Disordered iron homeostasis among nigerians with chronic heart failure: Pattern, prevalence, and clinical correlates

Adeseye Abiodun Akintunde; Mathias Olawale Akinlade; Oladapo Wale Aworanti

doi:10.4103/JCPC.JCPC_14_20

ORIGINAL ARTICLE

Year : 2021 | Volume : 10 | Issue : 1 | Page : 17-25

Disordered iron homeostasis among nigerians with chronic heart failure: Pattern, prevalence, and clinical correlates

Adeseye Abiodun Akintunde FWACP, FMCP, FACC, FESC ¹, Mathias Olawale Akinlade FWACP ², Oladapo Wale Aworanti FWACP ³
¹ Department of Medicine, Cardiology Unit, Ladoke Akintola University of Technology Teaching Hospital, Ogbomoso, Oyo State; Department of Medicine, Faculty of Clinical Sciences, Ladoke Akintola University of Technology, Osogbo, Nigeria
² Department of Medicine, Cardiology Unit, Ladoke Akintola University of Technology Teaching Hospital, Ogbomoso, Oyo State, Nigeria
³ Department of Haematology and Blood Transfusion, Ladoke Akintola University of Technology Teaching Hospital, Ogbomoso, Oyo State, Nigeria

Date of Submission	02-Apr-2020
Date of Decision	26-Sep-2020
Date of Acceptance	28-Sep-2020
Date of Web Publication	27-Mar-2021

Correspondence Address:
Dr. Adeseye Abiodun Akintunde
Department of Medicine, Cardiology Unit, Ladoke Akintola University of Technology Teaching Hospital, P.O Box 3238, Ogbomoso, Oyo State
Nigeria

Source of Support: None, Conflict of Interest: None

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DOI: 10.4103/JCPC.JCPC_14_20

Abstract

Background: Iron deficiency (ID) often coexists with heart failure and has recently become a therapeutic option in its management. Multiple markers are often required to adequately estimate iron status. This study was aimed at describing the status of iron homeostasis among heart failure patients in Nigeria. Materials and Methods: This was a cross-sectional study done at two tertiary centers in Nigeria. One hundred and forty patients with a diagnosis of heart failure were recruited into the study. Full blood count, total serum iron, total iron-binding capacity, and serum ferritin were measured. Anemia was defined by standardized criteria. Data analysis was done with SPSS 20.0. Results: The mean age of the study patients was 62.96 ± 16.34 years. Disordered iron homeostasis was common, often characterized by predominantly low total serum iron and low transferrin saturation in the presence of normal or high serum ferritin. ID was reported in 60.0% of all patients including 61.3% of anemic and 51.9% of nonanemic patients, P = not significant. High ferritin level was documented in fifty (35.7%) patients (36.8% anemic vs. 32.4% nonanemic patients, P = 0.40). Pulmonary hypertension was more frequent among anemic patients found in 45 patients (including 42.5% of anemic vs. 8.8% of nonanemic patients). ID was associated with poor functional status including ejection fraction, deranged renal function, and advanced disease. Conclusion: Functional ID is very common among heart failure patients in Nigeria irrespective of their anemia status. It is associated with poor functional status and may be a potential therapeutic strategy in Africans with heart failure.

Keywords: Ferritin, heart failure, iron homeostasis, Nigeria, transferrin

How to cite this article:
Akintunde AA, Akinlade MO, Aworanti OW. Disordered iron homeostasis among nigerians with chronic heart failure: Pattern, prevalence, and clinical correlates. J Clin Prev Cardiol 2021;10:17-25

How to cite this URL:
Akintunde AA, Akinlade MO, Aworanti OW. Disordered iron homeostasis among nigerians with chronic heart failure: Pattern, prevalence, and clinical correlates. J Clin Prev Cardiol [serial online] 2021 [cited 2023 Mar 29];10:17-25. Available from: https://www.jcpconline.org/text.asp?2021/10/1/17/312222

