Socioeconomic deprivation (SED) is inversely associated with mortality. The most deprived are at a higher risk of all cause mortality and cardiovascular mortality. However, only limited study of the relationship between SED and non-fatal cardiovascular disease has been previously undertaken. In those studies that have examined the relationship between SED and non-fatal cardiovascular disease, analyses have been limited to one form of cardiovascular disease (CVD), such as myocardial infarction or stroke and often prevalent disease. Furthermore, these studies have often failed to examine the association between SED and CVD whilst adjusting analyses for cardiovascular risk factors which are more prevalent in the most deprived. The aim of this work was to examine the association between SED and a number of cardiovascular outcomes after adjusting for the traditional cardiovascular risk factors of age, sex, smoking, blood pressure, diabetes mellitus and cholesterol. To determine is SED is in fact a risk factor for CVD after adjustment for these other risk factors, the relationship between SED and a number of fatal and non-fatal cardiovascular outcomes was examined. A number of forms of CVD were examined, including all coronary heart disease, myocardial infarction, stroke and heart failure A cohort of over 15,000 men and women who participated in the Renfrew Paisley cohort study was examined. These individuals were enrolled between 1974 and 1976 and underwent comprehensive screening for cardiorespiratory risk factors. They have since been followed for hospitalisations and deaths for 28 years. SED was measured using the Registrar General’s social class system and the Carstairs Morris index of deprivation. Rates of fatal and non-fatal outcomes were calculated, as were a number of composite outcomes. Adjusted analyses using multivariable regression were conducted to account for the risk factors of age, sex, smoking, blood pressure, diabetes and cholesterol. Further adjustment for the risk factors of lung function as measured by forced expiratory volume in 1 second, cardiomegaly on chest x-ray, body mass index, and a history of bronchitis was also made. The association between SED and the risk of recurrent cardiovascular hospitalisations, the burden of cardiovascular disease, as well as mortality and premature mortality was assessed for SED. I found that SED was associated with higher rates of hospitalisation for CVD disease in men and women irrespective of the measure of SED, either social class or the area based score of the Carstairs Morris index. This association persisted after adjustment for the traditional cardiovascular risk factors of age, sex, smoking, systolic blood pressure and diabetes and cholesterol. Further adjustment for lung function, the presence of bronchitis, body mass index and cardiomegaly on a chest x-ray did not explain the relationship between SED and each outcome. This risk was long lasting and persisted to the end of follow up. The strength of association of SED with coronary heart disease, myocardial infarction and stroke and all cause mortality was similar. The risk of a recurrent CVD hospitalisation was not higher in the most deprived after adjustment for CVD risk factors. However, I observed that SED was associated with higher mortality following an admission to hospital with CVD, before and after adjustment for cardiovascular risk factors of age, sex, smoking, systolic blood pressure, cholesterol and diabetes and after adjusting for the year of first developing cardiovascular disease. All cause mortality and cardiovascular mortality was highest in the most deprived. Again this association persisted after adjustment for cardiovascular risk factors. The most deprived also experienced longer hospital stays than the least deprived for a number of cardiovascular diseases including myocardial infarction and stroke. As a result the costs associated with cardiovascular disease admissions to hospital were highest in the most deprived despite their higher risk of dying during follow up. The cost differential was also explained by the finding that the most deprived experienced a higher number of admissions per person. Finally, the population attributable risk associated with SED is comparable to that of other traditional cardiovascular risk factors. In conclusion, I have found that the risk of CVD in the most deprived is higher even after adjustment for a number of cardiovascular risk factors. The numbers of hospitalisations, costs and mortality are also highest in the most deprived. Efforts are required to redress this imbalance. This can be achieved at the level of the individual through health care interventions to reduce the absolute burden of cardiovascular risk factors and to treat disease. However, societal level interventions are also required to tackle this problem as SED exerts complex effects on health that seem to also be independent of risk factors.

