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Introduction: Monocytes play important roles in inflammation, thrombosis, angiogenesis and tissue repair and may contribute to the pathophysiology of heart failure (HF). Functional diversity is likely to stem from the presence of three distinct monocyte subsets, defined by flow cytometry (FC) as CD14++CD16-CCR2+ (Mon1), CD14++CD16+CCR2+ (Mon2) and CD14+CD16++CCR2- (Mon3). The aims of this thesis were to study the following parameters in patients with ischaemic HF: 1) monocyte subset numbers, 2) monocyte subset expression of surface receptors for inflammation, angiogenesis, cell adhesion molecules (CAM) and tissue repair, 3) cross-talk between monocytes and platelets in the formation of monocyte-platelet aggregates (MPAs). Methods: Monocyte subsets were analysed by FC on venous blood samples at baseline in 51 patients admitted with acute HF (AHF), 42 with stable HF (SHF), 44 with stable coronary artery disease (CAD) without HF and 40 healthy controls (HC). Plasma levels of inflammatory cytokines were also measured by flow cytometric bead array technology. In AHF, additional longitudinal samples were taken at discharge and 3 months. Results: Compared to CAD controls, patients with SHF had higher counts of Mon2 and MPAs associated with Mon2, alongside increased expression of inflammatory markers and CAM receptors on Mon2. Compared to SHF, those with AHF had higher counts of Mon1, Mon2 and MPAs associated with Mon1 and Mon2. Patients with AHF also had increased expression of angiogenic receptors on Mon1 and increased expression of angiogenic receptors, scavenger receptors and CAM receptors on Mon2. After adjusting for confounders, counts of Mon2, MPAs associated with Mon2 and expression of VCAM-1R on Mon2 were associated with clinical outcomes in AHF. Conclusions: Differences in monocyte subset numbers and cell surface receptor expression are seen in patients with HF. Mon2 appears to have a prognostic role in patients with AHF, however larger studies are required to confirm these findings.

This study investigated the role of prouroguanylin (ProUGN) and proguanylin (ProGN), members of a novel class of peptides with natriuretic activity in heart failure (HF), a disorder of declining cardiac output associated with disturbed sodium and water homeostasis. The hypothesis was that ProUGN and ProGN activity is dysregulated in chronic and acute HF. Plasma ProUGN and ProGN were measured in 243 patients with chronic stable HF and plasma ProUGN and cGMP, an intracellular mediator of ProUGN activity, measured in 336 patients admitted to hospital with acute HF using immunoassays. ProUGN and cGMP levels were repeated in acute HF patients prior to discharge. The primary endpoints were all cause mortality, HF readmission and either outcome at 180 days. ProUGN and ProGN were significantly greater in patients with chronic HF compared to controls and inversely correlated with eGFR. ProUGN and ProGN were significantly greater in patients with hypertension and in those taking diuretics, with higher levels associated with increased severity of HF as assessed by NYHA class. In multivariate analysis, eGFR was the only independent predictor of plasma ProUGN and ProGN level. ProUGN and cGMP were significantly lower in patients with acute HF compared to in controls. Pre-discharge ProUGN and cGMP were significantly greater than at admission, with pre-discharge ProUGN significantly greater than in controls. Admission ProUGN was significantly greater in patients who died and a greater pre-discharge ProUGN was significantly associated with increased risk of early mortality. Pre-discharge cGMP levels were significantly lower in those readmitted with HF compared to those not, with higher levels significantly associated with reduced risk of early HF readmission. A greater pre-discharge ProUGN/cGMP ratio was significantly associated with increased risk of mortality or HF readmission. These results suggest that adverse outcomes in HF may be associated with hyporesponsiveness to ProUGN.

Objectives: To examine the impact of a specialist nursing intervention upon the illness representations, self-reported medication adherence, attitudes towards medication and psychological morbidity of heart failure patients. Design: A longitudinal study following a cohort of community based participants who had been previously hospitalised with heart failure over a three month time interval. Method: A total of 28 heart failure patients participated in the study. Participants completed a demographic questionnaire, the Illness Perception Questionnaire (IPQ), the Medication Adherence Report Scale (MARS), the Beliefs About Medicines Questionnaire-General Version (BMQ-G), the Beliefs About Medicines Questionnaire-Specific Version (BMQ-S), the Hospital Anxiety and Depression Scale (HADS) and the Significant Others Scale-Form B (SOS-B) at two interviews. Comparisons of data within the group at the two time points were undertaken. Results: Analysis revealed no statistically significant differences within the group from time one to time two of the nursing intervention in illness representation, self reported medication adherence, attitudes towards medication or physiological morbidity. The exception to this was a significant difference on the BMQ-S subscale, necessity. Between time one and time two participants' beliefs in the necessity of their medication had significantly reduced. Conclusions: Whilst specialist nursing interventions have significantly reduced hospital readmissions, no significant psychological impact of this programme was detected. The potential reasons for the lack of significant results as well as the clinical implications of the findings are explored. The value of routine assessment of psychological morbidity in this population is discussed.