Introduction

Heart failure is a common cause of morbidity and mortality worldwide and usually the end stage of adaptations to many intrinsic and extrinsic cardiac diseases.^[1],[2] Two large international registries, the Sub-Saharan Africa Survey of Heart Failure (THESUS-HF) and International Congestive Heart Failure (INTER-CHF) registries, have documented the current profile, etiologies, treatment, and challenges of managing heart failure among Africans with emphasizing the high prevalence of anemia as both a major comorbidity in heart failure and a contributor to cardiovascular mortality.^[3],[4]

Africans with heart failure are faced with many challenges including poor health financing for chronic disease such as heart failure, limited accessibility to contemporary device-based therapeutic options, clustering of comorbidities, and generally poor prognosis and outcome.^[3],[4],[5] Identification of potentially treatable comorbid factors among Africans with heart failure that are cost-effective and widely available will go a long way in reducing the cardiovascular and total risk associated with heart failure in our continent. Treating iron deficiency (ID) is an emerging therapeutic option and prognostic factor in heart failure irrespective of hemoglobin (Hb) parameters.^[6],[7] This has been extensively studied among Caucasians with the evidence that treating ID irrespective of the anemic status in heart failure is associated with improved prognosis, better quality of life, and reduced morbidity and mortality.^[8],[9] There is however lack of adequate epidemiological data in the sub-Saharan Africa on iron homeostasis in heart failure and its potential therapeutic impact with a need to provide insights into the peculiarities and burden of intervention for ID and anemia in heart failure patients in SSA.^[10]

Iron homeostasis can be deranged in chronic conditions including malignancies.^[11],[12] Total body iron is distributed across circulating, functional, and storage iron compartments, which can be affected independently of one another. Multiple markers are usually needed to adequately evaluate iron homeostasis. Iron is an important biocatalyst with many functions in body physiology.^[13] Iron indices have been shown to be a marker of prognosis and survival in coronary artery disease, chronic kidney disease, and acute inflammatory disorders.^{[14],[15],[16]}

Anemia was shown as a major predictor of 180 day-mortality in the THESUS-HF trial.^[3] The prevalence of anemia in several registries from the African continent varies due to varied definitions of anemia. Where internationalized standard definitions were used, anemia was reported in 36.7%–77.1% of heart failure patients.^{[17],[18],[19],[20]} ID is associated with decreased aerobic performance and exercise tolerance in chronic heart failure irrespective of the presence or absence of anemia. The causes of ID in heart failure can be multifactorial – including gradual depletion of iron stores due to low iron intake (absolute ID), blood loss from the intestinal tract or iron malabsorption, chronic inflammation, infestations, etc.^[21] The difficulty to mobilize iron in chronic diseases such as heart failure may lead to functional ID. Intracellular iron is stored as ferritin and during iron overload as hemosiderin and when they are present in excessive amount in macrophages. Ferritin levels usually reflect the body iron stores as they spill from the intracellular stores into the bloodstream. However, it is an acute-phase reactant and usually increases during acute and chronic inflammatory processes.^[21],[22] Transferrin binds the iron in the blood, and transferring saturation (TSAT) reflects the relative amount of transferrin that is loaded with iron. It usually reduces during inflammation and hence is a negative acute-phase reactant. Therefore, none of these parameters can be used independently to assess total iron status.^[23] ID exists commonly in heart failure and the prevalence increases with New York Heart Association (NYHA) classification and other conventional parameters.

