Author + information
- Received October 18, 2010
- Revision received April 14, 2011
- Accepted April 19, 2011
- Published online September 13, 2011.
- Darlington O. Okonko, MBBS⁎,⁎ (, )
- Amit K.J. Mandal, MBBS†,
- Constantinos G. Missouris, MD† and
- Philip A. Poole-Wilson, MD, FMedSci⁎
- ↵⁎Reprint requests and correspondence:
Dr. Darlington O. Okonko, 73D Babington Road, London SW16 6AN, United Kingdom
Objectives The aim of this study was to comprehensively delineate iron metabolism and its implications in patients with chronic heart failure (CHF).
Background Iron deficiency is an emerging therapeutic target in CHF.
Methods Iron and clinical indexes were quantified in 157 patients with CHF.
Results Several observations were made. First, iron homeostasis was deranged in anemic and nonanemic subjects and characterized by diminished circulating (transferrin saturation) and functional (mean cell hemoglobin concentration) iron status in the face of seemingly adequate stores (ferritin). Second, while iron overload and elevated iron stores were rare (1%), iron deficiency (transferrin saturation <20%) was evident in 43% of patients. Third, disordered iron homeostasis related closely to worsening inflammation and disease severity and strongly predicted lower hemoglobin levels independently of age, sex, erythrocyte sedimentation rate, New York Heart Association (NYHA) functional class, and creatinine. Fourth, the etiologies of anemia varied with disease severity, with an iron-deficient substrate (anemia of chronic disease and/or iron-deficiency anemia) evident in 16%, 72%, and 100% of anemic NYHA functional class I or II, III, and IV patients, respectively. Although anemia of chronic disease was more prevalent than iron-deficiency anemia, both conditions coexisted in 17% of subjects. Fifth, iron deficiency was associated with lower peak oxygen consumption and higher ratios of ventilation to carbon dioxide production and identified those at enhanced risk for death (hazard ratio: 3.38; 95% confidence interval: 1.48 to 7.72; p = 0.004) independently of hemoglobin. Nonanemic iron-deficient patients had a 2-fold greater risk for death than anemic iron-replete subjects.
Conclusions Disordered iron homeostasis in patients with CHF relates to impaired exercise capacity and survival and appears prognostically more ominous than anemia.
Despite optimal conventional therapy, many patients with chronic heart failure (CHF) remain symptom limited, exercise intolerant, and subject to high rates of mortality. The persistence of such poor outcomes suggests that additional adverse phenomena remain unmitigated by current therapeutic strategies and endure to accelerate disease progression.
Systemic iron homeostasis is frequently deranged in chronic disorders (1–5), but the integrity of iron metabolism in CHF is poorly characterized. Prior analyses are sparse and have largely been conducted in anemia patients (6,7) or based solely on serum iron and ferritin concentrations (8–10). However, total body iron is distributed across circulating, functional, and storage iron compartments that can be perturbed independently of one another (11–13). Because iron indexes typically reflect individual compartments and are influenced by factors other than iron status, multiple markers are generally needed to adequately gauge iron homeostasis (11,12). To date, no study has comprehensively delineated iron metabolism in anemic and nonanemic patients with CHF, and none have reported prevalence estimates for the full spectrum of iron disorders. Moreover, the diagnostic utility of iron markers in anemic patients with CHF has so far been poorly explored.
Iron is obligatory for optimal erythrocyte production, and iron-deficient erythropoiesis (IDE) due to defectively mobilized (functional deficiency = anemia of chronic disease [ACD]) and/or depleted (absolute deficiency = iron deficiency anemia [IDA]) stores is the most common cause of anemia globally (14–17). However, despite the high burden and adverse implications of anemia in CHF patients (18), the use of conventional iron indexes to distinguish ACD from IDA and to identify IDA in the midst of ACD (ACD + IDA) has not been reported. Additionally, it is unclear whether the etiologies of anemia vary with disease severity or whether iron deficiency has consequences in CHF besides anemia.
