Introduction: Options for imaging in acute stroke are expanding with the potential to select therapy based on imaging targets, as well as providing additional diagnostic and prognostic information. Multimodal CT has been used to image the ischemic penumbra, infarct core, and to detect leptomeningeal collateral flow although the optimum way to image these variables is not clear. Methods: In addition to a systematic literature review of imaging for leptomeningeal collaterals, Data from observational studies of acute stroke which employed multimodal CT imaging on admission and follow up was used to evaluate feasibility of acute stroke imaging with CT and MRI, Perfusion thresholds for core and ischemic penumbra, methods to quantify leptomeningeal collateral flow and sensitivity of non contrast CT for detecting infarct core pixels. Results: Advanced imaging in acute stroke and at follow up was more feasible with CT compared to MRI with the possible suggestion that imaging with MRI alone could introduce a bias regarding age and clinical severity for patients entered into clinical studies Heterogeneity in grading and detecting collateral flow was found in the literature providing an opportunity to devise a novel assessment method. Well developed collaterals were associated with imaging and clinical markers for good outcome as well as some potential biomarkers including atrial fibrillation and blood fibrinogen level. Relative cerebral blood flow and delay time were found to be the best predictors on infarct core and ischemic penumbra after derivation of optimum perfusion thresholds and subsequent validation in independent patient groups. Pixel based comparison of infarct core on CT perfusion and non contrast CT highlighted the lack of sensitivity of CT for detecting infarct core based on Hounsfield unit value alone. Conclusion: Multimodal CT for acute stroke assessment offers the potential for measuring infarct core, ischemic penumbra and leptomeningeal collateral flow status rapidly according to novel grading scales and thresholds and provides information on tissue viability which cannot be detected on non-contrast CT. Further evaluation on the impact additional imaging should have in clinical practice is needed.

Rheumatoid Arthritis (RA) is a chronic, progressive, multisystem inflammatory disorder for which there is, at present, no cure. It affects up to 1% of the population resulting in chronic pain, disability and, through loss of function, may lead to loss of employment. It is associated with major co-morbidities that account for premature mortality. There is now extensive published research that suggests early treatment with disease modifying drugs can retard joint damage and improve outcome. In a proportion, drug- free remission is possible. However, there remain both individuals with persistently active disease despite standard drug treatments and those with longstanding disease not exposed to effective early treatment that remain relatively unresponsive to therapy. There is a growing literature that epigenetic modifications may underpin, or at least accelerate the development of many autoimmune disorders. These include alterations in DNA methylation patterns, histone tail modifications, post-translational mRNA regulation by microRNA and combinations therein. Having established the human genome project and underlying human DNA sequence, the recognition of dynamic epigenetic regulation of the genome has added further complexity. Few data however are currently available in ‘real-world’ cohorts of patients. In order to explore the hypothesis that specific epigenetic changes may underpin differences in response to therapy, I first examined the characteristics of a cohort of fifty RA patients with longstanding and active disease (DAS28 >3.2) despite receipt of standard therapies (disease modifying drugs (DMARD) and biologic therapies. This included a detailed examination of clinical characteristics, immune profile, inflammatory markers and burden of co-morbid complications such as vascular disease and depression. Outcomes such as disability, quality of life assessments and fatigue were evaluated by means of previously validated questionnaires. These groups were assessed at baseline, three months and six months. I then measured one of the many epigenetic marks, namely microRNA, of this cohort. We analyzed the accessible profile of peripheral RA CD14+ cell microRNAs in treatment resistant RA patients, in healthy controls, DMARD inadequate responders and DMARD good responders in order to determine the presence of a microRNA profile indicative of biologic resistance. An analysis of the serum cytokine profile of the biologic resistant and DMARD resistant groups was also performed. Finally, to extend the analysis beyond conventional clinical and novel molecular biomarkers the influence of additional patient factors such as coping and illness perception were evaluated by questionnaire to determine subjective disease severity in discrete patient groups. Active inflammatory disease was present as judged by the DAS28 score and there was some improvements seen over the six-month assessment period reflecting treatment changes in all groups. Substantial disability and impaired quality of life was found particularly in the therapeutic resistant group but also in those with inadequate response to DMARD, and remained relatively unresponsive to treatment escalation. Clinical variables, deprivation, quality of life and fatigue were strongly correlated with mood suggesting close interactions and resultant increase in disease activity as measured by the DAS28. Multiple cardiovascular risk factors were determined