Iron deficiency in patients of heart failure with reduced ejection fraction

Abstract

Background

Heart Failure with reduced Ejection Fraction (HFrEF) is a common disorder affecting a large population. Iron deficiency (ID) with and without anaemia is an important variable which is often underreported and under treated in clinical practice, which contributes to patient symptoms. The present study was undertaken to study the prevalence and Spectrum of Iron Deficiency in patients of HFrEF.

Methods

This is a single-centre observational study. All patients with a clinical diagnosis of HFrEF presenting to the hospital were studied. Ejection Fraction (EF) was assessed on Echo and ID was diagnosed on basis of serum ferritin <100 micro g/dl or serum ferritin 100-300 micro g/dl with low Transferrin Saturation (TSAT) (< 20%).

Results

We have studied a total of 204 patients with a predominantly male population (73%) and a mean age of 62.88 years. Most of our patients were in mid-level functional class (mean 2.48 ± 0.50) and had low EF (mean 29.56 ± 6.52). Out of 204 patients, 88.7% patients had ID with 83% patients having absolute ID. Of the total patients with HF, 70% had anaemia. Amongst those with anaemia 93% had ID, and even without anaemia, 68% had absolute or functional ID, underlying the importance of evaluating iron status in all patients of HF irrespective of their haemoglobin levels.

Conclusion

This study highlights the burden of iron deficiency in heart failure patients in the Indian population and opens the way for large scale studies for better characterization of iron deficiency as well as therapeutic trials in the management of heart failure patients.

Introduction

Heart Failure (HF) is a common disabling comorbidity, affecting 1–2% of the overall adult population worldwide, and its prevalence increases with age and goes up to 8% in those aged >75 years in developed countries.^1,2 In India, there are few prevalence studies, one study that estimated rates in a rural population showed a prevalence of 1/1000.³ HF is an important cause of morbidity, mortality, frequent hospitalisations, impaired quality of life (QoL), and impaired exercise capacity. Anaemia is coexisting in about 20% of HF patients and is an established contributing factor in predicting poor outcomes and hospitalisations in patients with HF.⁴ Iron deficiency (ID) with or without anaemia in patients of HF has been shown to predict poor exercise capacity, QoL, NYHA class and also has been associated with poor outcomes in HF patients.^5,6 However, measurement of iron stores still does not form a routine place in the evaluation of patients of HF, thus making it a generally underdiagnosed entity in this subset of patients.

Most of the studies on ID in HF are from the western world; there are very few Indian studies that have dealt with this topic. With the vast prevalence of nutritional deficiencies in our country, it is expected that the prevalence of ID in our population would be more than what is encountered in developed countries. This study aims to find the prevalence of ID in HFrEF patients in the Indian population to emphasise the importance of recognition and treatment of this problem in our patients.

Material and methods

Our study was a single-centre prospective observational nonintervention study wherein we studied patients presenting to the cardiology department of a tertiary care hospital in western Maharashtra. Institutional Ethics Committee approval was taken for the study. All patients fulfilling the clinical definition of HF as per the European Society of Cardiology 2016 guidelines were considered (Table 1).⁷ Only patients with left ventricular systolic dysfunction (LVsd) were included in the study after obtaining written informed consent. Patients of both ischemic and nonischemic etiologies were included in the study. We took a detailed clinical history and evaluation in the form of hemogram, biochemical tests, electrocardiogram (ECG), echocardiography, and iron studies were done. All patients underwent a detailed echocardiogram on a Philips Epic 7 echocardiography machine by an experienced cardiologist. We studied the LVEF by Simpson’s method. LV size was estimated by M Mode, and Diastolic dysfunction was assessed by determining the E/e’. Left atrial (LA) size was measured in 2D, and pulmonary arterial pressures were estimated by Continuous-wave Doppler by assessing the Right ventricular systolic pressures (RVSP) and estimate of Right Atrial (RA) pressures.

Table 1.

Clinical definition of heart failure.

Clinical definition of heart failure (ESC Guidelines 2016)
HF is a clinical syndrome characterised by typical symptoms (e.g. breathlessness, ankle swelling, and fatigue) that may be accompanied by signs (e.g. elevated jugular venous pressure, pulmonary crackles and peripheral oedema) caused by a structural and/or functional cardiac abnormality, resulting in reduced cardiac output and/or elevated intracardiac pressures at rest or during stress.

Inclusion criteria

Patients with a clinical definition of HF and LVEF of less than 50%.

Age >18 years.

Exclusion criteria

Patients of Acute Decompensated Heart Failure (ADHF).

Patients with other aetiology for fluid overload conditions like patients with chronic kidney disease, and chronic liver disease.

