Heart failure (HF) is a prevalent cardiovascular disease with high morbidity and mortality rates, defined as a complex clinical syndrome stemming from structural or functional ventricular impairment, resulting in symptoms such as dyspnea and fluid retention [1]. 

Coronary artery disease (CAD) is the leading cause of death in India, where the prevalence of iron deficiency among HF patients is high (76%) [2]. HF is classified into heart failure with preserved ejection fraction (HFpEF; LVEF ≥50%) [3] and reduced ejection fraction (HFrEF; LVEF ≤40%) [4]. HFrEF symptoms include dyspnea, fatigue, and ankle swelling, while right-sided HF may cause abdominal discomfort and early satiety [5]. Prognostic biomarkers and risk scores for heart failure (HF) exist, but they face limitations in accurately predicting hospitalizations, despite some effectiveness in mortality prediction. Chronic heart failure (CHF) disrupts iron metabolism, leading to low circulating and functional iron levels, even if overall reserves appear adequate. Anemia, a common comorbidity in HF, worsens patient outcomes, increasing hospital admissions, reducing exercise capacity, lowering quality of life (QoL), and raising mortality rates. Recent clinical studies have explored this hypothesis, positioning ID correction as a key intervention in HF management.

Iron deficiency (ID), commonly seen in chronic HF, impairs exercise capacity, quality of life, and survival, increasing hospitalizations. ID is often inferred from blood tests; however, definitions vary widely. WHO defines ID as a serum ferritin level <15 ng/mL, whereas HF guidelines set thresholds at <100 ng/mL or ferritin levels between 100-299 ng/mL  [7, 8]. Elevated serum ferritin, despite low iron levels, complicates diagnosis due to inflammation, which can falsely elevate ferritin levels [11, 12]. Recently, red cell distribution width (RDW) has gained attention as a prognostic marker for HF as higher the RDW, poorer are the outcomes in heart failure.RDW is accessible and cost-effective indicator, unlike NT-proBNP, which can be expensive in limited-resource settings [13, 14].

Hence we tried to classify heart failure patients according to ejection fraction and NYHA classification and tried to find out the outcomes of heart failure in different categories with red cell distribution width, ferritin and TIBC (iron binding capacity).

This study was conducted at department of general medicine at Sri Aurobindo Medical College and PG Institute, Indore. A total of 180 adult patients, aged over 18 years and of either gender, who presented with heart failure to the emergency or outpatient department during the 18-month study period (September 2022 to February 2024) and met the inclusion criteria, were enrolled. The severity of heart disease was classified according to the New York Heart Association (NYHA) criteria and ejection fraction. Then we correlated them with red cell distribution width, serum ferritin and total iron binding capacity.

Inclusion Criteria

• Subjects aged > 18 years of either sex who are a known case of heart failure and diagnosed by heart failure by 2D echo, within the study period.

Exclusion Criteria

• Subjects not consenting; Subjects who are a known case of hematological disorders; Subjects on iron supplements and Subjects on recent blood transfusion

All patients diagnosed with heart failure underwent thorough investigations. Sociodemographic data, including gender and age, as well as personal history, family history and medical history, symptoms, and clinical signs, were recorded using a pre-designed proforma.  

A thorough clinical examination was performed, and patients were assessed for iron deficiency using the iron profile alongside two-dimensional echocardiography. 

The criteria for diagnosis of HFREF and HFPRF are specified. Three criteria (symptoms typical of HF

+ signs typical of HF+ reduced LVEF) are required for HFREF, and four criteria (symptoms typical of HF + signs typical of HF+ normal/ mildly reduced EF+ relevant structural heart disease and/or diastolic dysfunction). Severity of heart failure as per NYHA classification was also noted within 24hrs of admission/consultation.

Routine hematological (CBC, prothrombin time, INR, RBS, HbA1c, urea, creatinine, Serum bilirubin, thyroid profile, and lipid profile) radiological investigations (Electrocardiograms and echocardiograms), and biochemical parameters, including serum iron, serum ferritin, total iron binding capacity, and unsaturated iron binding capacity, were recorded.

Following details were noted in patients and appropriate analysis was conducted:

• Ejection fraction by 2D echo;
• Serum ferritin levels by iron profile;
• Red cell distribution width (RDW) by CBC; and
• Variation of RDW and Serum ferritin with severity of heart failure on the basis of NYHA classification and ejection fraction.

Statistical Analysis

The collected raw data were entered into Microsoft Excel 10.0, then tabulated and analyzed using the Statistical Package for Social Sciences (SPSS) version 21.0 (IBM Corp., Armonk, NY, United States). Descriptive statistics, such as mean (SD), were applied for continuous variables, while frequency and percentages were used for categorical variables. ANOVA and Student’s t-tests were utilized to compare means, with a p-value < 0.05 considered statistically significant.

