European Journal of Cardiovascular Medicine

Heart failure (HF) is a complex clinical syndrome characterized by the inability of the heart to pump blood adequately to meet the body’s metabolic demands. It arises from structural or functional cardiac abnormalities involving the myocardium, pericardium, endocardium, valves, or great vessels, and may also be precipitated by systemic metabolic disorders [1]. Based on left ventricular ejection fraction (LVEF), HF is classified into three categories: heart failure with reduced ejection fraction (HFrEF, LVEF ≤45%), heart failure with preserved ejection fraction (HFpEF, LVEF ≥50%), and heart failure with mid-range ejection fraction (HFmrEF, LVEF 45–49%). HFrEF, also referred to as systolic HF, is of particular clinical concern due to its high morbidity, mortality, and frequent hospitalizations. The clinical manifestations of HF include symptoms related to fluid overload—such as dyspnea, orthopnea, edema, hepatic congestion, and ascites—as well as those due to reduced cardiac output, including fatigue and exercise intolerance [2]. These symptoms are driven by neurohormonal activation, particularly the renin–angiotensin–aldosterone system and sympathetic nervous system, which perpetuate fluid retention and disease progression.

The global burden of HF is substantial, with an estimated 23 million individuals affected worldwide. In India, the prevalence is estimated at approximately 1% of the population, translating to 8–10 million individuals, with annual mortality ranging between 0.1–0.16 million according to the INDUS study [3, 4]. The prevalence of HF increases steeply with advancing age, as demonstrated by the Framingham Heart Study, which reported a prevalence of 8 per 1000 in men aged 50–59 years, rising to 66 per 1000 in those aged 80–89 years; similar trends were observed in women [5-11]. Furthermore, disparities exist across populations, with African-American individuals experiencing a 25% higher prevalence compared to White populations. With increasing life expectancy and improved survival from acute cardiovascular events, the prevalence of HF continues to rise, making it a major public health challenge [5-12]. Among the comorbidities that complicate the course of HF, iron deficiency has emerged as a particularly important yet under-recognized factor. Iron deficiency in HF is defined by serum ferritin <100 μg/L, or ferritin 100–300 μg/L with transferrin saturation <20% [13]. Importantly, iron deficiency may occur with or without anaemia, and its symptoms—fatigue, reduced exercise tolerance, and weakness—often overlap with those of HF itself, leading to underdiagnosis [12]. Evidence suggests that iron deficiency is associated with worse functional capacity, poorer quality of life, increased risk of rehospitalization, and reduced survival in patients with HFrEF. Clinical trials have demonstrated that correction of iron deficiency, particularly via intravenous supplementation, improves exercise capacity and reduces HF-related hospitalizations, as oral supplementation is often ineffective due to inflammation-driven sequestration and impaired absorption [12].

Despite these findings, there remain significant gaps in the literature. While international studies have highlighted the prognostic importance of iron deficiency in HF, data from low- and middle-income countries, including India, remain limited. The prevalence of iron deficiency in Indian patients with HFrEF, its correlation with hospitalization frequency, and its interaction with common comorbidities such as diabetes and hypertension are not well characterized. Given the high burden of HF in India and the financial and social implications of recurrent hospitalizations, addressing this knowledge gap is of both clinical and public health importance. The rationale for the present study lies in the need to better understand the association between iron deficiency and hospitalization frequency in patients with HFrEF in the Indian context. By evaluating iron status in this population and correlating it with hospitalization patterns and comorbid risk factors, this study aims to generate evidence that may inform routine screening and management strategies.

Based on existing evidence, the study hypothesizes that iron deficiency is significantly associated with increased hospitalization frequency in patients with HFrEF, independent of other risk factors such as diabetes and hypertension. The central research question is: Does iron deficiency contribute to increased hospitalization frequency in patients with heart failure with reduced ejection fraction, and how does this association interact with other comorbidities such as diabetes and hypertension?

The objectives of this study are twofold. First, to evaluate the iron status of patients with chronic HFrEF. Second, to examine the correlation between iron deficiency and hospitalization frequency, while also assessing the influence of additional risk factors such as diabetes and hypertension.

This was a hospital-based, cross-sectional observational study conducted in the Department of Medicine, S.S.G. Hospital, Vadodara, Gujarat. A total of 80 patients fulfilling the eligibility criteria were enrolled. The study was carried out over a period of six months, from November 2021 to April 2022, after obtaining approval from the Institutional Ethics Committee. Written informed consent was obtained from all participants prior to inclusion in the study.

