Atrial fibrillation (AF) is the most common cardiac arrhythmia. It is distinguished by fibrillating or trembling of the atrial muscle instead of normal contraction. Patients in AF have a much higher risk of stroke. AF is often driven by the left atrium (LA) and the diagnosis of AF is normally made from lead V1 in a 12-lead electrocardiogram (ECG). However, lead V1 is dominated by right atrial activity due to its proximal location to the right atrium (RA). Consequently it is not well understood how electrical activity from the LA contributes to the ECG. Studies of the AF mechanisms from the LA are typically based on invasive recording techniques. From a clinical point of view it is highly desirable to have an alternative, non-invasive characterisation of AF. The aim of this study was to investigate how the LA electrical activity was expressed on the body surface, and if it could be observed preferentially in different sites on the body surface. For this purpose, electrical activity of the heart from 20 patients in AF were recorded simultaneously using 64-lead body surface potential mapping (BSPM) and bipolar 10-electrode catheters located in the LA and coronary sinus (CS). Established AF characteristics such as amplitude, dominant frequency (DF) and spectral concentration (SC) were estimated and analysed. Furthermore, two novel AF characteristics (intracardiac DF power distribution, and body surface spectral peak type) were proposed to investigate the relationship between the BSPM and electrogram (EGM) recordings. The results showed that although in individual patients there were body surface sites that preferentially represented the AF characteristics estimated from the LA, those sites were not consistent across all patients. It was found that the left atrial activity could be detected in all body surface sites such that all sites had a dominant or non-dominant spectral peak corresponding to EGM DF. However, overall the results suggested that body surface site 22 (close to lead V1) was more closely representative of the CS activity, and site 49 (close to the posterior lower central right) was more closely representative of the left atrial activity. There was evidence of more accurate estimation of AF characteristics using additional electrodes to lead V1.

The adaptor protein Downstream of tyrosine kinase 1 (DOK1) was identified as a 62kDa protein highly phosphorylated as a result tyrosine kinase activation. The role of DOK1 in cell motility had not been extensively explored prior to this thesis, despite reports of DOK1 associations with several proteins involved with cell motility, including p130Cas and the β3-integrin subunit. Results in this thesis show that DOK1 is expressed in glioma cell lines and biopsy samples. DOK1 is tyrosine phosphorylated following PDGF-BB stimulation in the malignant glioma cell line U87, requiring the activities of Src, Abl, and phosphoinositide 3-kinase. siRNA-mediated knockdown of DOK1, or expression of a DOK1 mutant (DOK1FF; Tyr362/398Phe), resulted in inhibition of PDGF-BB mediated p130Cas phosphorylation and Rap1 GTP loading. Furthermore, PDGF-BB directed U87 cell migration and invasion were significantly reduced. These data indicate a critical role for DOK1 in the regulation of PDGF-BB mediated U87 cell motility through a novel DOK1-p130Cas-Rap1 signalling pathway, with implications for the mechanisms underlying the pathogenesis and metastasis of glioma. PDGF-BB mediated DOK1 phosphorylation was found to be suppressed during integrin activation in U87 cells. Additionally, adhesion (to fibronectin or vitronectin) and PDGF-BB-stimulation were respectively found to induce opposing effects on the phosphorylation of the proximal NXXY motifs of β1- and β3-integrin subunits. Treatment of U87 cells with the Abl/PDGFR/c-Kit inhibitor imatinib appeared to activate integrin signalling, inducing p130Cas and FAK phosphorylation in the absence of PDGF-BB, whilst inhibiting PDGF-BB-stimulated PDGFRβ and DOK1 phosphorylation. Conversely, treatment with an RGD-peptide integrin inhibitor induced the opposite effects. Additionally, inhibition of FAK and PYK2 induced an increase in PDGF-BB-stimulated DOK1 phosphorylation. These findings support a novel model in which PDGFRβ and integrin subunits β1 and β3 compete for Src association, resulting in an antagonistic relationship between integrin-driven adhesive signalling and PDGFRβ-driven chemotactic signalling.