Background Many patients are referred from primary care with suspected heart failure and are found to have preserved systolic function. These patients may be labelled as having normal ejection fraction or diastolic heart failure, the diagnosis of which is both controversial and difficult. Previous work has identified a large proportion of these patients to have an alternative, pre- existing diagnosis. This thesis prospectively assesses the prevalence of undiagnosed ischaemic heart disease and respiratory disease in this patient group and assess diastolic function using multiple methods. The central hypothesis being tested was that first third fractional filling, a radionuclide ventriculogram (RNVG) parameter previously used to assess diastolic function at rest, would identify diastolic dysfunction more accurately under stress conditions. Methods Patients were recruited from an open access echocardiography service. Echocardiography, including tissue Doppler assessment, was carried out independently by 2 experienced observers. Confounding diagnoses including coronary artery disease and respiratory disease were actively sought by myocardial perfusion imaging and spirometry. N-terminal proBNP was measured. List mode radionuclide ventriculography was performed at rest supine and during upright bicycle exercise with simultaneous measurement of VO2 max. Validation of the reliability and reproducibility of first third fractional filling, peak filling rate, time to peak filling and other radionuclide parameters of systolic and diastolic function was undertaken. This demonstrated that it was possible to measure both first third fractional filling and peak filling rate with the short acquisition times necessary for assessment during stress. Time to peak filling was poorly reproducible under these conditions. A normal range for first third fractional filling at rest and during exercise was established. Due to a strong inverse relationship between heart rate and first third fractional filling, a continuous reference range was constructed using an exponential model. This unique approach enables the calculation of the lower limit of normal at any heart rate. A more conventional mean ± 2 standard deviations was used for the other RNVG parameters. Results Eighty three patients were recruited and completed an extensive multi-modality assessment of systolic and diastolic function. As with previous work in this field, the patients were predominantly female (82%) and elderly (mean age 66.7). Mild left ventricular systolic dysfunction as determined by RNVG was missed by echocardiography in one third of patients. Systolic dysfunction more significant than this was not observed. N-terminal proBNP was elevated in 21 of 82 patients where it was available with no significant difference in left ventricular ejection fraction between those with normal and elevated levels. Myocardial perfusion scanning was normal in 46 of 83 patients and showed significant ischaemia in 20 of 83. Spirometry was normal in 58 of 82 patients, with mild airflow obstruction in 20 patients and moderate obstruction in 4. In only one patient were no alternative diagnoses present. There was poor correlation between indices of diastolic function at rest including first third fractional filling, echocardiographic parameters and NT-proBNP. The assessment of diastolic function using stress radionuclide ventriculography did not improve the correlation between measured indices. On stress, however, low first third fractional filling predicted exercise intolerance as an inability to reach anaerobic threshold. Conclusions Alternative diagnoses to diastolic dysfunction are present almost universally in patients with suspected normal ejection fraction heart failure. This is true even where these diagnoses are not previously established. This thesis underlines the need to fully assess this patient group to allow appropriate targeting of therapy. It is also clear that echocardiography alone is potentially misleading and it is suggested that it is better placed within a tiered assessment process. The assessment of diastolic function using stress radionuclide ventriculography, although an appealing concept, does not improve diagnostic accuracy within this patient group. The marked heterogeneity of this patient group is likely to have played a role in this and it may be of interest to reassess stress radionuclide ventriculography in a more acute heart failure population.

The use of ultrasound as an extended and more objective investigation performed as an extension of physical examination has a potential role in studying inflammation in different rheumatic diseases such as rheumatoid arthritis (RT) and spondylarthropathy (SpA). Rheumatoid arthritis is a chronic disease causing joint inflammation and destruction. Metacarpophalangeal (MCP) joint involvement is one of the earliest and most permanent signs of RA. US has been used to detect synovitis and erosions in MCP joints with high accuracy when compared to X-ray and magnetic resonance imaging (MRI). In RA joints, power Doppler has been used to detect increased blood flow as a potential sign of inflammation but grey-scale and power Doppler ultrasonography was not compared to another method to detect increased blood flow in MCP joints. After RA the next most common inflammatory group of diseases are the seronegative spondylarthropathies. In SpA joint inflammation and ankylosis occur in addition to periarticular enthesitis, which is one of the major hallmarks of the disease and has been poorly studied by ultrasonography. In order to reduce observer variation in musculoskeletal ultrasound examination to the level of other imaging methods it is necessary to avoid direct contact between the observer and the subject. This problem has been addressed in the aerospace industry and led to the development of air-coupled non-destructive testing. Air-coupled ultrasonography has the potential in medial imaging to exclude observer variation if it is able to depict human anatomy. There are currently no data regarding airborne ultrasound in the musculoskeletal ultrasound literature.