Patients with a diagnosed anaemia of another aetiology like chronic blood loss, anaemia of chronic disease like malignancy, etc. Patients with cyanotic congenital heart disease.

Anaemia was defined as Hb < 13  g/dl for males and <12 g/dl for females according to the World Health Organization definition.⁸ For diagnosing ID, serum ferritin <100 micro g/dl, functional ID was defined as normal serum ferritin (100–300 micro g/dl) with low Transferrin Saturation (TSAT) (<20%).⁹

The study was carried out over a one-year period from July 2021. All patients reporting to the centre who fulfilled the inclusion criteria and gave consent were screened for inclusion in the study. A total of 250 patients were screened for the study, out of which 46 were excluded based on the exclusion criteria, and 204 were enrolled in the study. With this sample size, the power of the study was calculated as 80% with an alpha error of 0.05.

Statistical analysis

Normally distributed data are presented as mean, Standard deviation. The Chi-square test and Student’s t-test were used to calculate P-value. For exploring the associations of ID and patient characteristics, univariate logistic regression was performed with variables for any association to obtain odds ratios and 95% confidence intervals. A two-tailed P < 0.05 will be considered statistically significant.

Results

A total of 204 patients with HF were included in this study, out of which 149 (73%) were males, and 55 (27%) were females. The mean age of subjects was 62.88 ± 10.13 years, the mean NYHA class was 2.48 ± 0.50, and the majority of patients had Coronary Artery Disease (CAD). The mean LVEF was 29.56 ± 6.52. The baseline demographic and clinical characteristics of patients are shown in Table 2.

Table 2.

Distribution of baseline demographic and clinical characteristics of cases studied.

		Male (n=149)		Female (n=55)		Total (n=204)
		n	%	n	%	n	%
Age group (years)	<50	13	8.7	10	18.2	23	11.3
	50–70	104	69.8	36	65.5	140	68.6
	>70	32	21.5	9	16.4	41	20.1
Co-morbidity	Diabetes	74	49.7	21	38.2	95	46.6
	Hypertension	65	43.6	19	34.5	84	41.2
	Coronary artery disease	101	67.8	23	41.8	124	60.8
Cardiac intervention	PCI	58	38.9	14	25.5	72	35.3
	CABG	3	2.0	1	1.8	4	2.0
	AICD/CRT	27	18.1	8	14.8	35	17.2
NHYA Class	Class 1	0	0.0	0	0.0	0	0.0
	Class 2	84	56.4	22	40.0	106	52.0
	Class 3	65	43.6	33	60.0	98	48.0
	Class 4	0	0.0	0	0.0	0	0.0
Duration of illness (months)	<6	89	59.7	25	45.5	114	55.9
	>6	60	40.3	30	54.5	90	44.1
Ejection fraction
	<30%	55	36.9	20	36.4	75	36.8
	30–39%	79	53.0	29	52.7	108	52.9
	40–49%	15	10.1	6	10.9	21	10.3

Out of 204 patients, 181 (88.7%) had ID, 170 (83.33%) had absolute ID and 11 (5.39%) had functional ID. In males, a total of 130 (87.2%) had absolute or functional ID, while in females, this figure was 92.7% (51 out of 55 females enrolled). Anaemia was present in a total of 144 (70.5%) patients. Among them, 93.8% had absolute or functional ID. Even in the absence of anaemia, up to 68.3% had absolute ID and 8.3% had functional ID; thus, a total of 76.6% of patients had some form of ID even in the absence of clinically detectable anaemia. The details of the distribution of absolute/functional ID in the patient population as per gender and presence/absence of anaemia are given in Table 3.

Table 3.

Association of anemia and iron deficiency in the study population.

Iron deficiency	Male (n = 149)				Female (n = 55)				Total (n = 204)
	Anemia Absent		Anemia Present		Anemia Absent		Anemia Present		Anemia Absent		Anemia Present
	n	%	N	%	n	%	N	%	N	%	n	%
No iron deficiency	12	26.7	7	6.7	2	13.3	2	5.0	14	23.3	9	6.3
Absolute iron deficiency	29	64.4	92	88.5	12	80.0	37	92.5	41	68.3	129	89.6
Functional iron deficiency	4	8.9	5	4.8	1	6.7	1	2.5	5	8.3	6	4.2
Total	45	100.0	104	100.0	15	100.0	40	100.0	60	100.0	144	100.0

When patient characteristics were subjected to univariate logistic regression analysis to find an association with ID, no significant association was found between most of them, including age, gender, EF, NYHA class, diabetes and hypertension (P > 0.05). Patients with anaemia had significantly more ID as compared to patients without anaemia, which is expected [Crude OR (95%CI) = 4.565 (1.853–11.248), P = 0.001]. Table 4.