Total hip/knee replacement (THR/TKR) surgery is associated with an increased risk of venous thromboembolism (VTE), and extended chemical prophylaxis is standard postoperative treatment. This thesis aimed to: (1) assess the impact of THR and TKR on thrombin generation (TG), measured in vitro via the TG test, and in vivo through TG markers - prothrombin-fragment 1.2 (F1.2), thrombin:antithrombin complexes (TAT) and D-dimer (D-D); (2) assess the impact of dalteparin, rivaroxaban and dabigatran prophylaxis on TG, 24 hours after surgery; (3) compare TG between THR and TKR patients 7 weeks after surgery. Seventy patients (36 THR/34 TKR) were studied: pre-operatively (Pre-); perioperatively (Peri-); 24 hours post-operatively (Day-1); and 7 weeks after surgery (Follow-up). Once-daily dalteparin, rivaroxaban or dabigatran prophylaxis, starting 4-8 hours post-operatively, was administered to 24, 26 and 19 patients respectively, and continued for 35 and 14 days following THR and TKR respectively. TG increased significantly during surgery, with THR showing greater in vivo TG increase than TKR. From Peri- to Day-1: dalteparin patients showed highly variable in vitro TG response with no significant changes in F1.2 and TAT; rivaroxaban significantly reduced in vitro TG, F1.2 and TAT; dabigatran showed spurious results on the TG test (due to its interference with the alpha-2 macroglobulin:thrombin complex in the TG-wells and TGcalibrator) and significantly reduced TAT but not F1.2. The reduction of TAT but not F1.2 for dabigatran suggests that thrombin is generated but blocked. TG increases during THR and TKR, indicating that administering thromboprophylaxis before surgery could be beneficial in terms of preventing and/or reducing these perioperative changes. Comparisons showed that rivaroxaban consistently lowered in vitro and in vivo TG more than dalteparin, and reduced F1.2 more than dabigatran. TAT and D-D were similar between groups. At follow-up, TG had returned to Pre- values in all patients but D-D remained elevated due to ongoing wound healing.

In this thesis, following development of extensive research collaborations, I use genetic epidemiology methods to understand disease pathways in abdominal aortic aneurysm (AAA). In the first replication study of a variant in DAB2IP found to be associated with AAA by genome wide association study I found that rs7025486 was consistently associated with higher risk of both AAA and coronary heart disease in newly genotyped studies, but was not associated with a panel of emerging cardiovascular biomarkers and did not interact with the 9p21 cardiovascular disease locus. Using a Mendelian Randomisation (MR) approach I provide strong statistical evidence that signaling through the interleukin-6 receptor is likely to be a causal pathway in AAA and may therefore represent a valid therapeutic target. Extending the MR paradigm, by utilizing multiple genetic variants combined into a score I provide evidence that HDL-C mediated pathways may also be causal in AAA, in support of a meta-analysis I performed that shows strong association between HDL-C concentration and AAA. Finally, by using a novel quantitative trait genomics approach I performed a gene centric scan of carotid artery remodelling and found variants on Chromosome 1 in DNM3-PIGC to be associated with both carotid artery size and risk of AAA, providing compelling evidence that AAA is a focal manifestation of a systemic dilating disease.

Physiotherapeutic treatment using passive and active exercise was used to study changes in cardiac axis deviation and ventricular dimension in both clinical cardiac patients and nomal healthy people. These changes appeared to be significantly different between these two groups of people suggesting a simple diagnostic method by which to identify clinical cases. Since different types of ·physiotherapeutic exercise result in different changes in the cardiac axis deviation and in ventricular dimension it can also be used to guide and evaluate the progress of cardiac patients undergoing physiotherapeutic programs. Tests were made on 27 normal subjects as a controlled group and 50 cardiac patients as the examined experimental group. The results showed that the cardiac axis deviation in normal people changes consistently and usually between 60 and 70 degrees. Coronary patients showed relative changes of between +10 and -40 degrees and rheumatic heart disease patients showed changes of between +30 and +140 degrees. Passive exercise caused left axis deviation in both normal people and cardiac patients but the effect was greater in patients. Active exercise caused right axis deviation in nromal people but left axis deviation in cardiac patients. Right ventricular dimension decreased in both passive and active exercise in normal people and cardiac patients but much more in the patients. Left ventricular dimension decreased in normal people and increased in cardiac patients in both types of exercises. The important application of this work is the design and evaluation of appropriate therapeutic procedures for individual cardiac patients undergoing treatment in physical therapy departments. An important advantage is to be able to select between passive and active therapeutic exercise routines in the earliest stages of cardiac malfunction. Passive routines can be used so much more safely on severe cardiac cases and yet can be seen to give circulatory training to the cardiovascular system. This work also shows the need to train physical therapists to use electrocardiography and echocardiography in their evaluation of physiotherapeutic programs for cardiac patients.