Iron is quantitatively the most important biocatalyst in human physiology, with critical roles beyond hemoglobin synthesis (19–25). Even in the absence of anemia, iron deficiency is a potent substrate for dyspnea and exercise intolerance (26,27) and identifies those in the general population at a heightened risk for mortality (28). In patients with uremia, lower levels of transferrin saturation (TSAT), a more reliable marker of iron deprivation than ferritin in inflammatory cohorts, also correlate to poorer survival (29). Whether lower TSAT relates to mortality independently and more powerfully than anemia in CHF remains unclear.
In a broad spectrum of patients with systolic CHF, we sought to characterize: 1) iron metabolism and its predictors; 2) the prevalence of the full spectrum of iron disorders, with an emphasis on discriminating between ACD, IDA, and ACD + IDA; 3) variations in the etiologies of anemia with New York Heart Association (NYHA) functional class; and 4) the relation of iron deficiency to exercise performance and survival.
We prospectively appraised clinical and iron indexes in 157 consecutively eligible patients with CHF who attended dedicated heart failure clinics and wards at Wexham Park Hospital (Slough, United Kingdom) and the Royal Brompton Hospital (London, United Kingdom). Control subjects (n = 22) with no known medical problems or regular medications were also recruited. The diagnosis of CHF was based on a >6-month history of appropriate symptoms and signs and a left ventricular ejection fraction ≤45%. Patients with recent myocardial infarctions, those with ongoing non-CHF inflammatory processes, and those using iron, erythropoietic, immunomodulatory, or renal replacement therapies within 3 months of recruitment were excluded. Informed consent was obtained from all subjects, and the local ethics and research governance committees at both institutions approved the study.
Peripheral venous blood samples were obtained in the morning from all participants. Full blood counts were measured from K3 ethylenediaminetetraacetic acid samples initially using a Coulter S-Plus Jr. electronic counter (Coulter Electronics, High Wycombe, United Kingdom) at Wexham Park and an ADVIA 120 analyzer (Bayer Diagnostics, Berkshire, United Kingdom) at Royal Brompton. Because of contractual issues, the ADVIA 120 was substituted by a Coulter S-Plus Jr. counter halfway through the study. Percent hypochromic red cells (%HRC) and red cell distribution width were assayed flow cytometrically using the ADVIA 120. Serum iron and total iron-binding capacity (TIBC) were measured colorimetrically (Alpkem RFA analyzer, Alpkem Corporation, Clackamas, Oregon). TSAT was calculated as 100 × serum iron/TIBC. Serum ferritin was determined using a Cobas Core analyzer (Roche Diagnostics GmbH, Mannheim, Germany). For soluble transferrin receptor (sTFR) concentrations, sera were spun (3,000 rpm for 15 min), separated, and stored immediately at −80°C for later quantification using an enzyme-linked immunosorbent assay (Dade Behring GmbH, Marburg, Germany) with a sensitivity of 0.3 pg/ml. All other biochemical tests were performed using standard techniques.
Definitions of anemia and iron deficiency
Anemia was defined as hemoglobin <13 g/dl in men and <12 g/dl in women (30). Iron deficiency was principally defined as TSAT <20% because TSAT is a more reliable marker of iron status than ferritin during inflammation (12,31,32), and diminished circulating iron status is a feature of both absolute (TSAT <20%, low ferritin) and functional (TSAT <20%, normal or high ferritin) iron deficiency. Because ferritin overestimates iron stores in inflammatory cohorts (32,33) prevalence estimates for absolute and functional iron deficiency are given using conventional (30 μg/l) (1,12) and pragmatic (100 μg/l) (34,35) cutoffs.
Prevalence of distinct iron disorders and the origins of anemia
To estimate the prevalence of distinct iron disorders and to discriminate the cause(s) of anemia, we adopted a multiple-measures approach based on TSAT, ferritin, and TIBC or sTFR. Patients with anemia with TSAT <20% had pure IDA if ferritin levels were <30 μg/l (1,12). Ferritin levels ≥30 μg/l identified those with ACD with or without coexistent IDA (1). Because TIBC and sTFR concentrations are augmented by iron store depletion but not by inflammation (11,12,36), their elevated levels were used to identify patients with ACD and concomitant IDA. Two multiple-measures models were constructed. The first used only clinically available indexes (TSAT, ferritin, and TIBC) and was therefore termed the clinical model. The second used TSAT, ferritin, and sTFR and was termed the research model, because sTFR assays are principally research tools. The research model served to validate the results of the clinical model in anemic subjects.
