervention. Patients without contact for up to 6 months were considered as lost to follow-up and were excluded from the survival analysis.

Statistical analysis

Continuous variables were tested for normal distribution using the Kolmogorov–Smirnov test and are expressed as means±standard deviations. Categorical data are expressed as numbers and percentages. Age, BNP, haemoglobin, creatinine and LVEF were considered in tertiles because of a lack of linearity. Ferritin was analysed as a dichotomous variable (<100μg/L or100μg/L). The association between categorical variables was investigated by the χ 2 test and the mean values of continuous variables were compared using Student's t test. Correlation between variables was assessed using Spearman's test or Pearson's test when required, and is expressed as r . All-cause mortality was summarized using Kaplan–Meier survival curves, and the log-rank test was used for initial comparisons. A stepwise selection was done using a P to remove from and a P to enter into the model of 0.05, with previous backward selection after inclusion of all selected variables (saturated model) and then forward selection. The P value refers to the likelihood ratio test of the hypothesis that the regression coefficient was zero. Results are expressed as relative risks with 95% confidence intervals. A significant increase in risk is obtained if the 95% confidence interval excludes 1 and the Wald test P value is<0.05. Differences were considered statistically significant for P values<0.05. All analyses were performed using StatView, version 5 (SAS Institute Inc., Cary, NC, USA).

Population characteristics

Among the 202 patients screened, 64 (31.6%) patients had anaemia and were excluded from the analysis. Among the 138 patients included, the mean age was 60.9±14.5 years, 69 (50%) were men, and the rate of ischaemic aetiology was low (35.2%). Population characteristics according to iron deficiency are presented in Table 1. As already described in the general population, there were more women in the AID group than in the non-AID group (64% vs. 26%; P =0.01). Sex was strongly correlated with iron deficiency (R=0.64; P <0.001); for the total population of non-anaemic patients, AID was found in 36 (52%) women versus 10 (15) men (P <0.001). The mean ferritin concentration was 487±714μg/L for men and 113±66μg/L for women (P <0.001).


The mean ferritin concentration was 62±45μg/L in the AID group and 426±637μg/L in the non-AID group (P <0.001). The AID group had a higher creatinine concentration (135±155 vs. 108±32μmol/L; P =0.05; Figure 1). BNP concentrations were significantly higher in the AID group (818±867 vs. 619±723pg/mL; P =0.046) (Figure 2). There was no significant difference in serum iron concentration between groups (13.3±7.1 in the AID group vs. 15.7±8.8mg/L in the non-AID group; P =0.13).

Figure 1

Figure 1. 

Comparison between heart failure patients with or without absolute iron deficiency (AID) in terms of (A) creatinine concentration, (B) creatinine clearance calculated with the Modification of Diet in Renal Disease (MDRD) formula or (C) creatinine clearance calculated with the Cockcroft and Gault formula.


Figure 2

Figure 2. 

Comparison between heart failure patients with or without absolute iron deficiency (AID) according to B-type natriuretic peptide (BNP) concentration and functional status, assessed by New York Heart Association (NYHA) stage of dyspnoea, 6-minute walking test (6MWT) and peak oxygen consumption (peak VO2 ).


Functional status

There was no difference in NYHA stage between groups, with a mean NHYA stage of 2.3±0.7 in the AID group vs. 2.5±0.7 in the non-AID group (P =0.11) (Figure 2). Most of the patients were classified as NYHA II (50% in the IAD group vs. 58% in the non-AID group; P =0.42).

Patients with AID had a reduced walking distance, assessed by the 6-minute walking test (342±111 vs. 387±109m for patients without AID; P =0.03), and a lower peak VO2 (13.8±4.5 vs. 16.0±5.5mL/min/kg for patients without AID; P =0.049) (Figure 2). By multivariable analysis, AID was associated with reduced exercise capacity, assessed by peak VO2 , independent of age, sex, creatinine, BNP and LVEF (coefficient of regression −3.04; P =0.024).


Twenty-two (15.9%) patients were missing from follow-up: eight (17%) in the AID group and 14 (15%) in the non-AID group (P =0.42). Among the other 116 patients, the mean follow-up time was 5.1±1.1 years. Kaplan–Meier survival plots for patients with systolic HF according to the presence of AID are shown in Figure 3. Mortality occurred in 50 (43.1%) patients, without difference between groups (15 [39%] in the AID group vs. 35 [45%] in the non-AID group; P =0.37). By univariate analysis there was no difference in all-cause mortality between the two groups (hazard ratio 0.98, 95% confidence interval 0.47–2.03).

Figure 3

Figure 3. 

Survival of patients with systolic heart failure according to the presence of absolute iron deficiency (AID).