Clinicodemographic Profile: 

A total of 180 patients with heart failure were included in the study, with a mean (±SD) age of 58.36 (±11.6) years, and the majority (52.4%) were below the age of 60 years. The baseline characteristics of the participants are presented in [Table 1]. The study population consisted of 94 females (52.2%) and 86 males (47.8%). Most patients, 64 (35.6%), belonged to the Obese I category of the body mass index (BMI) classification.  

Of the total patients, 113 patients (62.8%) had reduced ejection fraction (HFrEF), while 67 patients (37.2%) had preserved ejection fraction. Within the HFrEF group, 59 were male and 54 were female, with male patients exhibiting a significantly lower ejection fraction than females, yielding a p-value of 0.012. 

Among the 180 patients assessed, 108 (60%) were diagnosed with ischemic heart disease, 49 (27.2%) with hypertensive heart disease, 18 (10%) with rheumatic heart disease, and 5 (2.8%) with non ischemic cardiomyopathy. Comorbidities were common, with 105 patients (58.3%) having hypertension, 102 (56.7%) having diabetes, and 61 (33.9%) being smokers

According to the New York Heart Association (NYHA) classification, the majority of patients were classified as class II, indicating mild impairment of functional status (76, 42.2%). A statistically non-significant difference was seen between the different sociodemographic characteristics. (P>0.05) 

*NYHA – New York Heart Association   

Table 1: Baseline clinicodemographic characteristics of the participants (N=180)

The iron profile in heart failure cases is shown in [Table 2].   Among males, the majority (47, 50%) had serum iron (S. iron) levels ranging from 60 to 160 μg/dl, with a mean (±SD) S. iron of 143.51 (±46.15) μg/dl. Among females, the majority (43, 50%) had S. iron levels of 35 to 145 μg/dl, with a mean (±SD) S. iron of 164.23 (±53.28) μg/dl. 

Most participants (88, 48.9%) had total iron-binding capacity (TIBC) values of 250 to 425 μg/dl, with a mean (±SD) of 330.68 (±81.28) μg/dl.

A large majority of male patients (86, 91.5%) had serum ferritin levels between 60 and 400 ng/dl, with a mean (±SD) of 389.62 (±90.81) ng/dl, and none had serum ferritin levels below 60 ng/dl.. The mean (±SD) serum ferritin for all female heart failure patients was 363.42 (±132.68) ng/dl. Most participants (72, 40%) had unsaturated iron binding capacity (UIBC) values greater than 360 μg/dl, with a mean (±SD) UIBC of 301.26 (±134.56) μg/dl.

Mean RDW in cases was 16.166±3.242. RDW is higher in patients with heart failure as compared to normal values. 28 of the 113 i.e.,24.7% patients of HFrEF had RDW ≤ 13.6 and 85 (75.3%) of them had RDW >13.6. 15 of the 67 patients i.e.,22.4% of HFpEF had RDW ≤ 13.6 and 52 (77.6%) had RDW > 13.6. There was no significant difference in the distribution of RDW between these two subgroups of heart failure population. They were comparable with a p value of 0.706. Further, there was no correlation between the RDW and LVEF with r value of 0.016 and p value of 0.880. Also, a significant negative correlation was observed between the age of the patients and their red cell distribution width (RDW) (r = -0.316, p < 0.003), indicating that younger patients tend to have higher RDW values. Additionally, a strong negative correlation was found between age and left ventricular ejection fraction (LVEF) (r = 0.222, p = 0.042), suggesting that as age increases, LVEF decreases.

Table 2: Iron profile of the participants (N=180)

The association between iron profile and heart failure severity is shown in [Table 3]. The ANOVA test indicated that serum iron and serum ferritin levels were significantly lower as the severity of heart failure increased, according to the NYHA classification (p-value<0.05). There was no significant difference observed between serum TIBC, serum UIBC, and the severity of heart failure (p-value>0.05). Post hoc analysis showed a significant difference in serum iron levels between class I and class IV patients. RDW values demonstrated an increasing trend with the New York Heart Association (NYHA) classification, and the differences between the groups were statistically significant, with a p-value of <0.001. [Table 3].

*NYHA – New York Heart Association, TIBC – Total iron binding capacity, UIBC – Undifferentiated iron binding capacity

Table 3: Association between iron profile and severity of heart failure (N=180)

The present study found the mean age of heart failure (HF) patients to be 58.36 ±11.6 years, with most female patients under 60, potentially due to higher admission rates and increased ischemic heart disease (IHD) risk in older women. This aligns with studies by Moliner P et al. [15] and Jain D et al. [16], while Celik A et al. [17] and Rudresh et al. [13] reported similar mean ages. 