Chronic hypoxia, in animals and man, results in remodelling of the pulmonary vasculature with consequent pulmonary hypertension. The pulmonary artery fibroblast (PAF) has been shown to play an early and important role in hypoxia-induced pulmonary vascular remodelling. In acute and chronic hypoxia there is excess proliferation of PAFs. Morevoer, it is likely that cell-cell interactions between hypoxia-stimulated PAFs and other vascular cells – particularly smooth muscle cells - initiates and progresses the changes that occur in pulmonary vascular remodelling in the other vessel compartments. Although hypoxic proliferation of PAFs has been shown to be circulation specific and dependant on phosphorylation of p38 mitogen-activated protein (MAP) kinase, the cell signalling pathway(s)underlying this are incompletely characterised. Hypoxic activation of PAFs is a potential therapeutic target but, as p38 MAP kinase inhibitors are not established for clinical use, work was proposed to better characterise this pathway and identify agent(s) which may inhibit p38 MAPK indirectly. The HMG-CoA reductase inhibitor simvastatin was recently shown to inhibit hypoxic pulmonary vascular remodelling in rats, but the applicability of this finding to clinical practice is incompletely established and the mechanism of action of the statin is unclear. Statins have been shown to influence MAP kinase pathways in other cell types and, as their modes of action are well established, they can be used to interrogate uncharacterised upstream cell signalling pathways. On this basis, the aims of this study were firstly to determine whether statins had a therapeutically useful inhibitory effect on hypoxia-induced, p38 MAP kinase-mediated PAF proliferation. A second aim was to exploit the known effects of statins to better characterise hypoxic cell signalling upstream of p38 MAP kinase in PAFs. Lastly, comparison of the effects of statins with established pulmonary hypertension therapeutics and a preliminary assessment – also using statins as an experimental tool - of cell-cell interactions between PAFs and pulmonary artery smooth muscle cells (PASMCs) was proposed. 1μM of fluvastatin was found to selectively inhibit acute and chronic hypoxia-induced p38 MAP kinase phosphorylation and proliferation in rat PAFs. At this dose, fluvastatin had no effect on serum-induced proliferation in PAFs, no effect on systemic adventitial fibroblast proliferation, and no effect on the phosphorylation status of other MAP kinases. Selective use of mediators and inhibitors related to the HMG-CoA pathway indicated that a geranylgeranylated protein, probably Rac1, had an obligatory role upstream of p38 MAPK, in this signalling pathway. Co-culture and conditioned media experiments with bovine PAFs and PASMCs demonstrated the release of PASMC mitogens from hypoxic PAFs. 1μM fluvastatin and the p38 MAP kinase inhibitor SB203580 selectively blocked the hypoxic PAF-PASMC interaction. Results with hypoxic PAF proliferation with the prostacyclin analogue treprostinil, the phosphodiesterase-5 inhibitor sildenafil and the endothelin-1 antagonist bosentan were negative. Bosentan, however, inhibited the hypoxic PAF-PASMC interaction, suggesting endothelin-1 release by hypoxic PAFs, with proproliferative effects on PASMCs. The results reported in this thesis provide new information on hypoxic signalling,PAF proliferation and PAF cell-cell interactions in hypoxic states. A circulation and stimulus specific anti-proliferative effect of fluvastatin on PAFs was identified and this may be of clinical relevance in hypoxia-associated pulmonary hypertension.

Patients with nephrotic range proteinuria have a higher risk of cardiovascular disease through qualitative and quantative changes in lipids and lipoproteins. The aim of this study was to examine the effect of omega-3 fatty acids derived from fish oil in this population. Treatment with omega-3 fatty acids in these patients was well tolerated and had a number of beneficial effects. They reduced small dense LDL concentration, remnant lipoproteins, VLDL and triglyceride level. Postprandial lipaemia was improved with an improvement in chylomicron clearance. However, we found that treatment increased LDL-C and although there was a redistribution to protective HDL2 rather than HDL3, HDL-C was not significantly increased. Furthermore, there was no improvement in endothelial function or inflammatory markers. Thus, we do not recommend treatment with omega-3 fatty acids alone for dyslipidaemia in this population of patients. The combination of omega-3 fatty acids with a statin merits further work.

This thesis is based on a study of a consecutive series of acute head injured patients admitted to the Institute of Neurological Sciences in Glasgow over a three year period. Each patient had a CT scan performed which showed an acute traumatic intracranial haematoma. Literature is reviewed to highlight the earlier problems of diagnosis and controversies about different management policies now that diagnosis has been made easier by CT scan. The objectives of this study were: to analyse the features and management of a consecutive series of head injured patients found by CT scan to have an acute traumatic intracranial haematoma and whoeventually required an operation; to analyse the clinical, CT scan and intracranial pressure features in these patients and to determine the influence of each of these on the treatment of a patient; to evaluate the efficacy of intracranial pressure monitoring in the management of clinically `silent' acute traumatic intradural haematoma; and to determine the results of different initial decisions about operative and non-operative management. The overall results confirm the prognostic significance of clinical features. Patients who had abnormal CT scan features at the time of their initial assessment had a more unfavourable outcome than those with normal CT scan features. It was also found that in patients with coma score 3-10, the presence of abnormal CT scan features had the same predictive value as the coma score but that in those in the coma score group 11-15 the presence of abnormal CT scan features had an adverse effect worse than could have been determined basing on the coma score alone. The results of the patients managed by ICP monitoring in this series did not differ significantly from the previous Galbraith and Teasdale series. From the findings it is suggested that the present level of ICP at which to base the decision to operate is too high and a level of > 20mmHg is recommended. Furthermore when taking the initial decision about management it is suggested that the status of the CT scan features should be considered. Patients with abnormal CT scan features should all be operated upon immediately, regardless of how well they may appear to be. This is because the presence of abnormal CT scan features precedes neurological deterioration. In patients who are found to have low ICP, < 20mmHg, monitoring should be continued for 72 hours and thereafter a repeat CT scan should be done. The findings are finally considered in relation to patients with spontaneous intracerebral haematoma. The problems of the future are mentioned.