Cardiopulmonary exercise testing
Patients underwent a modified Naughton (37) symptom-limited treadmill exercise test. Minute ventilation (VE), oxygen consumption, and carbon dioxide production (Vco2) were monitored on a breath-by-breath basis using a respiratory mass spectrometer (Amis 2000; Innovision, Copenhagen, Denmark). Peak oxygen consumption adjusted for body weight (milliters per minute per kilogram) and the slope of the relation between VE and Vco2 (VE/Vco2) were calculated as previously described (37).
Data are presented as mean ± SD, frequency (percent), or median (interquartile range [IQR]). Intergroup comparisons were made using Student t test, Pearson chi-square test, the Mann-Whitney U test, 1-way analysis of variance with Fisher protected least significant difference post hoc testing, or nonparametric Kruskal-Wallis analysis of variance as appropriate. To validate TSAT <20% as a marker of iron deficiency, receiver-operating characteristics curve analysis was performed to determine which TSAT or ferritin cutoffs provided optimal sensitivity and specificity for predicting sTFR levels ≥1.76 mg/l (best noninvasive marker of cellular iron deprivation) (12,36).
Relations between variables were assessed by multiple linear regression using age, sex, ethnicity, CHF etiology, left ventricular ejection fraction, NYHA functional class, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), creatinine, platelet counts, beta-blocker use, and antiplatelet or anticoagulant drug use as covariates. Prognostic associations were determined using Cox proportional-hazards analyses (univariate, bivariate, and trivariate models) only for covariates that were available in all patients. To assess the interaction between iron deficiency and anemia on survival, patients were stratified into 4 groups (nonanemic iron-replete, anemic iron-replete, nonanemic iron-deficient, and anemic iron-deficient). Kaplan-Meier curves for cumulative survival were constructed for each group and differences in survival rates tested using the Cox-Mantel log-rank test. All-cause mortality status was obtained from direct physical or telephone contact with patients or their relatives, from the hospital information systems, and from the U.K. Office of National Statistics. No patient was lost to follow-up, and the minimum duration of follow-up for all survivors was 1.4 years.
Data were missing for certain indexes, with no imputation performed. Sensitivity analyses revealed no significant difference in baseline characteristics between those who were and were not quantified for each index. Data were analyzed using StatView version 4.5 (Abacus Concepts Inc., Berkeley, California). A p value <0.05 was considered statistically significant, without adjustment for multiple comparisons.
Patients were similar to controls with respect to age, sex, and ethnicity, but had significantly lower hemoglobin and higher creatinine levels (Table 1). Iron deficiency (TSAT <20%) was evident in 68 patients (43%). Iron-deficient patients did not differ from iron-replete subjects with respect to antiplatelet (p = 0.92) or anticoagulant (p = 0.17) drug use or platelet counts, but they had higher NYHA functional class designations, CRP, and white cell counts, and lower hemoglobin and beta-blocker use.
Abnormal iron metabolism in CHF
Diminished circulating iron status
Male (22.9 ± 9.5%) and female (20.4 ± 10.4%) patients had similar TSAT (p = 0.15) (Fig. 1A). Compared with controls, patients with CHF exhibited lower TSAT and serum iron and higher TIBC and sTFR levels (Table 2). Circulating deficits worsened with NYHA functional class and were greater in patients with anemia (Fig. 2A).
Attenuated functional iron status
The mean cell hemoglobin concentration (MCHC) was higher in male (33.1 ± 1.1 g/dl) than in female (32.4 ± 1.5 g/dl) patients (p = 0.005) (Fig. 1B). Compared with controls, patients with CHF exhibited reductions in MCHC and hemoglobin and increases in %HRC and red cell distribution widths (Table 2). Functional deficits worsened with NYHA functional class and were more marked in patients with anemia (Fig. 2B).