Heart failure is a risk to developing ID for many reasons. Heart failure is a chronic inflammatory condition with many cytokines playing significant roles. This causes reduced iron absorption and availability of iron recycled in the reticuloendothelial system, leading to functional ID in the presence of normal iron stores. Continuous iron store depletion also occurs due to low iron intake, gastrointestinal blood loss, or iron malabsorption (absolute ID occurring due to depleted stores of iron).^{[6],[10],[12],[14],[24]} Various abnormalities in iron metabolism have been reported in heart failure.^{[6],[7],[8],[9],[10]} ID affects almost all the substrates of iron metabolism and impairs cellular mechanism, whether absolute or functional ID. This results in impaired energy production, cardiac damage, diastolic abnormalities, and progressive heart failure associated with increase in inflammatory markers such as tumor necrosis factor-alpha. Chronic ID may therefore change the cardiac hypertrophy which was initially adaptive to permanent cardiac impairment. ID is associated with reduced peak oxygen consumption, higher rate of ventilation to carbon dioxide production, and increased red cell oxidative stress.^[25],[26].Thrombocytosis and enhanced hypercoagulability have also been reported to be associated with heart failure. ID coexisting with heart failure increases the risk of thrombosis.^[27],[28]

This study was aimed at describing the disorders of iron homeostasis among chronic heart failure patients in Nigeria and determining the pattern, prevalence, determinants, and associated clinical correlates of ID and anemia among Nigerians with heart failure.

Materials and Methods

Study population

This was a cross-sectional descriptive study. One hundred and forty consecutive patients with a diagnosis of heart failure that have been attending the clinic for at least 6 months were recruited. The study locations were the cardiology clinics of Ladoke Akintola University of Technology Teaching Hospital, Ogbomoso, and Bowen University Teaching Hospital, Ogbomoso. Recruitment was done between July and December 2018. Patients were included if they fulfilled the inclusion criteria which include the diagnosis of heart failure using the Framingham's criteria,^[25] they were >18 years of age as of their last birthday, they were willing to give a written informed consent to participate in the study, and they had at least a minimum life expectancy >2 years. Exclusion criteria include those with a previous history of recent blood transfusion; those with established chronic kidney diseases; pregnant patients; those with a history of chronic illnesses including malignancies, mental illness, chronic inflammatory disorders, stroke, Parkinson's disease, and acute coronary syndrome; and patients who were admitted for any reason in the previous month. Patients with a history suggestive of ongoing infection were also excluded from the study.

At study entry, each potential participant was screened and recruited if they fulfilled the inclusion criteria. A data collection form was deployed to obtain patients' sociodemographic data. Clinical and demographic variables taken using the data form included name, age, gender, occupation, marital status, address, and tribal status. History of hypertension, diabetes mellitus, smoking, and alcohol intake and family history of hypertension/diabetes were also obtained. All the study participants underwent full clinical and systemic examination. Ten milliliter of venous blood was taken into ethylenediaminetetraacetic acid and plain bottles and centrifuged at the plasma stored as −80° for laboratory analysis. Full blood counts including packed cell volume, Hb, total white cell count, platelet count, and blood film appearance were measured. The mean corpuscular volume, mean corpuscular Hb (MCH), and MCH concentration (MCHC) were also measured. Serum transferrin was measured by the immunoturbidimetric method using the kits from Fortress Diagnostics Limited, Belfast Road, Antrim, N. Ireland, United Kingdom (product code BXC 0741). Serum ferritin was measured using the enzyme-linked immunosorbent assay kits produced by CALBIOTECH (El Cajon Carlifornia, USA) (catalog No FR248T) with relevant color colorimetry. Total serum iron and unsaturated iron-binding capacity (UIBC) and total iron-binding capacity (TIBC) were measured using the colorimetric kits from Fortress Diagnostics (product code BXC0234) using appropriate iron buffer, reductant, chromogen, UIBC buffer, and ferrous reagent. Anemia was defined as Hb <13 g/L in men and <12 g/L in women. ID was defined as <20% because TSAT is a better marker of iron status than ferritin during inflammation as ferritin overestimates iron stores in inflammatory conditions.

TSAT was determined as 100 × serum iron/TIBC.