and, having applied cardiovascular risk scoring systems, unmet treatment of modifiable risk was demonstrated. Exploratory analysis of candidate microRNA -34a, -27b and -125a showed no correlation with clinical or biochemical variables other than swollen joint counts but differential expression between study groups. Exploratory microarray profiling between the four study groups demonstrated a number of differentially regulated microRNA. Of these, a unique microRNA profile of the biologic resistant group was found. MicroRNA-423 and -1275 showed higher expression in the biologic resistant group and fell in parallel with the DAS28 reduction between study visits raising their potential utility as biomarkers. MicroRNA-3178 showed higher relative expression in the biologic resistant group. Cytokine profiles demonstrated significant differences vs healthy controls but biologic resistant, DMARD resistant and DMARD good responder groups were less distinct and individual cytokines failed to discriminate in these study groups. Cytokine profiling did not correlate with observed clinical variables, inflammatory markers nor central processes such as mood or fatigue. Finally, those coping strategies favoured were adaptive and problem based. These were unaffected by the high prevalence of mood disturbance. Conversely, illness perception was influenced by mood and both affected subjective disease assessments. The strong influence of mood and fatigue raise the hypothesis that blunted treatment response may be partially driven by these variables. Ultimately we seek to explain, identify and target those patients with aggressive disease as early intervention may prevent established disease and it's accompanying co-morbid conditions. Undoubtedly, a personalised assessment of disease variables and co-morbid conditions is necessary where treatment response is being evaluated. In such a way, significant cardiovascular morbidity and mortality may be prevented. The question of true biologic resistance remains open. Undoubtedly residual inflammation exists in longstanding RA but significant ‘disease activity’ may be explained at least in part by those subjective clinical variables influenced by both external and internal factors. The identification of a ‘biologic resistant’ microRNA profile could act both as a biomarker of treatment response in longstanding disease, superior to the DAS28 scoring system and, through target identification, better understanding of the regulation of the molecular pathways of inflammation operating in such patients. In this way novel pathways of treatment resistance may be exposed and novel treatment targets revealed. However, mood and thus illness perception also contribute to resistance to therapy and should be sought, characterized, and directly addressed to add to the global improvements in outcome that we seek in a holistic model of care in the rheumatic diseases.

The stability study of drugs of forensic interest in human post-mortem blood is an important forensic study, because in some cases, a requirement for the laboratory to undertake a full drug screening is after a few months of storage due to a need for new evidence. Therefore, it is necessary and important to know if drugs are stable over a period of time under different conditions to enable a solid interpretation to be made from any results. Some studies have been published on the stability of drugs at different temperatures but none had covered the whole set of drugs that has been studied in this thesis. The periods of study that have been covered by other studies varied from a few days to a maximum of 70 weeks, but again not all drugs have been covered. The drugs studies in this thesis are two sets of drugs, benzodiazepines and tricyclic antidepressants, their stability being determined over twelve months and at three different temperatures 25,5 and -20°C. In this thesis, blood was 'spiked' with eight drugs, Diazepam, Temazepam, Triazolam, Desmethyldiazepam, Amitriptyline, Nortriptyline, Imipramine and Chlorpromazine. The samples were stored with blanks at different temperatures for different storage times. Each month a number of samples were removed from storage and analysed to test the effect of storage time and temperature on drug concentration. Different solid phase and liquid-liquid extraction methods were tested for the determination of benzodiazepines. Liquid-liquid extraction methods for - 2 - the determination of Diazepam, Temazepam, desmethyldiazepam and Triazolam proved after study to be tedious and time-consuming. A method based on solid phase extraction was used to determine the four benzodiazepine drugs. The extraction method gave good recoveries and was highly efficient. The method of analysis used for the determination of stability of benzodiazepine drugs was the high performance liquid chromatography (HPLC) method. Tricyclic antidepressant drugs are the other drugs studied for their stability in blood. Different solid phase extraction methods were used for the determination of drugs in post-mortem blood but gave poor recoveries. The best method of extraction used was a liquid-liquid extraction method which yielded high recoveries and proved to be quick. The method of analysis used for the determination of tricyclic antidepressants for the purpose of stability of the study was gas chromatography (GC). At a recognised toxic level for each drug under study a reasonable amount of the drug was found to be detectable after one year at storage regardless of the storage temperature or media. The decrease rate of each drug concentration with time at the three storage conditions (25, 5 and -200e) was obtained.