Seemingly preserved storage iron status
Median ferritin levels were higher in male (144 μg/l; IQR: 48 to 193 μg/l) than female (88.9 μg/l; IQR: 29 to 118 μg/l) patients (p = 0.01) (Fig. 1C). On comparing all patients with CHF with controls, no significant difference in ferritin or sTFR/log ferritin ratio was found. However, on stratifying for NYHA functional class, there was a progressive decline in ferritin levels from patients in class I or II (101 μg/l; IQR: 54 to 216 μg/l) to controls (85 μg/l; IQR: 47 to 137 μg/l) to patients in class III (70 μg/l; IQR: 40 to 123 μg/l) and then patients in class IV (59 μg/l; IQR: 21 to 121 μg/l; analysis-of-variance p = 0.04). Similarly, the sTFR/log ferritin ratio progressively increased from controls to patients in NYHA functional class I or II, class III, and then class IV (p = 0.05) (Fig. 2C).
Predictors of impaired iron homeostasis
For the circulating iron pool, higher CRP and NYHA functional class were independently correlated with lower TSAT (r2 = 0.2, p = 0.0012), and non-Caucasian ethnicity, higher NYHA functional class, and lower beta-blocker use predicted higher sTFR (r2 = 0.5, p = 0.0002). For the functional pool, only higher age and NYHA functional class remained correlated with lower MCHC (r2 = 0.18, p < 0.0001), and non-Caucasian ethnicity and higher NYHA functional class (r2 = 0.42, p = 0.0001) predicted higher %HRC. For iron stores, non-Caucasian ethnicity, female sex, and higher NYHA functional class were related to lower ferritin (r2 = 0.42, p < 0.0001), and higher NYHA functional class and non-Caucasian ethnicity predicted higher sTFR/log ferritin ratio (r2 = 0.55, p < 0.0001).
Prevalence of iron disorders
Receiver-operating characteristic curve analysis confirmed that TSAT (area under the curve 0.72, p = 0.002), but not ferritin (area under the curve 0.59, p = 0.28), predicted sTFR ≥1.76 mg/l and that a cutoff of 20% was optimal. Consequently, iron deficiency (TSAT <20%) was evident in 43%, 64%, and 30% of all, anemic, and nonanemic patients, respectively. Using a ferritin cutoff of >30 μg/l, functional iron deficiency was evident in 31%, 44%, and 22% of all, anemic, and nonanemic patients, respectively. Using a cutoff of >100 μg/l, it was present in 14%, 23%, and 8% of all, anemic, and nonanemic patients, respectively.
Using the FERRIC-HF (Ferric Iron Sucrose in Heart Failure) criteria (ferritin <100 or 100 to 300 μg/l with TSAT <20%), iron deficiency was present in 69%, 78%, and 65% of all, anemic and nonanemic patients, respectively. FERRIC-HF–defined functional (ferritin 100 to 300 μg/l with TSAT <20%) and absolute (ferritin <100 μg/l) deficiencies were evident in 10% and 59% of subjects, respectively.
Using the multiple-measures clinical model, distinct diagnoses were possible in 131 subjects (83%) (Fig. 3). Of the total population, 37 (24%) had normal iron status, none had iron overload, 57 (36%) had a nonanemic iron-deficient state, and 36 (23%) had an anemic iron-deficient state.
Etiology of anemia in patients with CHF and its variation with disease severity
Anemia was present in 61 patients (39%). Lower TSAT, higher ESR, and female sex were independently associated with lower hemoglobin (r2 = 0.47, p < 0.001). Applying the multiple-measures clinical model, ACD, ACD + IDA, and IDA were evident in 26%, 16%, and 16% of patients with anemia, respectively (Fig. 3). Stratification on the basis of NYHA functional class revealed that iron-deficient substrates (ACD and/or IDA) were evident in 17%, 72%, and 100% of patients in classes I or II, III, and IV, respectively, with ACD the dominant etiology in each stratum (Fig. 4). The multiple-measures research model was applicable to 21 patients with anemia. Six (29%) had isolated ACD, 5 (24%) had ACD + IDA, and 1 (5%) had isolated IDA.
Iron status and exercise performance
Twenty-seven patients underwent cardiopulmonary exercise testing. No significant difference in baseline characteristics existed between those who did and did not perform exercise testing. Peak oxygen consumption was lower in iron-deficient than in iron-replete (11.4 ± 2.1 ml/kg/min vs. 14.9 ± 1.7 ml/kg/min, p = 0.03) patients and positively correlated to TSAT (r = 0.71, p < 0.0001), MCHC (r = 0.63, p < 0.001), and ferritin (r = 0.48, p = 0.01) independently of NYHA functional class and hemoglobin. The VE/Vco2 slope was higher in iron-deficient than in iron-replete (54.8 ± 10.6 vs. 44.1 ± 9.1, p = 0.02) patients and related only to TSAT (r = −0.43, p = 0.03).