Table 4.

Association of iron deficiency with clinical variables.

Characteristics	Crude OR (95%CI)	P value
Age in years (>70 vs <70)	2.338 (0.664–8.228)	0.208NS
Sex (Male vs Female)	1.863 (0.604–5.744)	0.328NS
Diabetes (Present vs Absent)	1.735 (0.701–4.295)	0.229NS
HTN (Present vs Absent)	1.357 (0.548–3.363)	0.508NS
NYHA class (II vs III)	1.505 (0.620–3.652)	0.364NS
Anemia (No vs Yes)	4.565 (1.853–11.248)	0.001∗∗∗
EF (<30% vs >30%)	1.717 (0.710–4.150)	0.226NS

HTN, Hypertension; EF, Ejection fraction; NS, Not significant; ∗∗∗, Significant.

We also studied various echocardiographic parameters and studied if there was any correlation between any of these parameters and the presence of ID in HF patients. No differences in the mean value of echocardiographic parameters like left ventricular ejection fraction (LVEF), right ventricular systolic pressure (RVSP), left ventricular internal dimension in diastole (LVIDd) and left atrium (LA) size were found between iron deficient and noniron deficient groups. E/e’ that is an indirect measure of LA pressure was significantly higher values in both absolute and functional iron deficient groups compared to the noniron deficient group (P-value <0.05). Table 5.

Table 5.

Distribution of mean values of some selected cardiac parameters according to iron Deficiency in the study group.

Parameters	Iron deficiency status
	No iron deficiency (n = 23)		Absolute iron deficiency (n = 170)		Functional iron deficiency (n = 11)		P-value
	Mean	SD	Mean	SD	Mean	SD
EF (%)	30.43	8.38	29.48	6.24	29.09	7.00	0.781NS
RVSP	32.17	7.44	33.88	8.88	34.09	13.57	0.689NS
E/e’	11.57	3.03	14.26	5.23	14.91	3.91	0.044∗
LVIDd	52.04	12.34	49.91	10.25	51.91	8.17	0.566NS
LA size	40.83	7.00	41.92	6.08	43.36	8.02	0.533NS

P-value by ANOVA. ∗P-value <0.05, NS, statistically nonsignificant.

Discussion

Iron is an essential micronutrient in living beings due to its role in oxygen transport and a key element for many enzymes in the citric acid cycle and reactive oxygen species (ROS) scavenging reactions. It can transport electrons in myriad cellular reactions, by switching between ferrous (Fe²+) and ferric (Feᶟ+) forms.¹⁰ The average human body contains about 3.5–4.5 g of iron, the majority of which is intracellular and is either bound to haemoglobin in red blood cells (60%) or stored in hepatocytes and macrophages within the liver and spleen (25%), where it is bound to a specialised cytoplasmic protein called ferritin.¹¹ Iron absorption is principally regulated by hepcidin, a protein secreted by liver cells. Hepcidin levels are elevated in conditions with chronic inflammation and hence, do not allow iron absorption, as well as release from storage sites for use in bone marrow for erythropoiesis.

Iron deficiency (ID) is prevalent in 30–50% western population with heart failure.^12,13 In studies, ID is found to be an independent predictor of morbidity and mortality in heart failure patients.⁶ ID can be absolute when total body iron is decreased, or functional, when total body iron is normal or increased but inadequate to meet the needs of target tissues because of sequestration in the storage pool. Recently a retrospective cohort study done on 78,805 patients admitted with heart failure across England showed that ID with or without anaemia in heart failure patients is associated with adverse outcomes with significantly increased inpatient mortality.¹⁴

Unfortunately, very few Indian studies are available on this subject. Small studies done by Indian researchers have shown a much higher prevalence of ID in HF patients in Indian subjects as compared to the western world. In a study by Sharma et al. that comprised 150 patients, the prevalence of absolute ID was present in 48% and functional ID was present in 27.3%; thus, a total of 76% were detected to have some form of ID.¹⁵ Another small study by Verma et al. that studied only 67 patients, found a total prevalence of ID in 67.5% of the HF patients they studied.¹⁶ A study by Arora et al. that studied Anemia profile in 275 patients in Delhi found ID in 53% of patients. There was no distinction between absolute and functional ID in this study.¹⁷ In our study, we found the magnitude of ID much more than all these studies with absolute ID at 83.3%, functional ID at 5.3% and a total of 88.7% of ID in HF patients.