A 6-month intervention study with a quasi-experimental design and a 3-month follow-up was conducted to evaluate the effectiveness of an Internet-based, step-wise, tailored-feedback intervention promoting four key components of the Mediterranean diet (vegetables, fruits, nuts and seeds, legumes and ratio of monounsaturated to saturated fat). Fifty-three (intervention group) and nineteen (control group) healthy females, aged 25-55 years, were recruited from the Universities of Glasgow and Glasgow Caledonian, Scotland, respectively. Participants in the intervention group received tailored dietary and psychosocial feedback and Internet nutrition education over a 6-month period, while participants in the control group were provided with minimally-tailored dietary feedback and general healthy-eating brochures. Internet education was provided via an innovative Mediterranean Eating website. Between group comparisons carried out on an "intention-to-treat" basis, providing the strongest evidence of the effect of the intervention, showed that participants in the intervention group had made more favourable changes to their fruit, nut and seed intake over the 6-month intervention, as well as increased their vegetable intake over the 9-month trial. Over both the 6-month intervention and 9-month trial, participants in the intervention group had more favourable levels of HDL-cholesterol and ration of total:HDL-cholesterol, a higher proportion progressed through the stages of behavioural change regarding legumes and olive intake and self-efficacy skills were generally increased, compared with the control group. Participants in the control group however, showed more favourable urinary electrolyte levels throughout the study. Within group comparisons showed that at 6 months, participants in the intervention group had significantly increased their intake of vegetables, fruits, legumes, as well as the MUFA:SFA ratio in their diet, had increased their mean total MDS and had significantly increased plasma HDL-cholesterol levels and a reduced ratio of total:HDL-cholesterol, as well as higher nutrition knowledge scores compared with baseline. In addition, a higher percentage of participants in this group were in the action and maintenance stage of behavioural change for vegetables, legumes and olive oil consumption, as well as generally showing more favourable attitudes and self-efficacy skills towards consumption of most of the food components promoted by the study at 6 months. These changes were generally maintained at 9 months, when additional decreases in blood pressure and an increase in total cholesterol, compared with baseline, were reported. Participants in the control group increased their intake of legumes, as well as their mean total MDS, and had significantly reduced urinary sodium levels at 6 months, compared with baseline. In addition, a higher efficacy skills generally decreased, compared with baseline. These changes were not maintained at 9 months, but at this time point participants in this group had a higher nutrition knowledge score, compared with baseline.

