Iron deficiency (ID) is a frequent comorbidity in patients with heart failure (HF). Coexistent HF and ID make the issues more challenging to diagnose and treat. Iron deficiency exacerbates clinical symptoms, impairs quality of life and increases the risk of recurrent hospitalization for HF. Conversely, a proinflammatory state and altered gut kinetic in HF may result in absolute or functional ID, which conventional laboratory makers may not diagnose and differentiate accurately. Novel diagnostic markers like soluble transferrin receptor (sTfR), reticulocyte hemoglobin concentration, red blood cell distribution width, sTfR: log (ferritin) ratio and serum hepcidin levels may help to diagnose ID more accurately in the setting of HF. The intravenous (IV) iron formulation has shown promising results in improving the functional class and reducing recurrent hospitalization in patients with HF and ID. Futuristic therapies like nanosized iron preparations, hepcidin inhibitors and hepcidin antagonists may help manage ID more efficiently and conveniently in HF. This manuscript explores the relationship between ID and HF. It also provides the latest information related to the diagnosis and treatment of ID in HF patients.

Iron is essential to executing several physiological processes, such as oxygen transport and storage, cellular respiration, energy metabolism, and control of vascular tone¹. Like all other chronic inflammatory diseases, iron deficiency (ID) frequently afflicts patients with heart failure (HF). ID is a common comorbidity in patients with HF, affecting up to 50% of all ambulatory patients².  Prevalence varies depending on the criteria used to diagnose ID in the cohort analyzed³. ID is associated with worsening of the signs and symptoms of HF, poor quality of life, and increased risk of recurrent hospitalization and death⁴. Strategies targeting ID in the HF cohort significantly improve clinical outcomes, New York Heart Association (NYHA) functional class, exercise capacity, and quality of life^5-10.

Iron is vital for the human body. In free form, iron causes oxidative injury and may lead to premature cell death. Iron, therefore, must remain bound to protein to ensure safety and stability. Iron is stored as an iron-protein complex in the liver, spleen, and reticuloendothelial cells (storage pool). In the bloodstream, it is transported conjugated with apo-transferrin as transferrin. Transferrin carries iron around the body, which is physiologically usable by cells after uptake by transferrin receptor-1 (functional pool). Three key regulators are crucial in iron homeostasis. Ferroportin regulates iron absorption from the gut and its discharge from the stored pool. Hepcidin induces internalization and degradation of ferroportin and acts as a master regulator of iron metabolism. Lastly, erythroferrone is a negative regulator of iron metabolism. It inhibits hepcidin production, thus ensuring iron availability for erythropoiesis^11-13. All these proteins work in a coordinated manner to maintain a stable level of iron in the body.

Heart failure is a proinflammatory condition. It is associated with elevated levels of inflammatory cytokines, which result in elevated hepcidin levels. Hepcidin negatively interacts with ferroportin, hindering iron absorption from the gut and its release from the storage pool. In this way, patients with HF are at risk of both absolute (depleted iron stores) and functional ID (sufficient iron not available at the cellular level despite normal total body iron)¹³. Within the framework of HF, many other factors may precipitate the state of ID (Table 1). Some of these factors include nutritional deficiency, poor bioavailability of dietary iron, edematous gut, blood loss secondary to antiplatelet or anticoagulant medication and associated comorbidities².

Iron is crucial for synthesizing hemoglobin, myoglobin, cytochrome c, and many other proteins. It acts as a cofactor of several enzymes, including nitric oxide synthase. ID, therefore, has a deleterious effect on oxygen transportation (hemoglobin) and aerobic respiration of muscles (myoglobin), oxidative phosphorylation (cytochrome c), and other processes dependent on a sufficient level of iron (Table 2)^1,13. Patients with HF and ID exhibit a high prevalence of anemia, adverse remodeling, and worse muscular symptoms (such as muscle pain, fatigue, cramps, shortness of breath, and poor exercise capacity) secondary to insufficient heme production. ID disturbs oxidative phosphorylation and reduces adenosine triphosphate (ATP) production. Therefore, tissues with higher energy requirements (such as the myocardium, skeletal muscle, and the central nervous system) are affected most by ID. Lastly, ID disrupts the production of nitric oxide synthase (NOS), resulting in vasoconstriction. This, in turn, worsens symptoms like difficulty breathing and fatigue, which also result in recurrent hospitalization^1,13.