Study Population

The study population comprised adult patients (>18 years) with a confirmed diagnosis of chronic HFrEF (LVEF <50%) attending the medical outpatient department (OPD) and inpatient services of S.S.G. Hospital. Patients were recruited consecutively during the study period.

Inclusion criteria:

• Age >18 years
• Diagnosis of chronic heart failure with reduced ejection fraction (LVEF <50%) confirmed by echocardiography

Exclusion criteria:

• Patients with LVEF >50%
• Age <18 years
• Anemia due to causes other than iron deficiency (e.g., hemolytic anemia, megaloblastic anemia, hemoglobinopathies, chronic kidney disease-related anemia)

Data Collection

Data were collected using a structured case record form. Each patient underwent a detailed clinical evaluation, including demographic details (age, sex, hospital registration number) and clinical history.

Clinical data:

• Presenting complaints: cough, generalized weakness, dyspnea (graded according to NYHA classification), chest pain, pedal edema, facial puffiness
• Past history: duration of heart failure, number of hospitalizations due to HF exacerbations, presence of comorbidities such as diabetes mellitus and hypertension

Investigations: All patients underwent standard investigations to confirm diagnosis and assess iron status:

• Cardiac evaluation: 2D echocardiography, ECG, chest X-ray (PA view)
• Laboratory tests: Complete blood count (CBC), renal function tests (RFT), liver function tests (LFT), serum ferritin, serum iron, total iron-binding capacity (TIBC)
• Additional tests (if indicated): Vitamin B12 levels, lactate dehydrogenase (LDH), peripheral smear, reticulocyte count, haemoglobin electrophoresis, NT-proBNP

Iron deficiency was defined as serum ferritin <100 μg/L, or ferritin 100–300 μg/L with transferrin saturation <20%, in accordance with established guidelines.

Methodology

Patients were evaluated at baseline for demographic, clinical, and biochemical parameters. The severity of HF was assessed using the NYHA functional class. The number of hospitalizations due to HF in the preceding 12 months was recorded from patient history and hospital records. Iron status was determined using serum ferritin, serum iron, and TIBC. Patients were categorized into iron-deficient and non–iron-deficient groups, and hospitalization frequency was compared between these groups.

To minimize confounding, patients with anaemia due to other causes were excluded. Comorbidities such as diabetes and hypertension were documented to assess their modifying effect on the relationship between iron deficiency and hospitalization frequency.

Statistical Analysis

Data were entered into Microsoft Excel and analyzed using Graph Pad version 8.4.3. Descriptive statistics were used to summarize baseline characteristics: categorical variables were expressed as frequencies and percentages, while continuous variables were presented as mean ± standard deviation (SD). Comparisons between groups (iron-deficient vs. non–iron-deficient) were performed using the Chi-square test for categorical variables and Student’s t-test for continuous variables. A p-value <0.05 was considered statistically significant

A total of 80 patients with chronic heart failure with reduced ejection fraction (HFrEF) were included in the study. The mean age of the study population was 57 ± 11.65 years, with the majority belonging to the 60–69 years age group. Males constituted two-thirds of the cohort. The prevalence of comorbidities such as diabetes and hypertension was 26.2% each [Table 1].

Table 1. Baseline Characteristics of Study Population (N = 80)

Iron deficiency was observed in 43.8% of patients, while 56.2% had normal iron status. The majority of patients (65%) had severely reduced LVEF (<30%) [Table 1].

Figure 1: Past History of Hospitalization

When stratified by iron status, patients with iron deficiency were more likely to have multiple hospitalizations. In the iron‑deficient group, 40% had two admissions and 22.8% had >2 admissions, compared to 28.9% and 6.7% respectively in the non‑deficient group. This association was statistically significant (p = 0.026) [Table 2].

Table 2: Association Between Iron Deficiency and Hospitalization Frequency

A significant association was also observed between iron deficiency and severity of LV dysfunction. Among patients with iron deficiency, 82.9% had LVEF <30%, compared to 51.1% in the non‑deficient group (p = 0.003) [Table 3].

Table 3: Association Between Iron Deficiency and LVEF

Table 4: Association between Lab Parameters and iron deficiency

Individuals with iron deficiency had significantly lower levels of ferritin and transferrin saturation and significantly higher levels of total iron-binding capacity (TIBC) compared to the non-deficient group, as indicated by P values less than 0.001. In contrast, there was no significant difference between the two groups for hemoglobin, serum iron, and S Nt pro BNP, as their P values were greater than 0.05 [Table 4].

In this cross‑sectional study of 80 patients with heart failure with reduced ejection fraction (HFrEF), we evaluated the prevalence of iron deficiency (ID) and its association with hospitalization frequency and left ventricular function. A comprehensive clinical and laboratory assessment was performed, including iron studies, to delineate the burden of ID in this population.