Iron deficiency (ID) was more prevalent in women as compared to males in our study (92.7% vs 87.2%), though this difference was not statistically significant. Similar findings have been seen in a previous study by Sharma et al. wherein 68.6% of males and 91.6% of females had absolute or functional ID.¹⁵ The other two Indian studies did not mention the gender breakdown of the cases.^16,17 The increased prevalence of ID is expected as the prevalence of anaemia and ID is more common in women than men in our country; however, the difference was not statistically significant, as most of our patients were postmenopausal.

In our study, 93.75% of HF patients with anaemia had ID. In patients without anaemia, the prevalence of ID is 76.6% in our study, while in studies by Arora et al, and Sharma et al., these figures are 28.1% and 50.6%.^15,17 In our study distribution of NYHA class did not differ significantly across patients with or without ID (P > 0.05). This is in contrast to the results of previous studies, which had shown a significant correlation of higher NYHA class with ID. This could be explained by most patients in our study belonging to the mid-level NYHA class, and none were in class I or IV.

Ours is the first study where we have studied the correlation of various echocardiographic parameters with ID in HF patients to find out if any of these parameters could be a marker of ID in this subset. We found no significant difference with respect to EF, LA size, LVIDd and RVSP in HF patients with or without ID. Only E/e', a parameter of LA pressure and diastolic dysfunction, was significantly higher in ID patients. This might be due to cardiac fibrosis induced by myocardial ID. Animal studies have shown that ID anaemia induces the upregulation of cardiac hypoxia-inducible factor-1α gene expression, promotes cardiac fibrosis, decreases serum EPO concentration and cardiac STAT3 phosphorylation, which contribute to an inadequate transition from adaptive cardiac hypertrophy to cardiac dysfunction.¹⁸

Under normal conditions, serum ferritin correlates with body iron stores and is used as an indirect measure of iron status. For those with chronic HF, serum ferritin <100 ng/mL has been recommended as the cut point defining absolute ID. Similarly, functional ID in HF is defined as serum ferritin of 100–299 ng/mL with a TSAT < 20%.⁹ However, ferritin and transferrin levels are variable in HF patients being acute phase reactants, and hence, they have been questioned as ideal markers of ID in HF in recent studies. Alternate surrogate markers of ID like serum soluble transferrin receptor (sTfR) levels correlate best with bone marrow and myocardial ID in HF patients.^19,20 As of now, this test is far from the reach of the general population due to cost and widespread availability constraints. It is worthwhile to mention here that the 2016 ESC updated guidelines recommend ID evaluation based on assessments of serum ferritin and TSAT values.²¹

In this study, absolute ID was more common in all subsets of HF patients as compared to functional ID, which suggests that our patients have deficient iron stores and very few have adequate iron stores unavailable for use. The causes are many, e.g. poor oral intake, inadequate absorption due to gut wall oedema, loss from the gastrointestinal tract due to the use of antiplatelets and/or anticoagulants, etc. This makes them good therapeutic targets for iron supplementation.

In the past decade lot of stress has been given by researchers on oral and IV iron supplementation as potential targets to reduce morbidity and mortality in HF patients. Three large RCTs, FAIR HF, CONFIRM HF, and EFFECT HF, have proven the benefits of IV iron supplementation in HF patients in the form of improved quality of life scores, 6-min walk distance (6 MWD), NYHA class, and reduced rate of hospitalisation.22, 23, 24 Two meta-analyses, including these large RCTs and some small RCTs were published in succession to these studies and had shown reduced hospitalisation rates, as well as a reduction in overall mortality among HF patients with IV iron treatment.^25,26 In the IRONOUT HF study, oral iron supplementation was given to HF with ID patients for 16 weeks but no significant difference was found at 16 weeks in Peak Vo2, 6 MWD, NT pro BNP level and HF quality of life scores.²⁷ The 2017 ACC/AHA/HAS guidelines²⁸ state that IV iron may be reasonable in selected NYHA functional class II to III patients with HF (recommendation level II-B), and the 2016 ESC guidelines²⁰ recommend IV iron in symptomatic HFrEF to alleviate symptoms and improve functional status (IIA).

Limitations of study

This is a single-centre study conducted in a tertiary care hospital in Maharashtra, so the results of this study cannot be generalised. Second, it is an observational study with no controls. A larger sample size and follow up with treatment will further help in ascertaining the magnitude of the problem.

Conclusion

This study highlights the overwhelming prevalence of ID in heart failure patients with reduced EF with or without anaemia in the Indian population. A large number of patients will be missed if serum iron studies are not included in the evaluation of HF patients in addition to hemoglobin levels. Many large-scale studies worldwide have proven the benefits of iron supplementation in reducing morbidity and mortality in HF patients, and such studies are the need of the hour in the Indian population too.

Discloser of competing interest

The authors have none to declare.