At the time of starting this work, the syndrome of heart failure with preserved systolic function was a neglected area in clinical cardiovascular research. The aim of this study was to improve our understanding of this condition by investigating the prevalence of HF-PSF in a cohort of patients admitted to hospital with heart failure, examining their clinical characteristics and determining their prognosis. By comparing the detailed clinical characteristics of patients with HF-PSF to those of patients with reduced systolic function, this study has provided a number of important insights into this common syndrome. Patients with preserved systolic function heart failure tend to be older, and are more likely to have a history of hypertension. These findings have now become well established in the HF-PSF literature. In relation to comorbidity, I specifically examined the prevalence of chronic obstructive pulmonary disease (COPD) in the subset of my study patients with HF-PSF, with a view to determining if they may have been misdiagnosed. On the contrary, while few patients had both a normal BNP and abnormal PFTs, a significant number of those patients with HF-PSF who had previously received a clinical diagnosis of COPD, actually had normal spirometry but an elevated BNP. This rather suggests that they may have been misdiagnosed with COPD, when in fact, they were suffering from HF-PSF. The importance of the interplay between COPD and HF is increasingly recognised, and these results serve to underline the need for further study in this area. In addition to the idea that HF-PSF was merely misdiagnosis, until recently conventional expectations were that HF-PSF would produce a mild version of the clinical syndrome. However, in this study I found that patients with HF-PSF did indeed display markers of severe and complicated heart failure. The majority were classified as Killip IIA or greater on admission to hospital, and the majority had moderate renal dysfunction. This suggestion that HF-PSF is not a benign condition is borne out by the mortality data from this study. All-cause mortality in the HF-PSF group, although lower than that for heart failure with reduced systolic function, was significant, with a case fatality rate of 37% after three years. This high mortality rate underscores the need for effective treatments for patients with HF-PSF.

No description available.

A series of studies is described in which specific and conventional insulin immunoassays, the hyperinsulinaemic clamp technique and forearm venous occlusion plethysmography with local intra-arterial infusions have been used to investigate: the effect of insulin assay specificity on the relationships among serum insulin concentrations, insulin sensitivity, and blood pressure in diabetic and non-diabetic subjects with and without essential hypertension (Chapter 5) the effect of sustained physiological activation of the renin-angiotensin system induced by moderate dietary sodium restriction on insulin sensitivity in patients with non-insulin-dependent diabetes mellitus (Chapter 6) the relationship between endothelial function and insulin sensitivity in healthy subjects (Chapter 7) Prior to these investigations, preliminary studies (Chapters 3 and 4) were performed in order to validate aspects of the clinical physiological techniques required for the measurement of blood flow and insulin sensitivity. The reproducibility of bilateral forearm venous occlusion plethysmography Studies using this technique to measure changes in forearm blood flow (FBF) during intra-arterial infusions of vasoactive substances often report changes in blood flow ratio (expressing responses in the intervention arm as a ratio of responses in the control arm) rather than absolute values for flow. However, unilateral measurements are reported by other investigators, and the possibility was considered that the method used for expressing responses might influence the conclusions reached. A reproducibility study was performed (Chapter 3) which demonstrated that the between-day intra-subject variability of bilateral forearm venous occlusion plethysmography (FBF ratios) was less than that of unilateral FBF measurements. The bilateral technique was used thereafter where possible.

This thesis sets out to examine the hypothesis that some patients with idiopathic constipation, notably those who develop their symptoms following childbirth or hysterectomy, have regional as opposed to total colonic dysmotility. Such a group may be amenable to segmental rather than total colonic resection. Several clinical studies are presented which establish postchildbirth/hysterectomy constipation as a distinct subgroup of idiopathic constipation. Studies of gastric emptying demonstrate that patients with postchildbirth/hysterectomy constipation have normal motility in the proximal gastrointestinal tract. In contrast, patients with idiopathic constipation have prolonged gastric emptying indicating that proximal GI dysmotility may form a significant component of the presenting symptoms. Having identified that the proximal GI tract appears normal in patients with postchildbirth/hysterectomy constipation the next task was to identify in which region of the colon the dysmotility was most severe. Segmental colonic transit studies, using radio-opaque markers, identify delayed transit in the left colon, while dynamic radio-isotope studies localise the area of abnormality to the sigmoid colon. Colonic manometry studies, using a water-perfusion catheter point to a region of hindgut dysmotility which manifests as an excess of low pressure waves at rest and a specific failure to generate high pressure propagative waves. The usefulness of prostigmine provocation testing is examined critically in this group of patients and the pitfalls of this technique are presented.