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Title: Anaemia and metabolic pathways in chronic heart failure
Author: Okonko, Darlington Obinnaya
ISNI:       0000 0004 2718 4049
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2012
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Background: Anaemia is a common and adverse comorbidity in chronic heart failure (CHF), but critical aspects of its epidemiology, pathogenesis and treatment remain unclear. Objectives: This thesis tested the hypotheses that temporal trends in haemoglobin (Hb) relate to outcome in CHF, that anaemia might be subsequent to immune-mediated erythroid cell suppression, erythropoietin (Epo) resistance, cellular iron transport dysregulation, and altered adrenal steroidogenesis, and that low Hb levels could be amenable to recombinant Epo and intravenous iron therapies separately. Methods and Results: A post hoc analysis revealed that new onset anaemia occurred in 14% of patients at 1 year, developed more frequently on carvedilol than metoprolol, and was associated with increased mortality. Using flow cytomtry and cell culture techniques, CHF patients with anaemia of unknown origin were shown to exhibit markedly low reticulocyte production indices, and globally attenuated circulating erythroid lineage pools (C034+ stem cells, erythroid progenitors [BFU-E] and precursors). Only the depletion of anaemic monocytes from cultures enhanced erythroid colony growth. Only the addition of anaemic monocytes or sera to cultures blunted autologous and allogenic erythroid colony formation. Anti-TNFa neutralizing antibody abrogated the effects of anaemic sera on erythroid colonies. In additional assays, the ex-vivo responsiveness of erythroid cells to escalating doses of Epo was diminished in anaemic patients. This was not associated with Epo receptor downregulation but with a profound blunting of Epo-induced intracellular signalling. In biochemical analyses, the cortisol/dihydroepiandrosterone ratio, a marker of adrenal steroid hormone imbalance, was shown to inversely correlate to Hb levels. More importantly, disorded iron homeostasis was highly prevalent in CHF patients and independently predictive of anaemia, exercise intolerance and impaired survival. Sera from iron deficient subjects exhibited elevated pro-inflammatory cytokine and pro-hepcidin levels. Such sera downregulated ferroportin (iron export protein) and upregulated divalent metal transport-l (iron import protein) expression on monocytes ex-vivo, a pattern that facilitates inflammatory hypoferremia in vivo. Co-incubation with anti- TNFa neutralising antibodies abolished these effects. Finally, in separate randomised controlled trials, recombinant Epo escalated Hb levels but not exercise tolerance in anaemic CHF patients, whilst intravenous iron improved symptoms and exercise capacity but not Hb levels in anaemic and non-anaemic CHF patients.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available