Iron status and survival
Over a median follow-up period of 743 days (IQR: 304 days), 27 patients (17%) died. In univariate analyses, increased mortality was related only to TSAT <20% (hazard ratio [HR]: 3.38; 95% confidence interval [CI]: 1.48 to 7.72; p = 0.004), NYHA functional class (HR: 2.13; 95% CI: 1.28 to 3.55; p = 0.004), beta-blocker use (HR: 0.41; 95% CI: 0.19 to 0.87; p = 0.02), hemoglobin (HR: 0.74; 95% CI: 0.58 to 0.93; p = 0.01), and creatinine (HR: 1.009; 95% CI: 1.003 to 1.014; p = 0.001). Survival was unrelated to TSAT as a continuous variable. In bivariate and trivariate prognostic models, iron deficiency predicted mortality independently of all other covariates in each model.
On stratifying patients into hematological subsets, there was a significant difference in survival among the groups (Fig. 5). Patients with IDA had a 2-fold greater risk for death than those with nonanemic iron deficiency and a 4-fold greater risk for death than iron-replete patients with or without anemia.
We investigated iron metabolism and its clinical significance in anemic and nonanemic patients with systolic CHF and made 3 key observations. First, iron homeostasis was deranged in a predominately functionally iron deficient manner and related closely to NYHA functional class, ethnicity, CRP, and anemia. Second, the etiologies of anemia varied with disease severity, with an iron-deficient substrate increasingly evident with disease progression. Although ACD was more prevalent than IDA, both conditions frequently coexisted. Third, iron deficiency (TSAT <20%) was associated with exercise intolerance and exertional hyperventilation and identified those at an enhanced risk for death independently and more powerfully than anemia.
Iron homeostasis in CHF
Although the existence of iron deficiency (6–8,10) and potential benefits (34,35) of correcting it in CHF are emerging, little is known about the appropriateness of systemic iron allocation in this disorder. Normally, iron principally cycles from the circulation to the erythroid marrow to macrophages and back to the circulation, with the flow of iron between compartments matched to achieve equilibrium. Powerful homeostatic mechanisms orchestrate these movements to maintain the size of each iron pool, with the overriding objective of ensuring that circulating levels are sufficient to support normal erythrocyte hemoglobinization (11–13). Here, we found that the circulating pool of iron was contracted by 15% to 35% in patients with CHF, implying that defects in circulatory iron influx and/or efflux existed. In parallel, the function pool was similarly attenuated, and this reflected the decrease in circulating iron, as the means of iron entry into functional sites (i.e., transferrin receptors) were adequate. In contrast, the storage compartment appeared to be expanded by 24% in patients with CHF. Taken together, these data indicate that in the deranged milieu of CHF, iron is abnormally handled, being preferentially trafficked into storage sites and withdrawn from the circulation and erythroid marrow, triggering IDE. This is evident in anemic and nonanemic subjects and mirrors abnormal iron kinetics in a plethora of inflammatory disorders (1–5).
Although iron stores were biochemically enhanced in patients with CHF compared with controls, careful analysis of the data suggests that their progressive depletion occurs with worsening disease. Serum ferritin levels <15 to 30 μg/l unequivocally signify exhausted iron reserves (1,11,33). However, as an acute phase reactant, ferritin is 3-fold higher in inflammatory cohorts than in normal subjects for each grade of marrow iron (32,33). While ferritin levels in this study were, on average, higher in patients with CHF than controls, they progressively declined from patients in class I or II to controls to those in class III and then those in class IV. Thus, while ferritin levels are elevated early in the course of CHF, they do not escalate further, as would be expected if they simply tracked inflammation, but diminish with disease severity. Because elevated ferritin concentrations still correlate with the degree of stainable marrow iron in inflammatory cohorts (33), our findings suggest that a true depletion of iron stores occurs with advancing CHF. This is consistent with data from Nanas et al. (6) and is a feature of other inflammatory conditions (2).