Healthcare associated infection confers a significant burden of morbidity and mortality to renal patients and to renal dialysis patients in particular. Sepsis is second only to cardiovascular disease as the leading documented cause of death in patients requiring renal replacement therapy. Gram positive bacteraemia is common in the renal replacement therapy population and is highly associated with indwelling haemodialysis catheter use. Optimal prevention and management of bacteraemia in this setting has not been fully determined and requires a multidisciplinary and multifaceted approach. Each of the studies in this thesis investigates an aspect of healthcare associated infection in nephrology within the theme of exploring clinical problems arising from the development of antibiotic resistance or antibiotic associated infections in renal patients. Initially we examined risk factors and outcomes of acute kidney injury requiring renal replacement therapy in a tertiary renal unit and critical care population prior to and subsequent to a change in antimicrobial guidelines in response to an outbreak of Clostridium difficile associated disease. We performed this study to address concerns that the increase in the empiric use of gentamicin may have led to an increased incidence of acute kidney injury and a greater requirement for emergency renal replacement therapy. Secondly we explored the clinical implications of gram positive infection in a renal unit population by performing a retrospective review of Staphylococcus aureus and coagulase negative staphylococcal bacteraemia over a 2 year period with particular attention to admission rates, vascular access intervention, antibiotic resistance, metastatic infection and mortality. Thirdly we have analysed S. aureus toxin genes and assessed the epidemiology of S. aureus colonisation and infection to improve our understanding of the virulence of S. aureus in different patient populations including a large haemodialysis unit in Glasgow. Finally we undertook a prospective double blind randomised controlled trial of probiotic milk drink and placebo in renal unit inpatients commencing antibiotic therapy to assess if a probiotic was effective in the prevention of antibiotic associated diarrhoea and Clostridium difficile associated diarrhoea. We performed this study as patients with chronic kidney disease are at increased risk of infection and have a significant antibiotic burden, which can lead to antimicrobial resistance, antibiotic associated diarrhoea and pseudomembranous colitis due to Clostridium difficile infection. The study of healthcare associated infection is an evolving field and involves complex interactions between colonisation and infection. There is increasing emphasis on prevention of infection and minimising complications and side effects associated with standard antimicrobials. The rising incidence of multiresistant bacterial infections is likely to result in increasing focus on preventive bundles of care and alternatives to antimicrobial therapy such as the use of probiotics. The findings of this thesis contribute to the goal of prevention of antibiotic resistance and multiresistant infections in renal patients although further research is required.

Hydralazine is a vasodilator that has been in clinical use for nearly six decades. Despite this, the mechanism of its action in human blood vessels is uncertain. Understanding how hydralazine works may have importance for the better treatment of heart failure and other cardiovascular diseases. In the first Vasodilator Heart Failure trial, hydralazine was shown, in combination with oral nitrates, to reduce mortality in patients with heart failure, treated at a time when the benefits of ACE inhibitors, beta-blockers and mineralocorticoid receptor antagonists were not known. As the combination of hydralazine and isosorbide dinitrate was subsequently shown to be less effective than an ACE inhibitor in the second Vasodilator Heart Failure trial, it was little used. Recently, however, the same combination was shown to reduce mortality and morbidity in the African-American Heart Failure Trial. Crucially, in this trial, the patients were already treated with the best currently available drug therapy. Though the patients studied were self-designated African-Americans, it is widely believed that the incremental benefits of the combination of hydralazine and isosorbide dinitrate are as likely to be obtained in other patients. While the vasodilator action of nitrates is well understood, a better understanding of the action of hydralazine (and its interaction with nitrates) could lead to the development of more effective and/or better-tolerated drugs. Nitrate therapy is limited by the development of pharmacological tolerance, possibly secondary to the increased production of reactive oxygen species. Hydralazine co-treatment has been shown to prolong the vasodilator effect of nitrates in animal models and clinical studies, although the mechanism of this protection in humans is uncertain. There are many postulated mechanisms of the vasodilator action of hydralazine, based upon studies carried out - mostly in animals - or animal tissues. Hydralazine reduces contractile