Our study shows, by multivariable analysis, that the functional capacity of patients with chronic systolic HF, assessed by peak VO2 , is altered in patients with AID compared with patients without AID. This alteration of functional capacity has no impact on all-cause mortality after a mean follow-up of 5 years. These results are not explained by a difference in the severity of HF, as the LVEF and BNP concentrations were the same. It is well known that iron deficiency can lead to a worse functional status, by causing anaemia. However, because patients with anaemia were excluded from our study, our results suggest that AID per se may affect the response of the metabolism to exercise in patients with chronic systolic HF, without modifying the natural history of the disease.

In patients with HF, AID can be the consequence of a decrease in iron intake or absorption because of intestinal mucosal oedema. Relative iron deficiency can be the consequence of inappropriate expression of hepcidin associated with HF [17]. Iron is involved in the synthesis and function of numerous enzymes and proteins involved in oxygen transport and storage, electron transfer and oxidation-reduction; its role is particularly essential for the function of mitochondria via the iron-sulphur enzymes (i.e. cytochrome c, enzymes of the mitochondrial respiratory chain) [18, 19]. Iron deficiency induces a decrease in the mitochondrial content of these enzymes [20] and in mitochondrial oxidative capacity [21]. Furthermore, iron plays a crucial role in the transport of oxygen, independent of haemoglobin. Indeed, myoglobin is a haemoprotein that increases diffusion of dioxygen from capillary red cells to mitochondria; its concentration in skeletal muscle is drastically reduced (by 40–60%) in iron deficiency [22]. It is probable that, if anaemia limits the capacity of the individual to deliver oxygen to exercising muscle, tissular iron deficiency limits the capacity of the individual to perform oxidative metabolism. Indeed, Dallman, in a model of iron-deficient transfused animals, established a strong negative correlation between iron tissue deficiency and exercise endurance [23, 24]. These results suggest a direct role for iron deficiency in the reduction in exercise capacity.

One of the main issues is how to diagnose AID. There are many ways to diagnose AID, such as low ferritin concentration, low serum iron concentration, low TSR or high soluble transferrin receptor but standards vary according to sex and pathological context, such as inflammation or liver disease. In most of the trials in HF, the standards used for AID were ferritin concentration<100μg/L or between 100 and 300μg/L with TSR<20% [12, 13, 14]. In the general population without iron deficiency, Jacobs et al. found a mean ferritin concentration of 69μg/L in men and 35μg/L in women [25]. The normal value for ferritin concentration in our laboratory is between 15 and 200μg/L for women and between 20 and 300μg/L for men in the general population (chemoluminescence using Cobas 6000; Roche Diagnostics, Risch-Rotkreuz, Switzerland). In the particular case of renal failure, Kalantar-Zadeh et al. demonstrated, by using bone marrow iron as a the reference standard, that a ferritin concentration<200μg/L had a specificity of 100% but a sensitivity of only 41%, and that TSR<20% had a sensitivity of 88%, but a specificity of only 63% [26]. In the HF setting, the ferritin concentrations for the definition of AID are higher than in the general population. The reasons for higher ferritin concentrations in HF are not completely understood. Besides being a marker for the measurement of iron stores, ferritin acts also as an inflammatory acute phase protein, which can lead to an increase in ferritin concentration, potentially masking an AID status in HF patients. Advanced HF is an inflammatory state, with elevated concentrations of proinflammatory cytokines. Furthermore, ferritin concentration can also increase as a result of primary (hereditary haemachromatosis) or secondary (ineffective erythropoiesis) iron overload, liver disease, alcoholism or malignancies [27]. AID assessed by measurement of serum ferritin is highly underestimated compared with bone marrow biopsies [26]. Based on the FAIR-HF study, the recent European Society of Cardiology guidelines for HF define iron deficiency for HF differently, as a ferritin concentration<100μg/L or a ferritin concentration of 100–299μg/L when TSR is<20%.

Study limitations

Our study was a single-centre observational study and patients were referred for third-line management. Thus, the studied population is not representative of ambulatory HF patients. Patients were young, with a low rate of ischaemic cardiomyopathy and frequent severe systolic left ventricular dysfunction. Secondly, in this retrospective study, TSR was not measured at inclusion. Patients were included between January 2007 and December 2008, and assessment of transferrin saturation was added to the European guidelines from 2012 [28]. Consequently, it was not integrated into the study and this did not allow the determination of patients with functional iron deficiency. Thirdly, about 16% of patients were lost to follow-up. This can be explained by the duration of the mean follow-up time, which was 5.1±1.1 years. However, there was no difference in loss to follow-up between groups.


Patients with HF with absolute biological iron deficiency without anaemia have a poorer functional capacity assessed by peak VO2 and the 6-minute walking test, but we could not show any difference in terms of survival at more than 5 years. Further studies are required to confirm this result.

Sources of funding


Disclosure of interest

The authors declare that they have no competing interest.


We would like to thank Sandrine Mazon and Françoise Layrac for their technical support.


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