Introduction
Heart failure is linked to persistent inflammation. Ferritin is an acute-phase protein; hence, its levels are higher in the presence of heart failure. As a result, iron insufficiency can be identified even in the presence of elevated ferritin levels. No official validation studies have defined iron shortage in heart failure. However, research from other medical disciplines, such as nephrology and hematology, has been used to develop a definition of iron shortage in heart failure. The current definition of iron insufficiency in heart failure is a ferritin level below 100 ng/ml regardless of transferrin saturation (TSAT) or ferritin between 100 to 300 ng/ml if TSAT is less than 20 percent. Importantly, this definition of iron deficiency can identify heart failure patients with more advanced symptoms, a lower quality of life (QoL), reduced exercise capacity, and a higher probability of hospitalization for heart failure.
What Is the Role of Iron Deficiency in Heart Failure?
Iron is vital for all kinds of human life, mostly because of its capacity to collect and give electrons, switching between its ferrous (bivalent, Fe2+) and ferric (trivalent, Fe3+) forms. In contrast, iron deficiency (ID) affects up to one-third of the global population. Infants, young children, teenagers, the elderly, and women, particularly during menstruation and pregnancy, are among the most vulnerable populations. Over the last few decades, there has been much research into iron deficiency in patients with chronic diseases with underlying inflammatory activation. These efforts have finally led to the realization that patients with heart failure, chronic kidney disease, cancer, and inflammatory bowel disease are also at an increased risk of developing iron deficiency. Thus, it is now established that juvenile growth, blood loss, and inflammatory activity are indicators of iron deficiency, even if only measurable as a cytokine or c-reactive protein activation.
What Are the Causes of Iron Deficiency in Heart Failure?
Anemia associated with heart failure can be caused by various factors, including a blunted erythropoietin response, dilutional anemia, and chronic illness anemia. Iron shortage is the most common cause, and iron deficiency can be absolute or functional.
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Absolute iron shortage is characterized by significantly diminished or nonexistent iron storage in the bone marrow, liver, and spleen.
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Functional iron deficit is defined by normal or increasing total body iron reserves unavailable for incorporation into erythroid precursors during erythropoiesis.
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Absolute iron shortage in heart failure can be caused by appetite loss, inadequate nutrition, decreased gastrointestinal absorption of iron due to edema, and gastrointestinal blood loss from using anti-aggregates and anticoagulants.
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Functional iron shortage, also known as iron-restricted erythropoiesis, is a chronic inflammation-induced anemia caused by hepcidin, a peptide that restricts intestinal iron absorption and iron release from circulating macrophages.
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Inflammation in heart failure can cause hepcidin expression independent of iron storage, limiting iron absorption.
What Are the Impacts of Iron Deficiency in Heart Failure?
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Clinical Impact of Iron Deficiency: Given iron's many biological roles, it is not unexpected that iron shortage is associated with various clinical symptoms. Iron is a necessary cofactor in the first three elements of the electron transport chain, and it is associated with decreased oxidative phosphorylation and intracellular phosphocreatine and adenosine triphosphate (ATP), which manifests in tissues with high energetic demand, such as the myocardium, skeletal muscle, and the central nervous system.
Patients with iron deficiency frequently experience fatigue, a lower quality of life, headaches, impaired focus, decreased exercise ability, and shortness of breath. Furthermore, heart failure is linked to an increased chance of hospitalization for heart failure or death from a cardiovascular cause. Even in the absence of anemia, iron deficiency is associated with decreased exercise capacity and a poorer clinical outcome; anemia caused by something other than iron deficiency has a smaller impact on exercise capacity and clinical outcome than iron shortage does in the lack of anemia.
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The Effect of Iron Deficiency on Cardiac Function: A hemodynamic research using invasive cardiopulmonary exercise testing (CPT) in heart failure patients with low ejection fractions. Individuals with iron insufficiency had a worse ability to enhance their cardiac output than patients without iron deficiency. The volume or amount of oxygen difference was similar in patients with and without iron deficiency, indicating a similar skeletal muscle oxygen extraction level. Nonetheless, the impact of iron shortage on skeletal muscle has been well established, demonstrating early muscle acidification, decreased energy content, and slower recovery kinetics.
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Cellular Effects of Iron Deficiency: Understanding the impact of iron shortage on the macroscopic cardiovascular system requires understanding the effect of iron deficiency at the cellular level. On a cellular level, it is critical to recall the relationship between the cellular excitation-contraction coupling of heart cells and energy metabolism.
What Is the Treatment of Iron Deficiency in Heart Failure?
One of the first studies to investigate intravenous (IV) iron in HF (heart failure) patients. This was single-arm research in which patients with systolic HF were given one gram of iron sucrose daily for 12 days. This study incorrectly categorized iron deficiency as a <400 ng/mL ferritin level. Ron therapy could be investigated as a treatment for chronic HF patients. The effects of treating iron deficiency in heart failure while maintaining ejection fraction and the long-term safety of iron therapy in HF remain uncertain.
Conclusion
Iron deficiency impairs myocyte and myocardial function and structure. Data from small mechanistic studies and larger RCTs show that ferric carboxymaltose therapy improves heart function and structural integrity. These explain how ferric carboxymaltose improves functional status, exercise capacity, and the risk of being hospitalized for heart failure. Several lines of evidence suggest that iron deficiency is a target for the treatment of both acute and chronic heart failure. Patients with symptomatic heart failure should be evaluated for iron deficiency both during the chronic stable period and during acute decompensation, which requires hospitalization. Ferric carboxymaltose infusion should be delivered to patients with heart failure with a reduced ejection fraction, in whom iron deficiencies have been proven to enhance functional capacity, and to patients with acute heart failure to reduce rehospitalization after discharge.
