Anaemia, neurohormonal activation, and myocardial iron depletion in heart failure: can this vicious circle be broken?

The vicious circle of anaemia, neurohormonal activation, and myocardial iron depletion in heart failure. Systemic iron deficiency reduces iron availability for the bone marrow, the myocardium, and skeletal muscle, resulting in anaemia (1), myocardial iron depletion (2), and skeletal muscle iron depletion (3), respectively. In patients with heart failure (HF), the vasodilatory effects of chronic anaemia contribute to chronic neurohormonal activation (4). Iron deficiency, both systemic and myocardial, inhibits monoamine oxidase (MOA), impairing catecholamine metabolism and clearance, further augmenting neurohormonal activation (5, 6). Chronic neurohormonal activation has direct detrimental effects on the myocardium, bone marrow, and skeletal muscle. In the myocardium, excessive adrenergic signalling contributes to or exacerbates myocardial iron depletion by impairing iron uptake or retention (7). In the bone marrow, excessive adrenergic signalling inhibits the differentiation of erythroid progenitors, contributing to the development of anaemia (8). In the skeletal muscle, excessive adrenergic signalling results in malperfusion, and reduced O2 delivery (lower peak VO2) and exercise intolerance (9). Chronic neurohormonal activation also leads to adverse left ventricular (LV) remodelling through haemodynamic stress (10). This adverse remodelling is exacerbated by myocardial iron depletion, due to the inability of the iron-depleted myocardium to meet the energetic demands of higher workload (11). Exercise intolerance is further compounded by anaemia due to reduced levels of blood O2 (12) and by skeletal muscle iron depletion, due to impaired production of myoglobin for oxygen storage and mitochondrial enzymes for oxygen utilization (13). IV iron therapies and sodium–glucose co-transporter 2 inhibitors (SGLT2i) could break up this vicious circle by inhibiting or reversing critical links within it. IV iron therapy replenishes iron in the myocardium, bone marrow, and skeletal muscle, and restores MOA to promote sympatholysis. SGLT2i counteract the detrimental effects of chronic neurohormonal activation on the myocardium, skeletal muscle, and bone marrow. Beta-blockers may also prevent neurohormonal activation from driving myocardial iron depletion.