responses to a number of vasoconstrictors, and this effect appears greater in arteries than in veins. The most (though not entirely) consistent findings are those suggesting that hydralazine leads to the activation of guanylate cyclase. This action to increase intracellular cGMP, could explain the favourable clinical benefits of its combination with oral nitrates. Hydralazine may affect a number of other vascular enzymes. These include key regulators of vascular superoxide production such as NAD(P)H oxidases. These systems are regulated in vivo and ex vivo by angiotensin-II and aldosterone, and are believed to be pivotal in the development of endothelial dysfunction, a key pathophysiological abnormality in heart failure. Renin-angiotensin system activation and oxidative stress are important (and inter-related) pathophysiological processes in heart failure and other cardiovascular problems. There is experimental evidence that hydralazine may inhibit these vascular and mitochondrial oxidases, and may also act as a radical scavenger, thus helping restore the balance between NO and superoxide in endothelial dysfunction. Inhibition of superoxide production may also help prevent nitrate tolerance: this may be critical in permitting therapeutic synergy between hydralazine and nitrates. However, the evidence emanating from different animal species is contradictory. Surprisingly, the antioxidant effect of hydralazine has never been directly characterised in human blood vessels. In this thesis I investigated the action of hydralazine in human blood vessels. To make this project clinically relevant, I characterised the actions of hydralazine in arteries and veins of various calibre (saphenous vein and internal mammary artery taken at the time of coronary artery bypass surgery and subcutaneous resistance arteries dissected from gluteal biopsies), from patients with low ejection fraction heart failure secondary to coronary artery disease. I also investigated the purported ability of hydralazine to reduce vascular superoxide production. 40 patients undergoing elective coronary artery bypass surgery were recruited for large vessel studies and 20 patients underwent gluteal biopsy, which yielded subcutaneous resistance arteries. Vascular reactivity was assessed using organ bath techniques and wire myography with the construction of cumulative concentration response curves. Production of vascular superoxide was measured using lucigenin chemiluminescence. Summary of results: 1. There was no direct vasodilator effect of hydralazine at therapeutic concentrations (<1 µmol/L). This suggests that the favourable benefits of hydralazine are not simply dependent on direct vasodilatation. 2. There was a modest – but not statistically significant – interaction between hydralazine and endothelium-dependent vasodilatation using carbachol. This is consistent with a trend of potential biological relevance. There was a similarly modest interaction with organic nitrates. These data are consistent with theories that the therapeutic benefits of hydralazine may be partly explained by improved endothelium-dependent vasodilatation and that the interaction with organic nitrates in vivo is not simply dependent on augmented vasodilatation. 3. Hydralazine reduced basal superoxide production in both internal mammary artery [1.09 ± 0.14 nmol/mg/min vs. 0.77 ± 0.16 nmol/mg/min (P=0.026) controls and pre-treated vessels respectively] and saphenous veins [0.77 ± 0.08 nmol/mg/min vs. 0.68 ± 0.08 nmol/mg/min (P=0.018) controls and pre-treated vessels respectively]. A dose-response in superoxide production in saphenous vein (which were more readily available for experimentation) was also evident. 4. Hydralazine significantly inhibited angiotensin-II mediated superoxide production in internal mammary arteries [1.68 ± 0.434 nmol/mg/min vs. 0.843 ± 0.144 nmol/mg/min (P=0.032) controls and pre-treated vessels respectively]. Angiotensin II plays a key role in the pathophysiology of heart failure, with pleotropic effects including increased vascular superoxide production through stimulation of NAD(P)H oxidase. Attenuation of angiotensin-II stimulated superoxide production by hydralazine could mechanistically be through interaction with the NAD(P)H oxidase enzyme group; supporting the best available animal data suggesting that hydralazine prevents nitrate tolerance through modulation of this enzyme group. Appropriate recognition must be had to the limitations innate in this work and recognise that all protocols were ex vivo and, as such, none could accurately reflect the complex phenotype recognised in chronic heart failure. The relatively small sample sizes in the study protocols must also be given recognition; however, my group - and others - have published, scientifically meaningful results utilising similar sample sizes. Future developments ought to include larger scale bench and in vivo studies of hydralazine and organic nitrate interaction with particular emphasis on assessing endothelium-dependent vasodilatation. In my studies hydralazine functionally reduced vascular superoxide production; future studies will evaluate this mechanistically with particular emphasis on the NAD(P)H oxidase system.

