Garbowski, MW; (2017) Molecular and clinical factors affecting myocardial iron retention in transfusional haemosiderosis. Doctoral thesis , UCL (University College London).

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Abstract

Myocardial haemosiderosis (MH) complicates Transfusion Dependent Thalassaemias (TDT), increasing mortality from cardiomyopathy. Plasma non-transferrin-bound iron (NTBI) and its redox-active component, labile plasma iron (LPI), are potential causes of MH. In 73 TDT patients, those with MH had significantly lower soluble transferrin receptors (sTfR) than those without. By contrast, transfusion duration, iron-loading rate (ILR), NTBI and transferrin saturation (TfSat) were similar in both groups. MH occurred only when ILR exceeded the erythroid transferrin uptake rate (ETUR) derived from sTfR, by >0.21mg/kg/d. LPI was >3-fold higher above this ETUR threshold, while NTBI and TfSat showed no difference, implicating the LPI fraction of NTBI in MH. We hypothesized that high ETUR decreases MH through increased generation of apotransferrin by the erythron. We used a cardiomyocyte (HL-1) cell line to explore the effects of NTBI speciation (iron:citrate ratio) and apotransferrin on iron uptake. Uptake was most efficient when citrate exceeded iron >100-fold, as was intracellular ROS formation and extracellular iron detectability using the LPI assay. Apotransferrin, when in excess, inhibited iron uptake, decreased intracellular ROS and decreased NTBI species detectable by LPI assay. However, at very high NTBI concentrations (≥10µM), when the iron content of ferric citrate (FC) exceeded the binding capacity of ApoTf, iron uptake was increased above that seen without transferrin present. Under these conditions ferric monocitrate species exist that are both LPI-detectable and enter myocardium. We propose that in TDT, transient generation of ApoTf under conditions of high residual erythropoiesis decreases MH by binding LPI-detectable species of NTBI. Qualitative differences in NTBI are therefore crucial to predict MH in TDT. Attempting to demonstrate relevant NTBI speciation differences we compared two methods: NTA-NTBI and a novel bead-NTBI. This approach, however, highlighted important methodological drawbacks rather than positive species identification; therefore, more work is needed in NTBI detection to elucidate the speciation further.

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