Objective: To assess the prognostic significance of iron deficiency (ID) in a chronic heart failure (CHF) outpatient population. Methods and Results: We prospectively evaluated 127 patients with stable CHF and left ventricular ejection fraction ≤45%. Clinical and analytical data as well as information regarding the occurrence of the composite endpoint of overall mortality and nonfatal cardiovascular events were assessed. Among the 127 patients enrolled [81% men, median age: 62 years (25th-75th percentile: 53-68)], 46 (36%) patients had ID. Women, patients with higher plasma brain natriuretic peptide levels (>400 pg/ml) and with right ventricular systolic dysfunction presented ID more frequently (p < 0.05 for all). At 225 ± 139 days of follow-up, the composite endpoint occurred in 15 (12%) patients. It was more frequent in ID (24 vs. 5%, p = 0.001) and anemic patients (25 vs. 8%, p = 0.014). In a Cox regression analysis, ID was associated with a higher likelihood of composite endpoint occurrence (HR 5.00, 95% CI 1.59-15.78, p = 0.006). In a multivariable analysis adjusted for clinical variables, including the presence of anemia, ID remained a significant predictor of the composite endpoint (HR 5.38, 95% CI 1.54-18.87, p = 0.009). Conclusion: In a CHF outpatient population, ID carried a higher risk of unfavorable outcome, irrespectively of the presence of anemia.

A great number of patients with chronic heart failure (CHF) remain symptom limited, exercise intolerant and subject to high rates of hospitalization and mortality in spite of optimal conventional therapy [1]. Anemia and iron deficiency (ID) are common in CHF patients and both are reported to have negative consequences [2, 3, 4]. In the past, the presence of ID was only considered clinically relevant in the presence of anemia. Although ID can often be detected in anemic CHF patients, almost one third of the patients with CHF and without anemia can present ID [2, 4].

Iron is an important part in many human biochemical reactions. Besides its role in hemoglobin synthesis, iron is essential to oxygen transport and storage, oxidative metabolism in skeletal and heart muscle, immune system regulation and protein transcription [5]. Because of its central role in oxygen transport and delivery, a frequent consequence of ID is poor exercise tolerance in patients with CHF [6]. Average daily iron intake is 10-20 mg but only a small amount (10-20%) of dietary iron is usually absorbed by specific transport systems, mainly duodenal enterocytes. Dietary iron is absorbed using distinct transmembrane transport systems and it is delivered to tissues through the plasma iron transport protein transferrin. Transferrin binds to transferrin receptor-1 on the cell membrane and is internalized by receptor-mediated endocytosis. Iron is used for cellular processes, and excess iron is stored within the protein ferritin [5, 7]. Systemic iron homeostasis may be deranged in heart failure (HF) [7]. CHF patients are predisposed to suffer from ID, given the gradual decrease of iron stores (absolute ID) due to low iron intake, gastrointestinal blood loss or iron malabsorption. Chronic inflammation causes the activation of proinflammatory cytokines, which, in turn, reduce iron absorption and availability of iron to target tissues and organs. This may happen in spite of appropriate iron stores inside the cells of the reticuloendothelial system, a condition described as functional ID [7]. In absolute ID, iron stores are decreased [7].

The scientific community became more alert to this issue as the evidence of a negative impact of absolute or functional ID on morbidity in CHF patients grew. Besides, intravenous iron supplementation in ID CHF patients has been proved to have a positive impact on the functional status, the quality of life and exercise capacity of both anemic and nonanemic patients [8, 9, 10, 11]. These findings reinforce ID as a potential therapeutic target in HF [10].

Until now, few studies have reported ID as an independent predictor of outcome in CHF [4, 12, 13]. In addition, comparison of the prognostic influence of ID per se, in anemic versus nonanemic CHF patients, has not yet been addressed. Therefore, this study assesses the prevalence, determinants and prognostic significance of ID irrespective of anemia in a systolic CHF outpatient population.

This prospective, observational study included ambulatory CHF patients who were clinically stable in the last 3 months, with a left ventricular ejection fraction (LVEF) of ≤45% (assessed by the echocardiographic planimetric Simpson method). Exclusion criteria were hospitalization due to HF deterioration, acute coronary syndrome, coronary revascularization or any major surgery within the 3 months preceding the study; any acute/chronic illness other than HF that might influence iron metabolism (including known malignancy, active bleeding, infection, severe renal disease requiring dialysis, and hematological diseases), and treatment for anemia and/or ID (blood transfusions, erythropoietin therapy, iron supplements) within the past 6 months.

Demographic, clinical and echocardiographic information and laboratory data were collected during the screening phase of this project. The study protocol was approved by the local ethic committees, and all subjects gave written informed consent. The study was conducted in accordance with the Helsinki Declaration.

Iron Status and other Laboratory Measurements

In all patients, peripheral venous blood samples were obtained in the morning following an overnight fast. Hematologic indices were assessed from fresh venous blood with EDTA in the same local laboratory. Serum concentrations of iron, ferritin and transferrin were measured. Transferrin saturation (TSAT) was calculated based on the local laboratory converter factor as a ratio of 71.24 × serum iron/transferrin, multiplied by 100 (http://www.pubinfo.vcu.edu/pathLabs/calc/transferrin.html) [14]. In addition, complete blood count, plasma concentration of brain natriuretic peptide (BNP), creatinine and electrolytes were evaluated using standard techniques.