The aim of this project was to develop a lab-on-chip platform upon which activities in engineering and parasitology can be brought together to create new low cost diagnostic technologies for Human African Trypanosomiasis, a disease also known as sleeping sickness, for use in resource-poor environments like Sub-Saharan Africa. Filtration and separation of particles is essential for many biochemical and analytical assays. This work describes the development of novel techniques to enhance the separation/enrichment of parasites from whole blood. Techniques like chemotaxis, inertial microfluidics and density based separation were used to achieve the separation/enrichment. This thesis describes (i) development of an assay to confirm the chemotaxis of Trypanosoma brucei towards higher concentrations of glucose, (ii) designing, fabrication and use of inertial microfluidic device for continuous sorting of trypanosomes from blood cells, (iii) density based separation of trypanosomes from whole blood using a two phase Dextran-Ficoll system, and (iv) density based enrichment of trypanosomes using surface acoustic waves. This work represents an important step towards improving the detection of trypanosomes in blood for which microscopy is still considered to be the gold standard.

Prevalent patients were over-represented in many pulmonary hypertension registries and clinical trials. These patients have better survival compared with incident patients. As pulmonary hypertension (PH) is diagnosed and managed in designated pulmonary hypertension centres only in the United Kingdom (UK) and Ireland, this provides a unique opportunity to define the demographics, epidemiology and outcomes of a large cohort of purely incident, treatment-naive idiopathic, heritable and anorexigen-associated pulmonary arterial hypertension (PAH) patients. We included all newly diagnosed, treatment naive patients diagnosed in all eight PH centres in the UK and Ireland between January 2001 and December 2009 in our study. We used the same inclusion criteria used in the French and Scottish registries to define our idiopathic, heritable and anorexigen-associated PAH patients. We further refined our criteria for idiopathic, heritable and anorexigen-associated PAH by excluding patients with evidence of parenchymal lung disease on thoracic CT. These excluded patients (refer as Pre-capillary pulmonary hypertension co-existing lung disease in this thesis) were managed as idiopathic PAH by their PH physicians and otherwise satisfied the usual haemodynamic and pulmonary function criteria used to define idiopathic PAH in many PH registries and clinical trials. We divided our idiopathic, heritable and anorexigen-associated PAH patients into two age subgroups according to their median age to study the effect of age on their phenotypes and survival. We also divided our idiopathic, heritable and anorexigen-associated PAH patients into three subgroups according to their year of diagnosis to study the changing epidemiology of the disease over the past decade. We also compared the baseline characteristics and outcomes of our idiopathic, heritable and anorexigen-associated PAH patients with PAH with ‘co-existing lung disease’ patients. Firstly, we confirmed that the demographics, epidemiology and survival of incident idiopathic, heritable and anorexigen-associated PAH has changed compared with patients from the pre-disease targeted therapy era of the 1980s, and continued to evolve in the UK and Ireland over the past decade. The incidence of idiopathic PAH continued to increase over the past decade in the UK and Ireland, most likely reflecting increased referral to the pulmonary hypertension centres. Patients were still referred late with severe functional and haemodynamic impairment. Greater education is needed to raise awareness amongst the non-pulmonary hypertension community of the changing epidemiology of the disease. We have used our incident study cohort of idiopathic, heritable and anorexigen-associated PAH to validate currently available survival prediction models in PAH. Our results suggested that some survival prediction models performed better than others. We observed different phenotypic characteristics and survival between younger and older idiopathic, heritable and anorexigen-associated PAH patients. Baseline variables with prognostic significance were also different between younger and older idiopathic, heritable and anorexigen-associated PAH patients. Interestingly, obesity was associated with better survival in older patients but the contrary in younger patients. We also explored the prognostic significance of short term improvement in six minute walk distance and functional class in response to treatment in incident idiopathic, heritable and anorexigen-associated PAH. Change in six minute walk distance after three months of pulmonary hypertension treatment was associated with improved survival in patients with low baseline six minute walk distance. Change in functional class at six months was also predictive of survival in our idiopathic, heritable and anorexigen-associated PAH patients. Finally, we observed that pre-capillary pulmonary hypertension with co-existing lung disease patients who otherwise satisfied the usual haemodynamic and pulmonary function criteria for idiopathic PAH had significantly different demographics and worse survival compared with idiopathic PAH patients. Better characterisation of this subgroup of PH patients will avoid bias from inclusion of these patients as idiopathic PAH in future clinical trials.