Cardiac fibroblasts play an important role in the function of the myocardium by regulating the extracellular matrix of the heart. Changes in the function of cardiac fibroblasts are a feature of heart failure. A subset of patients with heart failure that receive Left Ventricular Assist Devices, in combination with pharmacological therapy, are able to recover cardiac function to the point that the devices can be explanted. The response of cardiac fibroblasts to a combination of unloading and the pharmacological therapy given to these patients, which includes the Β₂-adrenoceptor receptor (Β₂-AR) agonist Clenbuterol, may play an important role in the reverse remodelling process. This thesis focuses on the response of cultured cardiac fibroblasts to Clenbuterol and mechanical stretch.

People with heart failure frequently experience poor quality of life, often exacerbated by co-morbidities. This demands complex self-management activities, often supported by family members in care roles, and includes input from community Heart Failure Specialist Nurses (HFSNs) that is known to reduce hospital readmissions. There is, however, a paucity of knowledge about the perceptions of people living with heart failure concerning self-management strategies. Aim This thesis is a longitudinal study exploring emergent patterns and styles of self- management of persons with heart failure, the impact of family members and HFSNs. Method Thirty-one theoretically sampled participants with heart failure were recruited from a district general hospital between October 2004 and September 2006. The sample participated in home-based, audio-taped, semi-structured interviews prior to nurse intervention, describing how heart failure affected their lives, focusing on self-management strategies. The HFSNs conducted home visits and telephone contacts according to individual needs independent of the research. At five months, 23 participants completed a diary for 14 days. Twenty- seven participants (three died, and one withdrew) were interviewed at six 3 months to explore how self-management strategies had changed. The HFSNs participated in a focus group. Constructivist grounded theory and reflexive accounting informed data collection and analysis, leading to the inductive development of an explanatory framework for emergent themes, one of which, Informed Support, serves as an original and significant contribution to the literature. Results Successful management is a complex biopsychosocial activity, involving reconstructions of identity, symptom management, and relationship management, while living with a chronic and uncertain condition that severely compromises life activities. Central to successful management is Informed Support, where family members collaboratively develop a range of activities and attributes to augment self-management. This was perceived as most effective when the HFSNs were able to adopt a 'whole family' approach. Conclusion Heart failure self-management is a dynamic, complex and adaptive activity that can be positively and significantly shaped by Informed Support from family members. Community based HFSNs can influence, but need to recognise differing styles of, self-management.

This thesis describes a randomized, double-blind, placebo-controlled, clinical trial investigating the effect of a multiple micronutrient supplement in patients with stable chronic heart failure. Seventy-nine patients with chronic stable heart failure were recruited and randomized to treatment with a multiple micronutrient supplement or placebo. The primary end-point of the study was left ventricular ejection fraction (LVEF), assessed using cardiovascular magnetic resonance imaging or 3·dimensional echocardiography. The secondary end·points were quality of life (assessed using the Minnesota Living With Heart Failure Questionnaire), physical functioning (assessed using six-minute walk test distance), blood levels of N·terminal prohormone of brain natriuretic peptide, blood levels of Creactive protein, blood • levels of pro· and anti-inflammatory cytokines (tumour necrosis factor alpha. interleukin·6 and mterleukin-10) and urinary levels of a marker of oxidative stress (8· iso·prostagtandin F2 alpha). All end-points were assessed at baseline and after 12 months of treatment with the study medication . Compliance with the study med ication was assessed by measuring blood levels of a number of micro nutrients contained within the multiple micronutrient supplement. There was evidence of good compliance with the study medication in nearly all subjects. With respect to the primary end-point , complete follow-up data were available for 68 subjects (35 patients in th~ placebo group and 33 patients in the multiple micronutrient supplement group). There was no evidence of a significant effect of multiple micronutrient supplementation on LVEF In addition, there was no evidence of a significant effect of multiple micronutrient supplementation on any of the secondary end·points. This study, therefore, provides no evidence to support the routine treatment with a multiple micronutrient supplement of such patients with chronic stable heart failure.