1 Intravenous iron therapy results in rapid and sustained rise in myocardial iron content through a novel pathway

<h3>Introduction</h3> Intravenous (IV) iron therapies such as ferric carboxymaltose (FCM), are commonly used to treat iron deficiency. Unlike incremental oral iron supplementation, they deliver supraphysiological dose of iron directly into circulation. How this iron is handled in the body is poorly understood. Our study aims to investigate the short-term and long-term impacts of FCM on myocardial iron. <h3>Methods</h3> 12 patients receiving FCM for iron deficiency underwent longitudinal Cardiac Magnetic Resonance (CMR) to collect myocardial relaxation time (T1) which is inversely correlated to tissue iron content and blood sampling to measure plasma iron markers. To determine whether the iron taken up by the myocardium remains reactive, the effects of FCM were assessed in mice harbouring luciferase reporter system injected with an iron-caged luciferin. <h3>Results</h3> A single dose of FCM in patients raised myocardial iron rapidly and maximally within 3 hours and remained sustained for at least 42 days. Plasma iron and transferrin saturation also rose maximally at 3 hours, accompanied by the appearance of non-transferrin bound iron, the reactive form of iron. In iron-deficient mice, a single dose of FCM compared to saline treatment raised myocardial reactive iron 1 hour after infusion and remained elevated 42 days after infusion. In cardiomyocytes, exposure to FCM raised reactive iron rapidly when compared to saline treatment, and this was dependent on the known NTBI transporters L-type and T-type calcium channels. <h3>Conclusions</h3> FCM rapidly delivers iron to the myocardium through NTBI transporters and remains in reactive form for weeks, indicating the heart’s limited capacity for iron storage. The persistence of reactive iron in the heart following a single dose of FCM highlights the potential for cumulative build up with repeated doses which may lead to cardiac complications. These findings have important clinical implications for patients on long term intravenous iron therapy.