Introduction

Heart failure (HF) is a leading global cardiovascular public health crisis, affecting approximately 56.5 million people worldwide, with an age-standardized prevalence that rose from 647.9 to 682.7 per 100,000 between 1990 and 2021, and estimates suggest over 80 million individuals may be affected when broader diagnostic criteria are applied [1,2]. Heart failure with preserved ejection fraction (HFpEF) has emerged as the dominant HF phenotype, currently accounting for approximately 50% of all HF cases, with its prevalence expected to surpass that of heart failure with reduced ejection fraction (HFrEF) in the coming decades [3]. Despite a five-year survival below 50%, comparable to HFrEF and a rising hospitalization burden, HFpEF lacks disease-modifying therapies with proven mortality benefit, underscoring its formidable clinical challenge [3,4].

The pathophysiology of HFpEF reflects a systemic, multifactorial syndrome driven by common comorbidities such as obesity, hypertension, type 2 diabetes, and chronic kidney disease, which induce chronic low-grade inflammation, endothelial dysfunction, and oxidative stress [5]. These processes result in myocardial microvascular inflammation, reduced nitric oxide bioavailability, titin hypophosphorylation, and increased cardiomyocyte stiffness, producing the hallmark diastolic dysfunction, elevated filling pressures, and exercise intolerance characteristic of HFpEF [5]. Concurrent mitochondrial dysfunction further impairs cellular energy generation, explaining why HFpEF remains resistant to neurohormonal therapies that are effective in HFrEF [5].

Iron deficiency (ID) is an increasingly recognized and clinically important comorbidity in chronic HF. Iron is indispensable for oxygen transport, mitochondrial electron transport, and cellular energy metabolism; its deficiency directly impairs cardiac and skeletal muscle oxidative function, contributing to fatigue and exercise intolerance independent of anaemia [6]. ID affects 30-70% of HF patients, including approximately 50% of outpatients and 72-83% of those with acute decompensated HF, and is associated with higher NYHA functional class, elevated NT-proBNP, increased HF hospitalization, and greater mortality risk [7,8].

In HFpEF specifically, ID is highly prevalent - a systematic review estimated a pooled prevalence of 59% - and is associated with worsened diastolic dysfunction, impaired exercise capacity, poorer quality of life, and worse prognosis [9]. Intravenous ferric carboxymaltose (FCM) has demonstrated clinical benefits in HFrEF, supported by the AFFIRM-AHF trial and a meta-analysis of 14 RCTs [10,11]. However, evidence in HFpEF remains limited; the dedicated FAIR-HFpEF trial was stopped early after 39 patients, though it showed a meaningful improvement in six-minute walk test distance, leaving the therapeutic role of iron repletion in HFpEF inconclusive [12].

In low- and middle-income countries (LMICs) such as Bangladesh, cardiovascular disease (CVD) has recently surpassed infectious diseases as the leading cause of death, and Bangladesh experienced a 27.4% increase in overall CVD burden in recent decades [13]. Data from the GBD study (Global Burden of Diseases, Injuries, and Risk Factors Study) place Bangladesh's age-standardized HF prevalence at 275 per 100,000, with South Asia showing an increasing regional trend [14]. Despite this growing burden, local evidence characterizing ID in HFpEF patients remains virtually absent, and the distinct nutritional status and comorbidity profiles of Bangladeshi patients may differ substantially from Western cohorts [15]. Regional data are therefore essential for evidence-based screening and management. This comparative observational study aimed to examine the association between iron deficiency and heart failure severity among patients with HFpEF attending a tertiary cardiac center in Dhaka.