Most HF patients in our study were classified as Obese I or at-risk according to BMI, similar study by Jankowska EA et al.showed 38.3% as class 1 obese [18], as obesity is a known HF risk factor. However, some research associates anemia with low BMI, as cachectic HF patients often experience anemia due to high levels of proinflammatory cytokines [19][20].

The left ventricular ejection fraction was noted from the echo report of the patients and they were divided into HFPEF and HFREF subgroups. Patients with EF ≤ 50 % were grouped into HFREF and those with EF > 50% were grouped into HFPEF (DHF). [21] Of the 180 patients 113(62.8%) patients had HFREF and remaining 67(37.2) had HFPEF. This was in concurrence with study dine by Rudresh et al. [13]

In the present study of 180 HF patients, 60% had ischemic heart disease (IHD), 27.2% had hypertensive heart disease, 10% had rheumatic heart disease, and 2.8% had nonischemic cardiomyopathy. This distribution is consistent with the findings by Yahya Al-Najjar et al. [23] and Rudresh et al. [13], where IHD was the primary HF etiology.

According to the NYHA classification, most HF patients in this study were classified as Class II (slight limitation in function), which contrasts with Bhutia A et al. [22], who found most patients in Class IV due to the tertiary care setting’s focus on more severe cases [23].

Regarding serum iron levels, most male HF patients had serum iron between 60-160 μg/dl, while most female patients ranged between 35-145 μg/dl. Mean serum iron was 143.51 (46.15) μg/dl for males and 164.23 (53.28) μg/dl for females. A significant inverse relationship between serum iron and HF severity (p < 0.05) was observed, aligning with Bhutia A et al. [22], who noted that HF-induced iron deficiency anemia worsens with disease progression.

In this study, the mean (SD) serum ferritin levels were 389.62 (90.81) ng/dl for male HF patients and 363.42 (132.68) ng/dl for female HF patients. Anemia in HF patients often results from reduced erythropoietin production or response, critical for red blood cell formation, as noted by Bauer C et al. [24], Jelkmann W et al. [25], and Donnelly S et al. [26]. Reduced erythropoietin affects erythrocyte maturation, while iron deficiency—observed in 30% of anemic HF patients—contributes to normocytic anemia, typically labeled as anemia of chronic disease [28].

Red cell distribution width (RDW), indicating the variability in red blood cell size, was assessed in this study to differentiate anemia types and detect early iron and folate deficiencies. A higher RDW, with values above 13.6 as indicated by Celik A et al. [17], correlates with poorer outcomes in patients with cardiovascular events. Elevated RDW is also associated with inflammatory conditions such as ulcerative colitis, often alongside other markers like C-reactive protein and erythrocyte sedimentation rate [9].

Elevated red cell distribution width (RDW) in heart failure (HF) may stem from factors like impaired bone marrow function or increased red cell destruction, with inflammation potentially playing a role due to its established link with HF. Celik et al. [17] suggest that elevated RDW in HF patients is related to neurohormonal activity, impaired renal function, and increased filling pressure, though they found no significant connection with inflammation, leaving the mechanism for RDW elevation unclear and in need of further investigation.

An abnormal iron profile, including parameters like serum iron, binding capacity, serum ferritin, and

RDW, is significantly associated with HF severity, consistent with studies by Yeo TJ et al. [29], Parikh A et al. [30], Bhutia A et al. [22], and Bolger AP et al. [31]. However, a direct causal relationship could not be confirmed. With HF's rising global prevalence, managing associated comorbidities such as iron deficiency is increasingly prioritized, as it adversely impacts HF outcomes. Intravenous iron, especially ferric carboxymaltose, has shown clinical benefits regardless of anemia status, a treatment approach endorsed by cardiology societies worldwide [32].

Limitations: Larger, multicenter longitudinal studies are recommended to explore temporal associations further. This study did not include hemoglobin levels or anemia severity, limiting the assessment of anemia's role in HF outcomes.

The study demonstrates that heart failure (HF) is associated with significantly altered serum iron levels, serum ferritin, and total iron-binding capacity, especially as HF severity increases. Red cell distribution width (RDW), available as part of a standard complete blood count, serves as an effective prognostic marker and is a cost-effective alternative to NT-proBNP measurements in assessing HF risk. Given these findings, screening for iron deficiency in HF patients is highly recommended, as correcting iron deficiency may improve functional capacity and reduce rehospitalization rates following acute HF.

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