The use of cardiovascular magnetic resonance (CMR), particularly in the cardiovascular research setting, has grown exponentially in the past 20 years. While CMR is increasingly used in clinically, it has yet to be incorporated into routine clinical practice and guidelines in the majority of conditions. One of the main reasons for this is the relative paucity of evidence for its diagnostic and prognostic utility and cost-effectiveness compared to more established non-invasive imaging techniques such as echocardiography and nuclear imaging. For CMR to become part of routine clinical care, more evidence of its utility is required. The aim of this thesis was to demonstrate the clinical utility of CMR by using it to examine 5 clinical questions that pose a relevant dilemma to physicians in a cohort of patients referred for clinically indicated CMR studies. CMR has two major advantages over echocardiography, the most commonly used technique in our centre (and most worldwide). Firstly, it is the gold standard for assessment of left ventricular volumes and function, and secondly, it has the ability to characterise the myocardium using specific imaging sequences and intravenous gadolinium contrast (known as late gadolinium enhancement – LGE). The first study in this thesis explored the potential benefit of a CMR protocol using these benefits to predict prognosis in an unselected cohort of patients. In this study I found that the assessment of myocardial function using ejection fraction and deformation imaging (strain) and assessment of the presence of fibrosis using LGE had incremental prognostic significance in addition to clinical predictors of outcome in all patients, including in those with ejection fractions greater than 35% (commonly thought to predict higher risk patients). During scanning of this cohort of patients, it became apparent that CMR imaging of myocardial scar in patients with a history of prior myocardial infarction (MI) had the ability to identify fat within the infarcted territory, known as lipomatous metaplasia, which had been recognised pathologically but is not identified by echocardiography. The tissue characterisation ability of CMR has for the first time allowed this to be identified non-invasively ante-mortem. Pathological studies had suggested that lipomatous metaplasia was associated with adverse remodeling, while recent animal studies had suggested that the presence of myocardial fat within infarcts was pro-arrhythmogenic. In this study I showed that the presence of lipomatous metaplasia was indeed independently associated with mortality and ventricular arrhythmias, suggesting that it perhaps provides an arrhythmogenic substrate. The next study explored the use of LGE in addition to established clinical markers in patients undergoing implantable cardioverter-defibrillator (ICD) implantation for ischaemic or dilated cardiomyopathy. These patients met the current clinical criteria for ICD implantation and also had testing of NT-proBNP, a marker of cardiac strain that is associated with adverse prognosis. The patients all underwent pre-implantation CMR. I found that the presence of LGE and a high NT-proBNP was associated with a higher risk of death and ICD activation, perhaps hinting at a role for CMR in providing further risk stratification in this group of patients. Following on from this, I looked at the diagnostic capabilities of CMR. Characterisation of patients with mildly impaired left ventricular systolic function is important as early identification of cardiomyopathy can potentially allow early institution of life-saving therapies. Mild left ventricular impairment can however also be associated with the normal myocardial adaptations to exercise, known as athlete’s heart. This poses a diagnostic dilemma, which may not be easily solved using current imaging techniques. I found that the use of a further CMR parameter to characterise tissue, T1 mapping, was able to discriminate between patients with early DCM and exercisers with normal physiological myocardial adaptation, perhaps providing a solution to this diagnostic challenge. The final study explored the utility of dobutamine stress CMR (DSCMR) to diagnose significant coronary artery disease (CAD) in patients with left bundle branch block (LBBB) and clinically suspected CAD. CAD is the most common cause of LBBB, yet LBBB causes myocardial abnormalities that can make it difficult diagnose CAD non-invasively, leading many patients to be referred for invasive coronary angiography (ICA) to confirm the diagnosis. Despite this, a substantial proportion of the patients with LBBB will not have significant CAD, meaning that ICA would be unnecessary. This study compared DSCMR with dobutamine stress echocardiography, with ICA as the gold standard. I found that DSCMR was significantly more accurate in diagnosis than dobutamine stress echocardiography, perhaps providing a technique that could be used as a gatekeeper to ICA. This thesis shows that CMR can provide important diagnostic and prognostic information in a variety of cardiac conditions and can potentially help guide clinical decision-making. Larger studies should be performed to confirm these findings, allowing for determination of cost-effectiveness and incorporation of CMR into routine clinical management.