Anemia was further defined as:

Pure ID anemia − anemia + TSAT <20%, low ferritin levels <30 μg/L

Anemia of chronic disease (ACD): anemia + TSAT <20%, normal/high ferritin levels ≥30 μg/L.^[18]

Other investigations done for the participants included a 12-lead resting electrocardiography (ECG), trans-thoracic echocardiography, electrolytes, urea and creatinine, urinalysis, and fasting blood sugar. Weight was taken to the nearest kilogram, while height was taken using a stadiometer. Body mass index (BMI) was determined and categorized as normal BMI, overweight (BMI 25.0–29.9 kg/m²), mild obesity (BMI 30–34.9 kg/m²), moderate obesity (BMI 35.0–39.9 kg/m²), and severe obesity (BMI >40 kg/m²).^[19]

Functional classification was defined according to the NYHA Classification as Class I–IV.^[20]. All participants had 12-lead resting ECG using AT-2 Schiller ECG machine. Interpretation of the ECG was done independently by at least two investigators in this study.^[21]. Echocardiography was done according to the American Society of Echocardiography guidelines.^[22] Parameters that were taken include left ventricular internal dimension in diastole (LVIDD), left ventricular end-systolic dimension, posterior wall thickness dimension in diastole, interventricular septal thickness in diastole, right ventricular dimension, left atrial dimension, aortic root dimension, and aortic cusp separation. Left ventricular mass, left ventricular mass index, and aortic root index were determined. Ejection fraction (EF) and the fractional shortening were determined using the Teicholz formula. Heart failure phenotypes were classified using the EF. The study was based on the Declaration of Helsinski. Ethical approval was obtained from the Ethics Committee of Ladoke Akintola University of Technology Teaching Hospital, Ogbomoso, Nigeria. All participants gave a written consent.

Statistical analysis

The Statistical Package for Social Sciences SPSS version 20.0 (IBM, United States of America, Chicago, IL, USA) was used. Quantitative variables were summarized as means ± standard deviation, whereas qualitative variables were summarized as frequencies (percentages). Student's t-test, analysis of variance, and Chi-square were used to determine the statistical significance of differences between groups with continuous and nominal variables. Pearson's correlation statistics was also used to determine univariate correlation between continuous data. Logistic regression was also done to determine the determinants of iron status among the study participants. P < 0.05 was taken as statistically significant.

Results

The prevalence of anemia defined by gender-specific standardized criteria was very high among heart failure patients. One hundred and six (75.7%) study participants were shown to have anemia. There was no gender difference with the presence of anemia among the study participants: 40.6% of anemic patients were male compared to 50.0% of nonanemic subjects who were male (P > 0.05). Heart failure patients with anemia were more likely to have significantly lower EF indicating poorer systolic function (38.8 ± 8.2 vs. 47.3 ± 10.4%, P < 0.000, respectively), lower thrombocyte count (174.5 ± 92.9 vs. 213.7 ± 94.4 × 10⁹/cm³, respectively, P = 0.034), significantly higher likelihood of having pulmonary hypertension (42.5% vs. 8.8%, respectively, P < 0.05), and low total serum iron level (37.4 ± 17.7 vs. 45.3 ± 27.7 μg/dL, respectively, P = 0.049). Left ventricular mass was also significantly high among anemic heart failure patients as shown in [Table 1] (325.8 ± 124.5 vs. 290.3 ± 129.2 g, respectively, P = 0.021). In addition, those with anemia were more likely to be significantly older than those without anemia. Mean total transferrin, mean ferritin, and mean TSAT were similar between the two groups, as shown in [Table 1].

