Iron deficiency impact on exercise performance in patients with heart failure

Iron deficiency is a highly prevalent and clinically significant comorbidity in patients with heart failure, occurring in up to 80% of acute heart failure and over 50% of chronic heart failure cases. It can occur independently of anemia and contributes to impaired oxygen transport and utilization, mitochondrial dysfunction, ventilatory inefficiency, and reduced exercise capacity, ultimately diminishing quality of life and worsening prognosis. Mechanistically, iron deficiency in heart failure involves systemic and molecular alterations, including dysregulation of iron-related genes, hepcidin-mediated ferroportin inhibition, and inflammatory sequestration of iron. These changes impair hemoglobin synthesis, aerobic enzyme activity, and skeletal and cardiac muscle function. Clinically, iron deficiency is associated with reduced peak oxygen uptake (VO2) and increased ventilation to carbon dioxide production (VE/VCO2) slope, even in the absence of anemia. Intravenous iron supplementation with ferric carboxymaltose might improve ventilatory efficiency (e.g. VE/VCO2 slope) and could be of importance to regain functional capacity. This review aims to explore the impact of iron deficiency, with and without concomitant anemia, on exercise performance in patients with chronic heart failure, linking molecular mechanisms to clinical manifestations and summarizing therapeutic implications.