Intravenous iron therapy with ferric carboxymaltose results in a rapid and sustained rise in myocardial iron content through a non-canonical pathway: a translational study

Background and AimsIntravenous iron therapies contain iron-carbohydrate complexes, designed to ensure iron becomes bioavailable via the intermediary of spleen and liver reticuloendothelial macrophages. How other tissues obtain and handle this iron remains unknown. This study addresses this question in the context of the heart. MethodsA prospective observational study was conducted in 12 patients receiving ferric carboxymaltose (FCM) for iron deficiency. Myocardial, spleen and liver magnetic resonance relaxation times, and plasma iron markers were collected longitudinally. To examine the handling of iron taken up by the myocardium, intracellular labile iron pool (LIP) was imaged in FCM-treated mice and cells. ResultsIn patients, myocardial relaxation time T1 dropped maximally 3hrs post FCM, remaining low 42 days later, while splenic T1 dropped maximally at 14 days, recovering by 42 days. In plasma, non-transferrin bound iron (NTBI) peaked at 3hrs, while ferritin peaked at 14 days. Changes in liver T1 diverged amongst patients. In mice, myocardial LIP rose 1h and remained elevated 42 days after FCM. In cardiomyocytes, FCM exposure raised LIP rapidly. This was prevented by inhibitors of NTBI transporters T-type and L-Type calcium channels and divalent metal transporter 1. ConclusionsIntravenous iron therapy with FCM delivers iron to the myocardium rapidly through NTBI transporters, independently of reticuloendothelial macrophages. This iron remains labile for weeks, reflecting the myocardiums limited iron storage capacity. These findings challenge current notions of how the heart obtains iron from these therapies and highlight the potential for long-term dosing to cause cumulative iron build-up in the heart. TRANSLATIONAL PERSPECTIVEO_LIMany patients now receive long-term IV iron therapy. The finding that a single standard dose of IV iron causes a sustained rise in myocardial iron underscores the risk for cumulative build-up to occur with multiple doses. Magnetic resonance monitoring of myocardial iron may be required to safeguard against progression towards pathological myocardial iron overload in these patients. C_LIO_LIPlasma ferritin levels reflect the iron content of reticuloendothelial macrophages. The finding that myocardial iron elevation following IV iron therapy is independent from reticuloendothelial macrophages highlights the limitations of using plasma ferritin cut-offs to safeguard against the risk of tissue iron overload. C_LI GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=197 HEIGHT=200 SRC="FIGDIR/small/24301496v2_ufig1.gif" ALT="Figure 1"> View larger version (46K): org.highwire.dtl.DTLVardef@1ee1e6corg.highwire.dtl.DTLVardef@f78bborg.highwire.dtl.DTLVardef@1bf7884org.highwire.dtl.DTLVardef@1813471_HPS_FORMAT_FIGEXP M_FIG C_FIG