Table 1: Clinical, laboratory, and echocardiographic parameters among the study participants between those with anemia and those without anemia

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Heart failure patients with ID (TSAT <20%) were older even though it did not achieve statistical significance with reference to those without ID (normal TSAT) or iron overload. Functional status as evaluated by the NYHA was significantly different between the TSAT groups. Iron-deficient heart failure patients were more likely to be in NYHA III/IV functional class compared to those without ID and iron overload (73.8% vs. 67.3% vs. 50.0%, respectively, P < 0.05). ID was more closely related to female gender among heart failure patients, as shown in [Table 2]. The systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR), fasting blood sugar, and echocardiographic parameters (including the LVIDD, right ventricular dimension, left atrial dimension, left ventricular mass index, and aortic root dimension) were similar among the study participants stratified based on their TSAT. Serum ferritin was significantly different between the different groups. Serum ferritin was significantly lower among those with ID and iron overload compared with those without ID. Similarly, the mean corpuscular volume and MCH were significantly different between the two groups of study participants. The mean corpuscular volume and MCH were lowest among heart failure patients with ID and highest among those with iron overload (86.7 ± 9.7 vs. 90.6 ± 7.0 vs. 102.6 ± 5.3 fL, respectively, P < 0.001). Total iron also followed a similar trend (30.0 ± 6.3 vs. 46.4 ± 9.2 vs. 142.1 ± 5.2 μg/dL, respectively, P < 0.001). MCH was significantly lowest among iron-deficient heart failure subjects and highest among heart failure subjects with iron overload (29.3 ± 4.0 vs. 30.4 ± 3.2 vs. 33.0 ± 1.2 pg respectively, P < 0.05). Aortic root dilatation was more significantly associated with ID in heart failure as compared to those without ID (29.8% vs. 25.0% respectively, P < 0.05). ACD was more commonly associated with ID as shown in [Table 2] and this was statistically significant. Serum Hb and MCHC were similar between the three groups of heart failure subjects stratified based on their TSAT as shown in [Table 2].

Table 2: Clinical and demographic variables based on their transferrin saturation

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The gender variation of clinical, laboratory and iron indices are as shown in [Table 3]. Males were fewer but more likely to be older than their female counterparts (63.0 ± 12.8 vs. 62.9 ± 18.6 years respectively, P < 0.05). Mean packed cell volume was lower among females than males (33.9 ± 7.4 vs. 31.1% ± 5.3% respectively P < 0.05). Hb and mean corpuscular volume were lower among females compared to males but did not reach statistical significance. Conversely, MCH and MCHC were higher among females than males but did not also reach statistical significance. Mean serum ferritin was significantly higher among males compared to females (294.9 ± 172.4 vs. 176.5 ± 135.9 ng/ml, respectively, P < 0.05). Despite a barely significantly higher mean serum total iron among females, (41.3 ± 25.8 vs. 36.7 ± 10.6 μg/dL respectively, P = 0.05), the proportion of males with low total iron was significantly higher compared to their female participants (96.7% vs. 60.0%, P < 0.05, respectively). Mean transferrin and TSAT were similar between the two genders. The proportion of males with left ventricular hypertrophy was statistically significantly higher compared to that of female heart failure patients (86.7% vs. 46.3%, respectively, P < 0.05). Functional ID and anemia were more associated with female gender as there was statistically significantly higher proportion of females with ID (63.8% vs. 53.3%, respectively, P < 0.05) and anemia (78.8% vs. 71.7%, respectively, P < 0.05) than that of males.

Table 3: Gender distribution of clinical and iron indices among the study participants

