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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.

Against the background of a dilemma experienced by researchers during a genomics study at an established biomedical research centre in Kenya, the broad aims of this thesis are to develop appropriate responses to important ethical questions on sharing information on a common and serious genetic condition, sickle cell disorder, and assess the responsibilities of researchers in this regard. Using an empirical approach to normative reflection across two phases of qualitative research, I explore the nature of important moral concerns related to sharing sickle cell disease information from researchers’ and community members’ points of view; and develop a bottom-up normative analysis around the questions generated. This analysis interweaves community experiences, processes of community reasoning and ex situ normative reflection; placing community views and values centrally while referencing these to wider ethical debates, commentaries and guidelines in the literature. Two main outputs of this thesis are to provide recommendations for information sharing on SCD findings in the genomics study in Kilifi; and to propose a set of key issues to consider for this type of information in other studies and geographic settings. I conclude that researchers have a strong responsibility to share SCD information on affected children with families as a form of ancillary service (validating tests, counselling and care); but less responsibility to actively share carrier information. Concurrent responsibilities are working collaboratively with the Ministry of Health/District General Hospital to plan and implement services for SCD; ensuring counselling services support family stability as far as reasonably possible; and to build forms of community engagement and informed consent that counter risks of diagnostic interpretations of research.