Introduction: Erectile Dysfunction (ED) is known to impact on the lives of men but few studies have sought to assess the impact of ED on women and there are no qualitative studies that have compared accounts from women and their partners on the impact of ED on the relationship. Current trends in prescribing of ED treatment focus on men and consider ED to be a male medical problem. Aim: The aim of this study was to obtain knowledge on how ED affected the lives of women and their partners and to gain insight into the impact of ED from a couple’s perspective. Methods: Qualitative accounts from women on the impact of ED were obtained from one to one semi structured interviews and from clinical interviews with their partners. Interviews were audio taped and tape recordings transcribed. The study sample consisted of heterosexual couples and compared feedback on the impact of ED from interviews with men seeking erectogenic treatment and their partners. Men attended routine appointments at a secondary care specialist clinic following referral to the clinic by their GP and were interviewed. Feedback from interviews with men was recorded in hospital case-notes. Men with severe ED that met the inclusion criteria were invited to participate in the study and if they agreed were asked to deliver information about the study to their partners. Interview appointments were arranged for women that agreed to participate in the study and informed consent was obtained from both partners. Transcriptions of interviews with women were analysed using grounded theory. The size of the population sample was dictated by the theoretical relevance of the data in relation to the research enquiry. New concepts and new avenues of enquiry ceased to emerge from analysis of transcriptions after fifteen interviews. Results: Women expressed that ED consumed their partners and reported that their partner’s perception of “solving the problem” focussed on restoration of erectile function. These data were verified by men. Women expressed that they attempted to confront “the problem” by encouraging their partners to seek help but men delayed seeking help due to embarrassment. Women felt isolated and upset at the lack of reciprocity and struggled to make sense of their partner’s perspective, as men communicated to women that the sexual act was of optimum importance in terms of defining the relationship. Men expressed concern that their partners might seek sexual activity “elsewhere” which reinforced perception among women that men defined the relationship in terms of sex. Women were concerned that ED was a symptom of an underlying condition yet men ignored their advice to seek help. Erectile dysfunction affected men’s confidence and caused lack of self esteem. Men reported that ED impacted on their masculinity. Women expressed that ED caused significant disruption to their lives and agreed to their partners using treatment if it was likely to improve their quality of life by having a positive effect on their partner’s mood. Conclusions: Women were aggrieved and disappointed that ED had such a devastating influence on their relationship. The emotional trauma that women experienced and expressed suggested that feelings of hurt might prevail regardless of treatment outcomes. Women were disappointed that the bond in their relationship was weakened by ED and their partner’s reluctance to communicate. Men expressed fear of “losing everything” and felt that restoration of erectile function would solve all of theirs and their partner's problems. Lack of communication resulted in men and women relying on perception of how ED affected their partners. Although this study did not provide solutions to the problems that couples experienced it produced data that was unique in terms of insight into the impact of ED on women and their partners and identified the importance of considering the couple’s perspective on the problem when assessing ED. Further research is required into the impact of ED on couples as understanding of how ED impacts on a couple’s relationship is poor.