Iron plays a pivotal role in both hematopoietic processes (erythropoiesis, oxygen transport, and storage) and non‑hematopoietic functions such as mitochondrial energy metabolism and substrate utilization. Deficiency of iron, even in the absence of anemia, impairs oxygen delivery and utilization, thereby contributing to hallmark symptoms of HF such as fatigue, dyspnea, and reduced exercise tolerance [14,15]. Several mechanisms underlie the development of ID in HF, including reduced dietary intake, impaired absorption due to hepcidin‑mediated blockade, chronic inflammation leading to iron sequestration in the reticuloendothelial system, and occult gastrointestinal blood loss, particularly in patients on antithrombotic therapy [16].

The mean age of patients in our study was 57 ± 11.65 years, which is slightly younger than that reported by Rangel et al. (62 years) and Okonko et al. (71 years) [17, 18]. This difference may reflect regional variations in disease onset and survival. Male predominance (66.2%) was observed, consistent with prior studies by Schou et al. (65.1%) and Okonko et al. (72%) [18, 19]. The prevalence of diabetes (26.2%) and hypertension (26.2%) in our cohort was somewhat lower than that reported in Western studies, where comorbidity rates often exceed 30–50% [17, 19]. This may reflect differences in referral patterns, population characteristics, or underdiagnosis.

Hospitalization is a key marker of HF severity and progression. In our study, 52.5% of patients had one prior hospitalization, 33.8% had two, and 13.7% had more than two. These findings are broadly comparable to Mini et al., who reported 34% with one admission and 35.5% with two [20]. Importantly, within our cohort, ID was strongly associated with higher hospitalization frequency: 40% of ID patients had two admissions and 22.8% had more than two, compared to 28.9% and 6.7% respectively in the non‑ID group. This underscores the clinical relevance of ID as a driver of recurrent decompensation.

We found that 43.8% of patients had ID, of which 82.9% had absolute ID and 17.1% had functional ID. This prevalence is consistent with prior reports: Rangel et al. (36%), Schou et al. (44.9%), Anand et al. (50%), and von Haehling et al. (42.5%) [17, 19, 21, 22]. Across studies, the prevalence of ID in HF ranges from 37% to 76%, highlighting its ubiquity [18, 23, 24]. Our finding of a higher proportion of absolute ID compared to functional ID contrasts with Rangel et al., where functional ID accounted for 43% [17]. This may reflect differences in inflammatory burden, nutritional status, or population characteristics.

In our study, 65% of patients had severely reduced LVEF (<30%). Notably, 82.9% of ID patients fell into this category compared to 48.9% of non‑ID patients, a statistically significant difference. This aligns with Rangel et al., who reported mean LVEF of 26.7% in ID patients versus 28.2% in non‑ID patients, and Schou et al., who found similar trends [17, 19]. These findings suggest that ID is not merely a comorbidity but may be mechanistically linked to worsening ventricular dysfunction, possibly through impaired myocardial energetics.

Laboratory analysis confirmed significantly lower ferritin and transferrin saturation, and higher TIBC in the ID group, consistent with diagnostic criteria. Hemoglobin levels were comparable between groups, reinforcing the concept that ID in HF often precedes or occurs independently of anemia. NT‑proBNP levels were elevated in both groups, reflecting advanced disease, but did not differ significantly. These findings mirror those of Rangel et al. and Schou et al., who also demonstrated marked differences in iron indices but not in hemoglobin [17, 19].

Our findings reinforce the growing body of evidence that ID is highly prevalent in HFrEF and is associated with worse outcomes, including more frequent hospitalizations and more severe LV dysfunction. Importantly, ID is a modifiable risk factor. Thus, routine screening for ID in HF patients should be considered an essential component of comprehensive care.

This study has certain limitations. Being cross‑sectional, it cannot establish causality between ID and hospitalization frequency. The sample size was modest and drawn from a single tertiary care center, which may limit generalizability. Furthermore, we did not assess long‑term outcomes such as mortality or response to iron supplementation

This study demonstrates a significant association between iron deficiency and increased hospitalization frequency in patients with heart failure with reduced ejection fraction (HFrEF), with iron-deficient patients experiencing a higher number of hospital admissions compared to those with normal iron status. Additionally, iron deficiency was strongly correlated with more severe left ventricular dysfunction, as indicated by a lower LVEF. These findings underscore the clinical and prognostic relevance of iron deficiency in HFrEF and highlight the importance of routine screening and management of iron status to potentially reduce hospitalizations and improve outcomes in this patient population.

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