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Based on functional classification of heart failure according to the NYHA classification, the clinical, demographic, and iron indices are shown in [Table 4]. Age, SBP, and DBP were similar between the participants. Serum creatinine was highest among those with advanced diseases in NYHA Stage IV compared to NYHA Stages III and I/II (158.3 ± 55.8 vs. 120.5 ± 168.1 vs. 71.7 ± 52.8 μmol/l, respectively, P < 0.05, suggesting deteriorating renal function as heart failure advances. The mean serum Hb (11.3 ± 2.1 vs. 10.9 ± 2.3 vs. 9.6 ± 2.9 g/dL, respectively, P < 0.05), mean corpuscular volume (90.8 ± 6.7 vs. 89.0 ± 5.9 vs. 85.9 ± 13.1 fL, respectively, P < 0.05), and MCH (30.8 ± 3.1 vs. 29.9 ± 2.1 vs. 28.6 ± 5.1 pg, respectively, P < 0.05) also progressively reduced as heart failure advanced from NYHA Stage I/II through Stage IV. The mean serum ferritin, total iron, and TSAT, as well as the total white cell count and the proportion of those with low total iron, were not significantly different between the NYHA classification. As heart failure worsens as evaluated with the NHYA classification, the proportion of those with low total serum iron and those identified as ID increases although it did not achieve statistical significance, as shown in [Table 4]. Among the study participants, the use of beta-blockers reduced as heart failure advanced, while the prevalence of left ventricular chamber hypertrophy increased, with both achieving statistical significance, as also shown in [Table 4].

Table 4: Clinical, laboratory, and demographic parameters of the study participants stratified based on New York Heart Association Classification of heart failure status

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Heart failure phenotypes are currently classified into three groups namely heart failure with reduced ejection fraction (HFrEF), heart failure with mid-range ejection fraction (HFmrEF), and heart failure with preserved ejection fraction (HFpEF), based on the EF obtained on echocardiography. The clinical, hematological, and iron index parameters are shown in [Table 5]. SBP was significantly different among the study participants. It was highest among patients with HFpEF compared to those with HFmrEF and HFrEF (133.4 ± 22.9 vs. 131.6 ± 22.8 vs. 120.5 ± 20.8 mmHg, respectively, P < 0.05). HR was highest among HFrEF compared to HFmrEF and HFpEF patients, and this was also statistically significant (96.9 ± 20.8 vs. 83.8 ± 14.7 vs. 86.4 ± 9.5 beats/min, respectively, P < 0.05). Expectedly, EF was lowest among patients with HFrEF compared to others, as shown in [Table 5]. Even though Hb concentration and mean corpuscular volume were highest among HFpEF compared to the two other phenotypes, this did not achieve statistical significance. The MCH and MCHC were higher among those with HFmrEF although only that of MCHC achieved statistical significance. The mean total ferritin, mean total iron, and TSAT were similar between the three phenotypes of heart failure. Anemia more commonly occurs among patients with HFrEF compared to HFmrEF and HFpEF patients (88.9% vs. 67.4% and 50.0%, respectively, P < 0.05). More than four-fifths of the patients with HFrEF had anemia compared to only half of those with HFpEF. Low total iron was more likely to occur among those with HFmrEF compared to those with HFpEF and HFrEF, and a similar pattern was described for low transferrin. Low transferrin and functional ID occur much more frequently among patients with HFpEF compared to other groups but only that of low transferrin was statistically significant [Table 5]. [Figure 1] shows the pattern of clusters of anemia types among study participants. Coexisting anaemia of chronic disease and iron deficiency occurs more as the severity of heart failure worsens whereas isolated iron deficiency anaemia was more common among those with less severe disease.

Table 5: Iron indices and clinical parameters stratified according to heart failure phenotypes

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Figure 1: New NYHA class. NYHA = New York Heart Association, ACD = Anemia of chronic disease, IDA = Iron deficiency anemia

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Discussion

Anemia frequently coexists with heart failure and is a major determinant of outcome and prognosis in many studies and registries.^{[1],[2],[3],[4],[7],[8],[9],[20],[21],[22],[23],[24],[25],[26],[27],[28],[29]} This study revealed that anemia is present in a significant majority of heart failure patients in Nigeria as about three-fourth of all participants were shown to have anemia. This is consistent with other reports from other parts of Africa where a large proportion of heart failure patients have been shown to have coexisting anemia.^{[17],[18],[19],[20]} The prevalence of anemia reported in this study is however higher than what has been reported from other regions of the world. Goh et al. reported the presence of anemia in a third to a little more than half of their patients with heart failure in Asia.^[30] Anemia is highly prevalent in patients with chronic heart failure with varying rates of prevalence depending on the population under study. A recent meta-analysis of 153,180 patients with CHF estimated a prevalence rate of 37.2% (10%–49%), whereas the Study of Anaemia in a Heart Failure Population registry (STAMINA-HFP) estimated a prevalence of 34%.^[31],[32] Variability in the definition used in defining anemia in heart failure accounts for the difference in prevalence estimation quoted from different studies.

