Heart failure (HF) is when the heart can't pump enough blood to meet the body's needs. Over the years, studies have shown that not having enough iron (ID) is a common and important issue in people with HF, even if they don't have anemia (Alnuwaysir et al., 2021) [1]. While low blood levels are often linked with HF and ID, recent research suggests that just being low on iron, no matter the blood levels, plays a big role in making HF symptoms worse and lowering how well a person can function (Caminiti et al., 2023) [2].

Iron is crucial for cardiovascular homeostasis since it plays essential roles in a plethora of physiological processes such as oxygen transport, mitochondrial function, and cellular energy production (Sindone et al., 2022) [3]. It has been demonstrated that the presence ID in HF subjects, without coexisting anemia, is closely linked with an adverse prognosis, lower exercise tolerance, and even more frequent hospitalizations (Ismahel & Ismahel 2021) [4]. This is why more attention has been (Shamsi et al., 2023) [5] paid to the detection and correction of iron deficiency in HF patients, with or without concomitant anemia, which is becoming increasingly important in cardiovascular research and clinical practice.

The pathophysiology of ID in HF is complex and consists of decreased dietary intake, deranged gastrointestinal absorption, chronic inflammation, and iron store redistribution resulting from elevated levels of hepcidin (Becher et al., 2021) [7]. Chronic inflammation in HF has been found to raise hepcidin, an inhibitory hormone that suppresses intestinal iron absorption and sequesters iron within macrophages, further promoting ID (Chopra & Anker, 2020) [8]. These mechanisms play a role in iron depletion even when there is no overt anemia, and hence it is a specific and important factor to be addressed in HF management (Camilli et al., 2025) [6].

Even with its high prevalence and adverse effect on HF outcomes, ID is underdiagnosed and undertreated in clinical practice. The European Society of Cardiology (ESC) and other guidelines suggest screening for ID in HF patients on a routine basis by using ferritin and transferrin saturation levels as markers (Alnuwaysir et al., 2021) [1]. The emerging evidence is in favor of intravenous iron therapy as an effective treatment to enhance symptoms, quality of life, and exercise capacity in HF patients with ID (Sindone et al., 2022) [3]. Nonetheless, the role of ID in non-anaemic HF remains a topic of current investigation, with the need for further studies on its prevalence, clinical influence, and best treatment approach.

The current article seeks to critically review the burden of iron deficiency in non-anaemic HF patients and underscore its clinical significance and implication for early diagnosis and intervention. Through the consolidation of recent scientific findings, the present study draws attention to the need to manage ID as an independent therapeutic objective in the management of HF.

This was a cross-sectional observational study aimed at establishing the prevalence of iron deficiency among non-anaemic heart failure patients. The study was set in a DDMCH, Keonjhar hospital, where patients with heart failure were recruited from the inpatient wards and cardiology outpatient department.

Study Population

Adult patients aged 18 years and above with a diagnosed heart failure, according to standard clinical guidelines, were studied. The inclusion criteria demanded that the patients must have stable heart failure, characterized by the fact that they did not have any hospitalization for acute decompensation in the past three months. Patients were defined as non-anaemic according to a haemoglobin concentration ≥12 g/dL in women and ≥13 g/dL in men, according to the World Health Organization (WHO) definition of anaemia. Patients with chronic kidney disease (stage IV or more), active infections, inflammatory conditions, recent blood transfusions, or known haematological diseases that influence iron metabolism were excluded to reduce confounding factors.

Data Collection and Clinical Assessment

Demographic and clinical data were collected through patient interviews and electronic medical records. Information on age, sex, comorbidities (such as diabetes, hypertension, and dyslipidemia), medication use, and New York Heart Association (NYHA) functional classification was recorded. A thorough physical examination was conducted to assess signs of congestion, fatigue, and reduced exercise tolerance.

Laboratory Investigations

Venous blood samples were collected after an overnight fast for biochemical and haematological analysis. Iron status was evaluated with serum ferritin, transferrin saturation (TSAT), and serum iron. Absolute iron deficiency was established by serum ferritin <100 ng/mL, and functional iron deficiency was determined by ferritin of 100–299 ng/mL with TSAT <20%. Complete blood count, serum creatinine, and inflammatory markers like C-reactive protein (CRP) were also determined to exclude other causes of iron dysregulation.

Echocardiographic and Functional Assessment

Transthoracic echocardiogram was done on all the subjects to evaluate the left ventricular ejection fraction (LVEF), diastolic performance, and anatomical abnormalities. The patients were classified into heart failure with decreased ejection fraction (HFrEF, LVEF <40%), heart failure with modestly decreased ejection fraction (HFmrEF, LVEF 40–49%), and heart failure with preserved ejection fraction (HFpEF, LVEF ≥50%). A six-minute walk test (6MWT) was performed to assess functional capacity, and patient-reported outcomes such as fatigue severity and quality of life were evaluated with validated questionnaires.