Iron deficiency in HF can be absolute iron deficiency (AID) or functional iron deficiency (FID). In AID iron, the total body stores of iron get depleted. Conversely, FID typifies a situation where iron stores are normal or elevated (Table 3)^14-16. However, the downregulation of ferroportin and upregulation of hepcidin and other inflammatory cytokines hinder iron mobilization from the storage pool. Ferritin levels (reflection of storage pool) and transferrin saturation (reflection of iron bioavailability) are the two most commonly used laboratory parameters to define ID in routine clinical settings (Fig. 1). Serum ferritin <30 µg/L and transferrin saturation (TSAT) <16% suggest a state of ID¹⁴. However, considering the effect of HF on serum ferritin and TSAT, it is imperative to change the criterion of diagnosing ID in the setting of HF. Serum ferritin is an acute phase reactant and gets nonspecifically elevated in conditions with activated inflammatory pathways such as HF. This change correlates with the extent of inflammation. Conversely, transferrin is a negative phase reactant and may get suppressed in HF¹⁵.

Figure 1. Absolute and functional iron deficiency in patients of heart failure. In AID, both iron storage and functional pools are depleted. However, in FID, the storage pool remains normal or even elevated, but the iron cannot move out of the storage pool. This may be due to the impact of the altered hepcidin-ferroportin axis in HF. This leads to improper iron availability to erythroid and nonerythroid tissue despite a regular storage pool.

Although there is no precise serum ferritin and TSAT cut-off, serum ferritin levels <100 µg/L or 100-300 µg/L if TSAT is <20% diagnose ID in HF with 82% sensitivity and 72% specificity¹⁶. Novel markers such as soluble transferrin receptor (sTfR), reticulocyte hemoglobin concentration, and red blood cell distribution width (RDW) can diagnose ID more accurately in patients with HF. However, these markers have yet to be routinely used. Additionally, measuring sTfR, sTfR: log (ferritin) ratio or hepcidin levels could be more effective in discriminating AID from FID¹⁷. A detailed description of all these investigations is beyond the scope of this manuscript.

Review of Literature

Clinical trials and meta-analyses have suggested beneficial effect of IV iron in patients with ID (Table 4)^5-10,18-20. In the FAIR-HF (Ferinject Assessment in patient with IRon deficiency and chronic Heart Failure) trial, the use of IV ferric carboxymaltose in patients of HF with ID showed significant improvement in NYHA classification, functional capacity, and quality of live⁵. The results were similar in patients with anemia and without anemia. AFFIRM-AHF, a randomized, double-blind, placebo-controlled trial comparing the effect of IV ferric carboxymaltose on hospitalizations and mortality in iron deficient subjects admitted for acute HF, investigated the effect of IV ferric carboxymaltose on outcomes in patients who were stabilized after an episode of acute HF. Patients who received IV ferric carboxymaltose, showed a significant reduction in HF hospitalization compared to placebo (relative risk [RR], 0.74; 95% confidence interval [CI], 0.58-0.94) but no reduction in cardiovascular death⁸. IRONMAN (Effectiveness of Intravenous Iron Treatment versus Standard Care in Patients with Heart Failure and Iron Deficiency) trial investigated the long-term safety and efficacy of IV ferric derisomaltose in a predominately outpatient HF population. Data suggested numerically lower HF hospitalizations and cardiovascular death in patients who received the ferric derisomaltose arm (22.4 per 100 patient-years) than in the placebo arm (27.5 per 100 patient-years). However, it failed to reach significance (p = 0.07)¹⁹.

A meta-analysis conducted by Myint et al revealed a 13.8% decreased risk of HF hospitalizations (odds ratio [OR] 0.59; 0.35-0.98, p = 0.040) and a 17.5% reduction in the composite outcome of HF hospitalizations or cardiovascular mortality. All-cause and cardiovascular mortality were not different between IV iron and placebo groups²⁰.

Similar results were observed in a meta-analysis of 10 randomized controlled trials by Graham et al. It suggested a significant reduction in composite outcomes of recurrent hospitalizations for HF and cardiovascular mortality (rate ratio 0.75, 95% CI 0.61-0.93; p < 0.01) and first hospitalization for HF or cardiovascular death (OR 0.72, 95% CI 0.53-0.99; p = 0.04) in the group of patients who received IV iron as compared to those who received placebo or standard care. Similar to the prior meta-analysis, effects on cardiovascular (OR 0.86, 95% CI 0.70-1.05; p = 0.14) and all-cause mortality (OR 0.93, 95% CI 0.78-1.12; p = 0.47) were inconclusive⁹.

Calculating Iron Deficit

Conventionally, the total iron deficit is estimated using the modified Ganzoni formula²¹. This equation estimates iron deficit by calculating iron attached to deficit hemoglobin. In healthy individuals, blood volume is 7% (0.07) of body weight. Iron content in hemoglobin is 0.34% (0.0034) g/dL. So, the total iron deficit in mg/L will be as below.