Definitions

ID was defined prospectively as serum ferritin <100 mg/l (absolute ID) or serum ferritin 100-299 mg/l in combination with TSAT <20% (functional ID). Similar definitions of ID have been used in recent observational and intervention trials in CHF [9, 11]. Anemia was defined as a hemoglobin level <12 g/dl in women and <13 g/dl in men, according to the corresponding WHO cut-offs [15]. Renal function was assessed using the estimated glomerular filtration rate (GFR) calculated from the modification of diet in the renal disease study equation [16]. Chronic kidney disease was defined as an estimated baseline GFR of <60 ml/min/1.73 m2 for 3 months or more, irrespective of the cause.

Follow-Up

The composite endpoint for the present study was overall mortality and nonfatal cardiovascular events (hospitalization for congestive HF, acute coronary syndrome, severe arrhythmia or stroke). Information regarding survival and clinical status was obtained directly from the patients or their relatives and from the hospital clinical records. The patients were followed at our outpatient CHF clinic (every 3-6 months, unless there was a clinical need for an extra visit).

Statistical analyses

Continuous variables with normal distribution were expressed as mean ± SD and skewed variables as median and quartiles. Categorical variables were expressed as percentages. The comparison of continuous variables with normal distribution was performed by an independent sample t test (Mann-Whitney U test for skewed variables). For categorical variables, the χ2 test was used. The associations between the analyzed variables and composite endpoint were established using Kaplan-Meier curves and Cox proportional hazards analyses (both univariate and multivariable models).

The baseline clinical characteristics of the 127 recruited patients are shown in table 1. ID was diagnosed in 46 patients, corresponding to a prevalence of 36%, with a slight nonsignificant predominance in the anemic group (43 vs. 34%, p = 0.408). Thirty-four patients (74%) had ID without anemia. From the 46 ID patients, 26 (57%) presented absolute ID and 20 (43%) functional ID. Anemia was present in 22% of the population, but patients with ID did not have anemia more frequently than those without.

Table 1

Baseline clinical characteristics

Baseline clinical characteristics
Baseline clinical characteristics

Female sex, plasma BNP levels >400 pg/ml, right ventricular systolic dysfunction (RVSD) and loop diuretics therapy were more frequent in patients with ID than in those without ID (table 1). No other significant differences were found in the baseline characteristics of the groups and of the patients with absolute ID comparing to those with relative ID.

No patient was lost to follow-up. At 225 ± 139 days of follow-up, the composite endpoint occurred in 15 (12%) patients: 1 (0.8%) cardiovascular death, 9 (7.1%) hospitalizations for HF, 3 (2.4%) for stroke and 2 (1.6%) for arrhythmia. It was more frequent in ID than in non-ID patients (24 vs. 5%, p = 0.001) and in anemic than in nonanemic patients (25 vs. 8%, p = 0.014). The composite endpoint occurred more frequently in patients with a BNP level >400 pg/ml than in those with a level ≤400 pg/ml (28 vs. 7%, p = 0.008). Patients in whom the primary endpoint occurred had a more advanced New York Heart Association (NYHA) functional class (2.2 ± 0.6 vs. 1.8 ± 0.6, p = 0.009) and a lower LVEF (20.0 ± 7.1 vs. 28.7 ± 8.9%, p < 0.001).

In univariate Cox regression analysis, ID was the variable associated with the second highest likelihood of composite endpoint occurrence. In the multivariable analysis adjusted for relevant variables, ID but not anemia or any other variable remained an independent predictor for the composite endpoint (OR 5.38, 95% CI 1.54-18.87, p = 0.009) (table 2).

Table 2

Univariate and multivariate regression analysis for the composite endpoint

Univariate and multivariate regression analysis for the composite endpoint
Univariate and multivariate regression analysis for the composite endpoint

On average, ID patients had a 5-fold greater risk for the composite endpoint than iron-replete patients with or without anemia, and this finding is adequately illustrated by the Kaplan-Meier curves in figure 1.

Fig. 1

Kaplan-Meier plot of the 1-year event-free survival curves for patients with and without ID.

Fig. 1

Kaplan-Meier plot of the 1-year event-free survival curves for patients with and without ID.

Close modal

A stratified analysis for the absence or presence of anemia regarding prognosis is illustrated by the Kaplan-Meyer curves in figure 2. ID remained a strong predictor of poor outcome in nonanemic patients (HR 5.77, 95% CI 1.16-28.76, p = 0.032). In the presence of anemia, ID patients also tended to show a greater risk for the composite endpoint than iron-replete patients, although this association did not achieve statistical significance (HR 4.13, 95% CI 0.77-22.03, p = 0.097).

Fig. 2

Kaplan-Meier plot of the 1-year event-free survival curves for patients with and without ID in an anemic (a) and a nonanemic population (b).