Statistical Analysis

Statistical software was used to analyze data, reporting continuous variables as mean ± standard deviation and categorical variables as frequencies and percentages. Independent t-tests or Mann-Whitney U tests were used to compare differences between iron-deficient and iron-sufficient groups for continuous variables, and chi-square or Fisher's exact tests for categorical variables. Independent predictors of iron deficiency among non-anaemic heart failure patients were determined using logistic regression analysis. All analyses had a p-value <0.05 as the cut-off for statistical significance.

Baseline Characteristics of the Study Population

In this study, 250 patients with heart failure were looked at, and 180 (72%) of them did not have anemia based on their haemoglobin levels. The average age was 62.5 years, and 58% were male. Among the group, 65% had high blood pressure, 48% had diabetes, and 30% had heart artery disease history. The types of heart failure were 45% HFrEF, 32% HFmrEF, and 23% HFpEF. Table 1 shows the main details of these patients.

Prevalence of Iron Deficiency in Non-Anaemic Heart Failure

Iron deficiency was found in 92 (51.1%) of the heart failure patients who were not anemic. Of these, 60 patients (65.2%) had absolute iron deficiency, and 32 patients (34.8%) had functional iron deficiency. Iron deficiency was most common in HFrEF patients (56.7%), then HFpEF patients (50.0%), and least in HFpEF patients (41.2%). Those with iron deficiency had much lower serum ferritin (average 82.4 ± 15.6 ng/mL) and TSAT (16.3 ± 4.8%) than those with enough iron. Table 2 shows a detailed comparison between the iron-deficient and iron-sufficient groups.

Impact of Iron Deficiency on Functional Capacity

Patients who lack enough iron showed much shorter distances in a six-minute walk test (6MWT) when compared to those with enough iron (310.2 ± 52.8 m vs. 370.5 ± 49.7 m, p<0.01). Also, the scores for feeling very tired were higher in the group with less iron, with an average score of 4.3 ± 1.1 versus 3.1 ± 1.0 in the group with enough iron (p=0.002). Figure 1 shows these differences in 6MWT distances between the two groups.

Association of Iron Deficiency with Inflammatory Markers and Cardiac Function

Chronic inflammation in ID, which led to the patients having higher CRP levels compared to those without ID (7.8±2.5mg/L vs. 4.6±1.8mg/L, p<0.05).Echocardiographic parameters showed that LVEF was lower in the ID group than in the iron-sufficient group (38.2 ± 6.4% vs. 41.5 ± 5.9%; p =0.034) suggesting that cardiac function is also involved in ID. The CRP and LVEF values in both groups were compared in Figure 2

Table 1: Baseline Characteristics of the Study Population

Table 2: Comparison of Iron-Deficient and Iron-Sufficient Groups

Figure 1: Comparison of Six-Minute Walk Test (6MWT) Distances Between Iron-Deficient and Iron-Sufficient Groups

FIgure 1 showing mean 6MWT distances in both groups, highlighting a significant reduction in functional capacity in patients with iron deficiency.

Figure 2: C-Reactive Protein (CRP) and Left Ventricular Ejection Fraction (LVEF) in Iron-Deficient and Iron-Sufficient Groups

Figure 2 illustrates the inverse correlation between CRP levels and LVEF, indicating the potential role of inflammation in iron deficiency and cardiac dysfunction.

However, it may be inferred that there is a great burden associated with the scarcity of iron in patients suffering from non-anaemic heart failure, which brings into light its connection with weak exercise tolerance, higher chances of tiredness and a damaged cardiac function. These results reinstated the fact that courses serving to enlighten and voice against the poverty of iron in this public need to be due attention and properly treated

The results of this research confirm the high burden of iron deficiency in non-anaemic patients with heart failure, at 51.1% in the study population. This is supported by earlier findings that ID occurs frequently in heart failure, irrespective of anaemia, and correlates with reduced functional capacity, higher inflammation, and deteriorating cardiac function (von Haehling et al., 2017) [9]. ID in the absence of haemoglobin levels emphasizes regular screening in patients with HF since iron is indispensable in mitochondrial energy metabolism, oxygen delivery, and cardiovascular homeostasis as a whole (Jankowska & Ponikowski, 2023) [12].

Absolute iron deficiency was more common than functional iron deficiency in this study, and 65.2% of ID patients had ferritin less than 100 ng/mL. These results are consistent with the PrEP Registry, which indicated that absolute iron deficiency was responsible for most ID cases of chronic heart failure (von Haehling et al., 2017) [9]. This is a clinically important distinction because patients with absolute iron deficiency would be more likely to gain from iron replacement therapy, specifically intravenous iron products, which are not limited by intestinal malabsorption and were found to increase exercise tolerance and quality of life (Tkaczyszyn et al., 2023) [11].