Predictors of impaired iron status
Disease severity, as quantified by NYHA functional class, was a powerful and inverse predictor of all iron compartments. Because it did so independently of other measured covariates, iron perturbations might be causally linked to CHF progression. Moreover, the fact that iron markers were related to NYHA functional class, an index of the overall impact of the heart failure syndrome on patients, but not to left ventricular ejection fraction, suggests that iron abnormalities are a consequence of CHF rather than a direct result of myocardial dysfunction.
Besides NYHA functional class, non-Caucasian ethnicity also predicted poorer global iron status. This likely reflects the fact that the diet of Southeast Asians, who were the predominant non-Caucasians, is typically high in phosphates and phytates that inhibit iron absorption (38). Predictably, higher CRP was correlated with lower TSAT, consistent with the fact that cytokines divert iron traffic away from the circulation into stores in chronic disorders (1,4). Importantly, we found no relation between iron indexes and antiplatelet or anticoagulant drug use or platelet counts, arguing against a dominant role for occult hemorrhage in iron derangements.
Prevalence of iron disorders
Iron disorders are a continuum, and to the best of our knowledge, this is the first study to report prevalence estimates for the full spectrum of anomalies in CHF. In contrast to healthy elders (39), iron-deficient states were more common than those of iron excess, suggesting that CHF per se might play a role in the genesis of iron insufficiency. Interestingly, 29 patients (15.6%) had nonanemic IDE, which can precipitate fatigue, depression, and exercise intolerance (11,26,27). Thus, identifying IDE before the onset of anemia is important, especially in patients with CHF, in whom evidence suggests that anemia is prevalent and adverse (18). Despite such evidence, however, the relation of iron indexes to hemoglobin in CHF remains poorly explored.
Iron status and its relation to hemoglobin and the etiologies of anemia
Impaired iron status strongly predicted anemia in this cohort. This is unsurprising given that iron is a critical structural component of hemoglobin (40), a direct trigger of erythroid proliferation (16), an enhancer of globin synthesis (15), and the strongest inducer of aminolevulinic acid synthase, the rate-limiting enzyme of heme production (14). Accordingly, lower TSAT predicted lower hemoglobin independently of higher ESR and female sex. That the ESR was independently predictive of hemoglobin likely reflects the fact that inflammation precipitates anemia also by directly suppressing erythroid cells and inducing their resistance to erythropoietin (1). That sex was also independently predictive may reflect the potent influence of androgens on erythropoiesis (41).
ACD (with or without IDA) was the dominant substrate for anemia in our cohort, evident in 44% to 53% of subjects. This is similar to the frequencies reported in prior analyses (7,18), concurs with experimental data (42), but supersedes the 33% burden seen in otherwise healthy anemic elders (43). Although less prevalent, IDA was evident in a substantial 29% to 34% of patients with anemia. This is higher than most prior estimates (7,9,10), possibly because of our use of TIBC and sTFR levels to identify IDA in those with ACD.
Next, we sought, for the first time, to determine whether the etiologies of anemia varied with CHF severity. We found that as NYHA functional class worsened, the prevalence of ACD and/or IDA rose, with ACD being increasingly complicated by IDA. This is consistent with the known evolution of ACD, whereby persistent hypoferremia ultimately impairs iron storage, giving rise to concomitant IDA that is masked by inflammatory hyperferritemia (1,2,44). Indeed, in an anemic NYHA functional class IV cohort, Nanas et al. (6) found definitive IDA in 73% of patients, whose mean ferritin level was 75 μg/l. In this study, only 53% of our anemic NYHA functional class IV patients had IDA, possibly because they were healthier. In contrast, our prevalence estimate for ACD is higher than that of Nanas et al. (18.9%), probably because we diagnosed ACD using positive criteria, whereas it was a diagnosis of exclusion in that analysis. However, given their mean ferritin levels, many of the Nanas et al. (6) cohort with definitive IDA also likely met biochemical criteria for ACD.
Iron status and its relation to exercise performance and survival
Iron-deficient patients were objectively more exercise intolerant and breathless on exertion and harbored a 3-fold escalated risk for death irrespective of whether they were anemic. Indeed, iron-deficient nonanemic patients had a 2-fold greater risk for mortality than iron-replete anemic subjects. This implies that iron deficiency per se might be prognostically more ominous than anemia in CHF. Although lower TSAT may merely reflect other unadjusted adverse factors, a causal prognostic role cannot be excluded.
