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Intravenous iron therapy results in rapid and sustained rise in myocardial iron content through a novel pathway
Mayra Vera-Aviles1, Syeeda Nashitha Kabir1, Akshay Shah2
1Department of Physiology, Anatomy & Genetics, University of Oxford, Sherrington Building, Parks Road, Oxford OX1 3PT, United Kingdom.
Insights
Intravenous iron therapy rapidly delivers iron to the heart via non-transferrin-bound iron (NTBI) transporters, not macrophages. This iron remains labile for weeks, suggesting potential for cardiac iron accumulation.
Area of Science:
- Cardiology
- Hematology
- Biochemistry
Background:
- Intravenous iron therapies use iron-carbohydrate complexes for bioavailability.
- Iron uptake by tissues like the heart from these therapies is not well understood.
- This study investigates iron handling in the myocardium post-intravenous iron administration.
Purpose of the Study:
- To determine how the heart acquires and handles iron from intravenous iron therapy.
- To assess the impact of ferric carboxymaltose (FCM) on myocardial iron levels.
- To explore the mechanisms and duration of iron accumulation in cardiac tissue.
Main Methods:
- Prospective observational study in 12 patients receiving ferric carboxymaltose (FCM).
- Longitudinal monitoring of myocardial, spleen, and liver T1 relaxation times and plasma iron markers.
- In vivo imaging of intracellular labile iron pool (LIP) in FCM-treated mice and isolated cardiomyocytes.
Main Results:
- Myocardial T1 relaxation time decreased rapidly post-FCM, remaining low for 42 days.
- Plasma non-transferrin-bound iron (NTBI) peaked at 3 hours, while ferritin peaked at 14 days.
- Myocardial LIP increased significantly in mice and cardiomyocytes after FCM, indicating rapid iron uptake via NTBI transporters.
Conclusions:
- Ferric carboxymaltose delivers iron to the myocardium rapidly via NTBI transporters, bypassing reticuloendothelial macrophages.
- Iron remains labile in the heart for weeks, suggesting limited cardiac iron storage capacity.
- Findings challenge current understanding and indicate potential for cumulative cardiac iron build-up with prolonged IV iron therapy.
Background And Aims:
Intravenous 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.
Methods:
A 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.
Results:
In patients, myocardial relaxation time T1 dropped maximally 3 h 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 3 h, while ferritin peaked at 14 days. Changes in liver T1 diverged among patients. In mice, myocardial LIP rose 1 h 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.
Conclusions:
Intravenous 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 myocardium's 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.