One interesting finding in this research was the correlation of ID with lower six-minute walk test (6MWT) distance and higher fatigue severity. ID patients walked 310.2 meters on average versus 370.5 meters in iron-replete patients, showing a definite impairment of functional capacity. The same has been observed by Dhaliwal and Kalogeropoulos (2023) [13], who highlighted that iron deficiency is a significant cause of decreased exercise tolerance in HF, regardless of anaemia. This impairment in exercise performance is thought to be owing to the contribution of iron in mitochondrial oxidative phosphorylation, deficiency of which handicaps ATP production and results in premature muscle fatigue and dyspnoea (Mareev et al., 2021) [10].

The inflammatory pattern of ID patients in the current study is also noteworthy in that increased levels of CRP were strongly related to ID. Inflammation has been identified as a main cause of HF-related iron dysregulation through hepcidin-mediated inhibition of mobilization and absorption of iron (Van Aelst et al., 2017) [14]. The presence of increased levels of CRP among ID patients indicates that iron sequestration by chronic low-grade inflammation is also a contributor to functional restriction. This is consistent with prior research showing inflammatory mechanisms in HF can not only induce iron deficiency but also adversely affect disease prognosis (Dhaliwal & Kalogeropoulos, 2023) [13].

Cardiac performance, as measured by echocardiographic indices, had a high correlation between ID and decreased left ventricular ejection fraction (LVEF). Patients with ID had an average LVEF of 38.2%, whereas that of the iron-sufficient group was 41.5%. Although this disparity appears small, it supports earlier findings indicating that iron deficiency is associated with compromised myocardial efficiency and enhanced ventricular stiffness (Bakogiannis et al., 2020) [15]. The function of iron in cardiac function is well documented, especially in the preservation of mitochondrial function in cardiomyocytes. Research has indicated that iron-deficient myocardium has decreased oxidative capacity, resulting in energetic deficits that contribute to cardiac dysfunction (Tkaczyszyn et al., 2023) [11].

Notably, this study also identified that ID was more common in HFrEF (56.7%) than in HFpEF (41.2%), though a considerable percentage of HFpEF patients were involved as well. This is in keeping with current literature indicating that iron deficiency is not limited to reduced ejection fraction phenotypes but is involved in HFpEF pathophysiology, perhaps through its implications on skeletal muscle dysfunction and endothelial nitric oxide bioavailability (Mareev et al., 2021) [10]. In view of the increasing acknowledgment of HFpEF as a significant public health issue, more studies must be conducted in investigating the role of iron supplementation in this subgroup.

The clinical significance of the results depends largely on the fact that iron deficiency has been recognized as a modifiable risk factor in heart failure. Modern practice recommends regular screening of ID in HF patients, irrespective of anaemia status, and intravenous iron therapy as a treatment, especially in symptomatic patients with low LVEF (Jankowska & Ponikowski, 2023) [12]. The additional benefits of iron supplementation beyond the correction of ID include exercise tolerance, NYHA functional class, and quality of life improvements after iron therapy (Bakogiannis et al., 2020) [15]. Nonetheless, amid these suggestions, iron deficiency continues to be underdiagnosed and undertreated in regular clinical practice, as evidenced by the emphasis on the necessity for greater awareness and implementation of screening protocols (Van Aelst et al., 2017) [14].

Although this research presents informative data regarding the prevalence and implications of iron deficiency among non-anaemic heart failure patients, some limitations must be noted. The cross-sectional nature restricts the determination of causality between ID and functional impairment. Moreover, the study did not evaluate long-term clinical outcomes like hospitalization rates or mortality, which would give a better insight into the prognostic value of ID in this group. Prospective trials on the effects of iron supplementation in non-anaemic HF patients should be aimed at in future research to establish optimal treatment.

In summary, this study highlights the very high prevalence of iron deficiency in non-anaemic heart failure patients and its strong association with lower functional capacity, higher inflammation, and adverse cardiac function. These observations highlight the need for routine iron status checking in HF patients and justify the need for specific therapeutic interventions to improve clinical outcomes. Considering the increasing amount of evidence pointing to the harmful impact of ID in HF, the treatment of iron deficiency must be a part of overall heart failure management plans.

This research emphasizes the frequent occurrence of iron deficiency in non-anaemic heart failure patients and its substantial influence on functional capacity, inflammatory status, and cardiac function. The results strengthen the increasing evidence that iron deficiency, even without anemia, is responsible for decreased exercise tolerance, greater fatigue, and deteriorating left ventricular function. With its reversible pathology and the existence of successful iron supplementation protocols, elective screening for iron deficiency must be integrated into heart failure treatment to maximize patient outcomes. Further investigation would be appropriate to determine the long-term advantage of iron repletion in this group and to define targeted therapeutic strategies for enhancing quality of life and disease prognosis in heart failure patients with iron deficiency.

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