Besides hemoglobin, iron is an obligate component of several metalloproteins that mediate pivotal functions, such as myoglobin (oxygen storage) (19), electron transport enzymes (oxidative phosphorylation) (20,21), ribonucleotide reductase (deoxyribonucleic acid synthesis) (22), monoamine oxidase (neurotransmission) (23), and cyclooxygenases (inflammation) (24). Iron is thus indispensable for life, and cellular iron deprivation triggers G1/S phase mitotic arrest and apoptosis (25). Iron deficiency also drives catecholamine production (45) and ventricular hypertrophy (46), factors that bode unfavorably in CHF. Such factors might therefore underlie the associations between iron deficiency and adverse prognosis evident here and in other analyses (28,29,47).
This study has important ramifications. First, it confirms emerging evidence that iron deficiency is another pathophysiological feature of CHF that likely arises from the syndrome itself to drive symptoms, exercise intolerance, and mortality irrespective of anemia. Second, it supports the routine assessment of iron status in patients with CHF, particularly in those with refractory symptoms, advanced disease, or anemia. Third, it suggests that low hemoglobin levels in CHF result predominately from true substrates and are not just spurious consequences of hemodilution. Fourth, it shows that the rational use of 3 simple indexes (TSAT, ferritin, and TIBC) enables the biochemically meaningful discrimination of ACD from IDA and the identification of IDA in the midst of ACD. Decisions regarding the mandatory (IDA and ACD + IDA) or adjuvant (ACD) need for iron supplementation can therefore be facilitated. Finally, it suggests that even if iron deficiency is not causally related to mortality, its presence might identify those in need of escalated care.
First, this study was observational, so causal links between variables cannot be established. Second, it represents data measured at a single time point and does not inform on temporal trends in iron status or anemic etiology. Third, for technical and logistical reasons, indexes such as %HRC and sTFR were quantified only in subsets of patients. However, no difference in clinical characteristics existed between those who were and were not measured. Fourth, brain natriuretic peptide measurements were unavailable, but the prognostic independence of iron deficiency from brain natriuretic peptide was suggested in a prior study (47). Fifth, we did not include patients with acute heart failure or recent infarcts, who may have greater iron derangements (6). Finally, a conventional ferritin criteria (<30 g/dl) (1,12) was used to diagnose IDA, despite evidence that higher cutoffs may be better in inflammatory cohorts. Thus, we might have overestimated the prevalence of ACD and underestimated that of IDA in this study. Because the absence of stainable iron in bone marrow aspirates is the optimal marker of iron deficiency, studies predicated on this are needed to define “normal” ferritin levels in CHF. However, by demonstrating that IDA remained substantially prevalent despite the use of a conservative cutoff, we contend that our study further highlights its importance in CHF.
Iron metabolism is deranged in CHF and is characterized by a diminished circulating and functional iron status in the face of seemingly adequate stores. Disordered iron homeostasis correlates to worsening inflammation, NYHA functional class, and non-Caucasian ethnicity, and increasingly underlies anemia with CHF progression. Iron deficiency, as defined by a TSAT <20%, relates to exercise intolerance and amplified mortality, and should be targeted in future survival trials.
This work is dedicated to the memory of Professor Poole-Wilson, who died suddenly in March 2009.
The British Heart Foundation (London, United Kingdom) supported Dr. Okonko (FS/03/104/16341) and Prof. Poole-Wilson. The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- anemia of chronic disease
- chronic heart failure
- confidence interval
- C-reactive protein
- erythrocyte sedimentation rate
- Ferric Iron Sucrose in Heart Failure
- hazard ratio
- iron deficiency anemia
- iron-deficient erythropoiesis
- interquartile range
- mean cell hemoglobin concentration
- New York Heart Association
- percent hypochromic red cells
- soluble transferrin receptor
- total iron-binding capacity
- transferrin saturation
- carbon dioxide production
- minute ventilation
- Received October 18, 2010.
- Revision received April 14, 2011.
- Accepted April 19, 2011.
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