Fig. 2

Kaplan-Meier plot of the 1-year event-free survival curves for patients with and without ID in an anemic (a) and a nonanemic population (b).

Close modal

ID and Anemia Prevalence

The prevalence of anemia (WHO definition) in CHF is estimated to lie within the range of 17-50%, with a lower prevalence in mild CHF and a higher prevalence in severe CHF [2, 3, 17]. In this population, the anemia prevalence was 22%, which is in agreement with the fact that most patients were in NYHA classes I and II.

Data on ID prevalence in CHF patients is scarce and has been reported to vary between 21 and 57% in anemic patients and between 32 and 65% in nonanemic patients [2, 4, 12]. ID prevalence was 36% in our study and it was more often observed in anemic patients. However, the difference was not statistically relevant. The relatively small sample size and the small proportion of anemic patients may have interfered with the detection of between-group differences regarding ID. On the other hand, this non-association underlines the independent role of these two comorbidities (anemia and ID) in HF. Moreover, this population may not be comparable to other similar study populations, as the prevalence of ischemic etiology (35%) in this cohort is much lower than the prevalence reported in other similar studies (60-65%) [4, 18]. It is relevant to notice that a significant percentage of patients (27%) had ID without anemia.

ID and Disease Severity

Recent studies have shown a close relation between ID and disease severity in CHF populations [12, 18]. In this cohort, ID was also associated with higher plasma BNP levels, which is in accordance with the literature [4, 18]. In addition, RVSD and loop diuretics use, both indicators of more advanced HF status, were more frequently observed in ID patients. A trend towards a higher number of cardiac resynchronization therapy device implantations in ID patients was also found. The non-association of ID with NYHA functional class may be a consequence of the homogeneous functional status of the patients.

This study also pointed to a relation between ID and female sex, which had already been described by Jankowska et al. [4] and Okonko et al. [12]. In fact, women tend to have lower iron stores than men, mainly due to the menstrual bleeding [19]. An increased iron need during pregnancy and lactation also predisposes to ID and anemia in women [19].

ID and Prognosis

Only a few studies have reported on ID as an outcome predictor in CHF [4, 12, 13]. Moreover, available data are conflicting. Jankowska et al. [4] and Okonko et al. [12] mentioned ID as a predictor of mortality. On the other hand, a recent observation study by Parikh et al. [20] did not find an association between all-cause or cardiovascular mortality and ID, but the diagnosis of HF was made through patient self-reports, and the study did not exclude HF with preserved ejection fraction. Our study shows that ID is a predictor of poor outcome, independent of other well-established prognostic markers. In a stratified analysis, ID remained an important predictor of the composite endpoint in both anemic and nonanemic patients. However, in the anemic patient group, this association did not achieve statistical significance. This may be explained by the relatively small number of anemic patients of the study population. Three controlled randomized studies [9, 11, 13] have mentioned intravenous iron therapy as beneficial in functional status in patients with systolic CHF with or without anemia. Nowadays, the European guidelines for the management of CHF already recommends the routine evaluation of iron status and the repletion of iron stores in symptomatic patients with systolic CHF and ID in order to improve functional status and quality of life [10].

Our results, by reinforcing the prognostic relevance of ID, bring new insights about the importance of iron supplementation as a therapeutic approach in patients with CHF with or without anemia. The positive impact may involve not only exercise tolerance and quality of life but also prognosis. Until now, randomized clinical trials did not show any relevant changes towards mortality rates, which may be related to the short duration of the follow-up period. Nevertheless, in the future, long-term follow-up randomized studies will surely assess this hypothesis. On the other hand, intravenous iron reposition should be administered with caution, avoiding the risk of iron overload. The term iron overload cardiomyopathy (IOC) has recently been introduced to describe a secondary form of cardiomyopathy resulting from the accumulation of iron in the myocardium [21]. IOC may be characterized by a restrictive cardiomyopathy with prominent early diastolic dysfunction, which invariably progresses to an end-stage dilated cardiomyopathy with left ventricular remodeling with chamber dilatation and reduced LVEF [21, 22]. Right HF can also be present early in the course of disease [21]. Until now, there is no evidence that HF patients under adequately monitored intravenous iron treatment are at a higher risk of IOC.

This study was observational, which means that it may not be correct to establish any causal associations between variables. It should be noted that our cohort differed from the general population with systolic CHF because our patients were younger, were most frequently men and had a higher prevalence of a nonischemic etiology of HF. Furthermore, this study did not address temporal trends of iron or hemoglobin levels.

Levels of C-reactive protein, hepcidin and interleukin-6 had already been related to ID [7]. In our study, iron kinetics parameters were the base for the absolute and functional ID definition, and we did not collect inflammatory markers. The composite endpoint was reached in most cases because of the occurrence of HF hospitalizations; thus, no conclusions on mortality can be drawn.

In our CHF population, ID was a common finding affecting 36% of the patients, independent of the presence of anemia. ID was an independent predictor of unfavorable outcome, irrespective of anemia. This study reinforces that iron status evaluation can be useful in the routine assessment of patients with systolic CHF and can stratify the prognosis.

None declared.

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