Discussion

This study examined the association between iron deficiency and heart failure severity in patients with HFpEF. Our findings revealed that iron deficiency was significantly linked to worse functional outcomes, including higher NYHA class, elevated NT-proBNP levels, and more advanced diastolic dysfunction. Iron-deficient patients were considerably more likely to present with Grade 2 or Grade 3 diastolic dysfunction, while iron deficiency was associated with echocardiographic and biomarker-defined disease severity in this HFpEF cohort.

One of the most notable observations in the present study was the significantly higher mean age among iron-deficient HFpEF patients compared to those with normal iron status. This finding aligns with evidence from previous investigations demonstrating that older patients with HF are disproportionately affected by iron deficiency, partly because ageing is accompanied by chronic low-grade systemic inflammation that upregulates hepcidin, the key iron-regulatory hormone, thereby impairing gastrointestinal iron absorption and promoting functional iron sequestration within the reticuloendothelial system [21]. A comprehensive review examining the interplay between inflammation, iron deficiency, and HF in older adults confirmed that hepcidin-mediated iron restriction is a prominent contributor to iron deficiency in elderly HF populations, independent of dietary insufficiency [22]. The substantially higher prevalence of anaemia among iron-deficient patients observed in the present study is consistent with the mechanistic understanding that prolonged or severe iron deficiency ultimately impairs erythropoiesis; indeed, Köseoğlu and Özlek reported comparable anaemia burden among iron-deficient HFpEF patients in a six-year follow-up cohort [9]. Crucially, however, a meaningful proportion of iron-deficient patients in the present study did not have anaemia, corroborating established evidence that iron deficiency exerts clinically significant effects on cardiac and skeletal muscle function through non-haematopoietic mechanisms, independent of haemoglobin concentration [6]. However, as age was not statistically adjusted for in this analysis, the extent to which the observed severity differences are attributable to iron deficiency independent of age cannot be determined from the present data.

Another important finding was the significant association between iron deficiency and both higher NYHA functional class and markedly elevated NT-proBNP levels. Iron-deficient patients were substantially more likely to exhibit severe functional limitation, whereas the majority of iron-replete patients demonstrated mild or absent symptoms. Similar findings have been reported in previous HF studies, demonstrating that the presence of iron deficiency, along with higher NYHA class and elevated NT-proBNP, predicted increased myocardial energy expenditure, underscoring the mechanistic link between iron status and functional cardiac severity [23]. In decompensated HF populations, iron-deficient patients consistently exhibited higher NT-proBNP levels and worse NYHA functional class compared to iron-replete counterparts, a pattern also observed in the present cohort [24]. Potential biological mechanisms that may contribute to this observed association include the essential role of iron in mitochondrial oxidative phosphorylation; iron deficiency may impair adenosine triphosphate (ATP) synthesis within cardiomyocytes and skeletal myocytes, potentially reducing contractile reserve and contributing to increased ventricular wall stress and natriuretic peptide release [25]. A systematic meta-analysis further confirmed that iron deficiency is associated with NYHA class severity and elevated NT-proBNP in HF patients, irrespective of ejection fraction, supporting the potential clinical relevance of the higher NT-proBNP levels observed among iron-deficient patients [8]. It should be noted that anaemia, which was significantly more prevalent among iron-deficient patients, may itself contribute to elevated NT-proBNP and worse NYHA class; the present analysis cannot fully disentangle the independent contribution of cellular iron deficiency from that of anaemia.

Findings from the present study further suggest a significant association between iron deficiency and the severity of diastolic dysfunction as assessed by the 2016 ASE/EACVI echocardiographic grading system. Iron-deficient patients were more likely to have Grade 2 or Grade 3 diastolic dysfunction, whereas Grade 1 predominated among those with normal iron status; thus, more advanced grades of diastolic dysfunction were observed more frequently in the iron-deficient group. The OptimEx-Clin subanalysis by Gevaert et al. was the first study to demonstrate a statistically significant association between iron parameters and echocardiographic indices of diastolic function in HFpEF patients, providing important precedent for the present findings [26]. Several potential biological mechanisms may help explain this observed relationship. Iron deficiency has been associated with mitochondrial dysfunction and oxidative stress within cardiomyocytes, which may impair energetic efficiency, reduce nitric oxide bioavailability, increase passive cardiomyocyte stiffness, and adversely affect diastolic relaxation [25,27]. A randomized controlled study by Mollace et al. demonstrated that intravenous ferric carboxymaltose significantly improved echocardiographic diastolic function parameters alongside reductions in oxidative stress biomarkers and improved endothelial reactivity; these findings provide experimental evidence that iron repletion may influence pathways related to diastolic function in HFpEF [28]. In contrast, the study by Barandiarán Aizpurua et al. involving 300 patients with HFpEF reported that iron deficiency was more strongly associated with prognosis than with exercise capacity itself, suggesting that its effects on diastolic function and haemodynamic burden may represent a mechanistic pathway distinct from its effects on skeletal myopathy [29].

This study is among the earliest from Bangladesh to examine the relationship between iron deficiency and HFpEF severity. Echocardiographic assessment followed the validated 2016 ASE/EACVI criteria, and standardized laboratory procedures were applied across both groups. However, the single-center setting and modest sample size may limit generalizability, while the comparative observational design precludes causal inference. Purposive fixed-quota sampling was used to enroll equal numbers of iron-deficient and iron-replete patients; participants were neither randomized nor matched, which may have introduced selection bias and prevents estimation of iron-deficiency prevalence. Significant differences in age and anaemia status were also present between groups. As multivariable regression and non-anaemic subgroup analyses were not performed, the independent contribution of iron deficiency could not be determined. Furthermore, the exclusion of patients with common HFpEF comorbidities, including atrial fibrillation, chronic obstructive pulmonary disease, and moderate-to-severe renal impairment, may limit the applicability of the findings to broader real-world HFpEF populations. Therefore, the findings should be interpreted as unadjusted, exploratory, and hypothesis-generating associations. Future multicenter studies with larger samples and appropriate adjusted analyses are warranted.