The reason for the higher prevalence of anemia among heart failure patients in this study may be connected with many factors including low socioeconomic status, the burden of poverty and malnutrition, the prevalent infectious and parasitic diseases, and poor state of health care among many others. Anemia is consistently shown to be an adverse prognostic factor in heart failure irrespective of EF and other conventional markers of prognosis. Left ventricular mass and the odds for pulmonary hypertension were significantly higher among heart failure with anemia compared to those without anemia. Left ventricular mass and pulmonary hypertension are poor prognostic indices in heart failure.^{[33],[34],[35]} Pulmonary hypertension is a severe complication of heart failure. EF and platelet count were significantly lower among heart failure patients with anemia compared to those without anemia. The monocyte–platelet interaction has been shown to be a pathophysiological link between inflammation, thrombosis, endothelial activation, and myocardial malfunction.^[36]

In a meta-analysis of 13,295 patients from nine registries and studies across Europe and Canada, anemia occurred similarly between those with preserved EF and reduced EF (42.8% vs. 41.6%, respectively).^[33],[34] This is in sharp contrast with the finding of this study where anemia was significantly more prevalent in HFrEF compared to others. This may be related to comorbid factors occurring in HFrEF, higher proportion of cardiorenal syndrome as estimated by higher creatinine, recurrent infections, and increased inflammatory status.^{[1],[19],[24]}

ID irrespective of is the presence or absence of anemia is an emerging potential therapeutic option in heart failure patients. The prevalence of ID in this study was 60%. This was higher than the one from a Tanzanian heart failure cohort where a prevalence of 49% was reported.^[10],[19] ID was not significantly different between anemia and nonanemic heart failure patients, similar to other reports.^[10],[14] Iron-deficient heart failure patients have found to be more likely to be older than those with normal iron status and were more likely to be female. Iron-deficient heart failure patients have found to be more likely to have an advanced disease as evaluated by the NYHA classification, as shown in this study. Compared to those with normal TSAT (normal iron status), SBP, HR, serum urea, and fasting blood sugar were higher among iron-deficient heart failure patients even though they did not achieve statistical significance. However, serum ferritin which is a form of stored iron was significantly lower among patients with ID compared to others. Other authors have reported that ID is closely related with female gender and poorer clinical status.^[37] In a study by Klip et al., several clinical characteristics including disease severity assessed by NYHA functional class and N-terminal pro-B-type natriuretic peptide (NT-pro BNP) serum levels were found to be independent predictors of disordered iron status in heart failure.^[37]

There are two types of ID: absolute and functional ID. Absolute ID is related with depleted iron stores, most often with intact erythropoiesis and iron metabolism.^[38] The causes in heart failure include low dietary iron, impaired gastrointestinal absorption, excessive blood loss from repeated investigations, parasitic infestations, and menorrhagia. Functional ID is inadequate iron supply for metabolism despite normal or excess body iron stores due to iron trapping in the reticuloendothelial system and unavailability for cellular metabolism. This is often caused by pro-inflammatory activation and hepcidin overproduction.^[37],[38] Several of the highlighted factors favor the development of absolute and functional ID in heart failure. Other related factors include impaired duodenal transport of iron and drug interaction (e.g., omeprazole). Heart failure is a chronic inflammatory disease associated with heightened immune response, overactive immune cells, and high circulation level of pro-inflammatory cytokines. Therefore, functional ID may likely be related to the inflammation or secondary to inflammatory associated with comorbid pathologies. This study revealed that functional ID is more associated with female gender, but there was no association with functional classification based on NYHA and heart failure phenotypes.^[39],[40]