Iron deficit = weight (kg) × (target Hb - actual Hb) × 0.0034*0.07*10,000 + Depot iron.

Depot iron here represents an extra depot dose to replenish iron stores. This is usually kept at 500 mg. Notably, the above-mentioned formula may not accurately reflect the actual iron needs of the patient. It is crucial to consider other factors, such as inflammation, comorbidities and medication while estimating iron deficits in HF patients.

Selection of Iron Formulation

Oral iron formulations are not the preferred choice to treat ID in patients with HF. The IRONOUT HF (Iron Repletion effects ON Oxygen UpTake in Heart Failure) trial investigated the effects of oral iron therapy on exercise capacity and quality of life score in patients with HF with reduced ejection fraction and ID. Despite improvement in iron biomarkers such as transferrin saturation and ferritin levels, exercise capacity was not improved compared to placebo⁷. Unlike oral iron therapy, IV iron therapy benefits the 6-minute walk test distance, peak oxygen consumption, quality of life, and improvement in NYHA class⁹. IV iron formulations contain a core of iron hydroxide enveloped by variable carbohydrate complexes²². The carbohydrate envelope in the earlier formulation was composed of high molecular weight dextran. These formulations are no longer preferred due to the high risk of serious drug events associated with them⁴. Iron sucrose, ferric carboxymaltose, and ferric derisomaltose are the three most commonly studied nondextran IV iron formulations to treat ID in patients with HF (Table 5)^{5,6,8,18,19,23,24}. Data from a recent meta-analysis demonstrated no significant difference in outcome between different IV iron-carbohydrate formulations when similar end points were measured²⁵.

Current Guidelines

Based on ample evidence, the 2021 European Society for Cardiology guidelines and the 2022 AHA/ACC/HFSA guidelines recommend using IV iron to improve functional status and quality of life in groups of patients with HF and ID (Table 6)^26,27.

Novel markers and therapeutic options for managing ID are in the research spotlight. Newer diagnostic markers diagnose ID more accurately in the HF setting and can differentiate AID from FID. Some key diagnostic markers are sTfR, reticulocyte hemoglobin concentration, RDW, sTfR: log (ferritin) ratio, and serum hepcidin levels. sTfR levels increase in response to ID to absorb more iron. sTfR, therefore, may diagnose functional iron status more accurately than traditional markers.

Reticulocyte hemoglobin concentration represents iron available for new red blood cell production. Low levels of reticulocyte hemoglobin concentration are a clear sign of ID. RDW measures the red blood cell size variation. Higher RDW values suggest disrupted red cell production, which could indicate ID. sTfR: log (ferritin) ratio is another marker that helps distinguish FID from AID. Higher levels are consistent with FID. Lastly, the estimation of hepcidin levels helps to understand iron homeostasis. Hepcidin inhibits iron’s release from body stores. Thus, elevated levels are consistent with FID¹⁷. Nanosized iron preparations are emerging oral iron therapies that may help to resolve concerns of poor absorption and gastrointestinal side effects related to traditional oral iron therapy²⁸.

Compounds that antagonize hepcidin or its effects could help ameliorate HF-associated ID and are in the research phase. The use of such compounds in clinical settings warrants further investigation and testing²⁹. While more research is needed to fully understand the safety and efficacy of these newer therapeutic options, they represent exciting advances in cardiovascular medicine.

Iron deficiency is a frequent comorbidity in HF patients. HF adversely affects iron homeostasis, leading to states ranging from AID to FID. According to current guidelines, ID in HF is diagnosed using serum ferritin and transferrin. However, upcoming markers such as sTfR, reticulocyte hemoglobin concentration and RDW may help diagnose ID more accurately in patients with HF. Further, novel investigations such as sTfR, sTfR: log (ferritin) ratio, or hepcidin levels could more effectively discriminate AID from FID. Once diagnosed, nondextran IV iron therapy is safe and effective in improving functional class and quality of life in patients of ID with HF.

Although current therapy does not offer cardiovascular mortality benefits, innovative therapies (hepcidin inhibitor, nanoparticle and gene therapy) may be more effective for treating ID.

Disclosure: No funding was received in the publication of this article.

Declarations of interest: None.

Declaration of Generative AI and AI-assisted Technologies in the Writing Process

During the preparation of this work the authors used Grammarly AI tool in order to improve readability and language. After using this tool/service, the authors reviewed and edited the content as needed and take full responsibility for the content of the publication.

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