The prevalence of ID among heart failure patients from other reports is far less than what was reported in this study. Adlbrecht et al. reported a prevalence of 26% among patients with chronic systolic heart failure, whereas 37% was documented from another study from Europe.^[41] This study showed an independent association of ID with female gender and advanced NYHA class, as shown in other studies across Europe.^{[40],[41],[42]} Other independent predictors shown in related studies include the high plasma NT-pro-BNP and high serum high-sensitivity C-reactive protein.

This study also revealed that iron homeostasis was predominantly deranged in the functional ID manner, a situation in which TSAT is low with normal or high ferritin. This pattern of iron homeostasis is similar to what has been described by other authors in other parts of the world.^[43]

It has been said that iron stores which could be estimated as ferritin are biochemically enhanced in patients with chronic heart failure; we found that HFmrEF and NYHA Class III were often more associated with a significantly higher ferritin and lower total iron than the two end of the spectra of iron and ferritin indices. This may be due to amplified inflammatory response coupled with other factors such as coexisting comorbidities and infections, which could further derange iron metabolism as heart failure advances.^[44]

ACD with or without ID was the most common form of anemia found among the study participants. This was reported in 76.2% of iron-deficient heart failure patients compared to 73.1% of those without ID. This is far higher than what has been reported from the Caucasian population where a prevalence of 44%–53% has been reported.^[42],[43] The prevalence of ACD was also shown to be positively related to the severity of heart failure as those with advance heart failure tend to have more of ACDs associated with ID.^[44] This suggests that anemia, ID, and other measures of iron homeostasis are much more deranged in the Caucasians, and there is a need to further evaluate the potential therapeutic benefit of iron replacement across the region of Africa. Evidence abound to the fact that iron supplementation may activate molecular pathways protecting the heart and reversing cardiovascular remodeling. Iron replacement among Caucasians has been shown to be well tolerated with improved quality of life, functional status, and exercise capacity.^{[29],[45],[46]}

ID has been demonstrated among many patients with chronic diseases in Nigeria. Iyawe et al. demonstrated the prevalence of ID among predialysis chronic kidney disease patients in Nigeria to be 14%.^[47] A similar value was quoted by Raji et al. among adults with chronic kidney disease.^[48] This showed that heart failure may even be associated with poorer iron indices compared to chronic kidney diseases among Nigerians and portend a poorer prognostic outcome when compared to chronic kidney disease, a disease that is known for its high morbidity and mortality. This study has some limitations: first, the cross-sectional design precludes that the ID may not only be causally related to heart failure alone but may also be influenced by other factors; second, some of the measures of iron status are markers of chronic inflammation for which other silent preclinical chronic inflammatory diseases may have contributed. Another possible limitation is the impact of several medications on the pattern of anemia and iron indices among the participants, which was beyond the scope of this study.

Conclusion

This study revealed that iron homeostasis is severely deranged among heart failure patients in Nigeria irrespective of the presence or absence of anemic. Functional ID is very common among heart failure patients in Nigeria irrespective of their anemia status. It is characterized majorly by elevated serum ferritin, low TSAT, and low serum total iron, and it is associated with poor functional status and female gender and may be a potential therapeutic strategy among chronic heart failure patients to reduce cardiovascular morbidity and mortality.

Acknowledgments

The authors would like to thank the resident doctors in the Department of Medicine, Ladoke Akintola University of Technology Teaching Hospital, Ogbomoso, Nigeria, and Dr. Alamu Olubola for the editorial assistance.

Financial support and sponsorship

This study was sponsored in part by the Institutional Based Research Grant of the Tertiary Education Fund, Nigeria.

Conflicts of interest

There are no conflicts of interest.

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