Chronic superficial venous insufficiency (CSVI) of the lower limb - commonly termed varicose veins (VV) - is a common and potentially debilitating condition, affecting between one third and two fifths of men and women in Britain. Traditional open dperative techniques are effective and have remained the definitive treatment modality, but modern endovascular techniques, introduced over the last decade, are increasingly perceived to confer the benefits of decreased operative time, invasiveness, patient discomfort and recovery time, making them attractive to clinicians and patients alike. Attempts to gauge the available evidence to support this incipient change in practice prompted us to undertake a systematic review and meta-analysis of all studies reported in the literature that provide objective data regarding the efficacy of open surgery and the principal endovascular techniques - radiofrequency ablation (RP A) and endovenous laser therapy (EVL T). Most published data relate to chronic venous insufficiency caused by primary great saphenous vein reflux, which is commonly encountered, and therefore an appropriate model from which to draw conclusions on treatment efficacy. The results of this study show that endovascular techniques have already achieved outcomes at least equivalent to open surgery. This has principally been quantified by duplex ultrasound measured occlusion of the primary refluxing vems. Published data, when pooled, also suggest lower complication rates with endovascular varicose vein ablation. The relative efficacy and merits of RP A and EVL T were not addressed in the literature at the commencement of our enquiry. Most published studies compare one or other of these endovenous ablation technologies with open surgery. This dearth of clinical data prompted me to set up a prospective double-blind randomized controlled trial (RCT), to investigate the null hypothesis, that "there is no difference in the efficacy of radiofrequency ablation and endovenous laser therapy for the treatment of primary great saphenous territory varicose veins ". The results of the endovascular varicose vein EVLT or RFA treatment trial (EVVERT study, ISRCTN 63135694) comprise the main body of results within this thesis. Our study confirmed that both EVL T and VNUS ClosureF AST (the latest, most efficacious, and now widespread method of RF A) are highly effective, achieving 100% occlusion as measured by duplex ultrasound one-week post-operatively. Significantly less post-operative pain and bruising was experienced among patients ;1 undergoing RFA, however (P = 0.001). At three months the occlusion rates were 97% for RF A and 96% for EVLT respectively (P = 0.67). Quality of life in both groups demonstrated a similar (P = 0.12) improvement at 3 months follow-up, with mean (± SD) reduction in A VVSS scores in the EVLT group of 1 1.2 (±8.9), while for the RP A treated patients symptom score improvement was 10.3 (±6.8), confirming the overall benefit of both procedures. Given published long term (ten year) VV recurrence rates of 60 percent following open surgery, further long term follow up data would ideally be gathered from the participants of the trial, although we note the difficulties in collecting such data from a young and mobile patient population.

Nox2 nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and peroxisome proliferator-activated receptor-alpha (PPARa) play important roles in the development of chronic heart failure (CHF) with evidence suggesting that an interaction between PPARa and Nox2 may occur during CHF. The aim of this study was to investigate the roles that PPARa and Nox2 play during cardiac hypertrophy and identify whether an interaction between the two occurs following transverse aortic constriction (TAC) and identify potential candidates that mediate an interaction.

Diabetes mellitus is the most common cause of end-stage renal disease requiring renal replacement therapy in the United Kingdom. However, many aspects of the prevalence, management and outcomes of diabetic patients with chronic kidney disease (CKD) remain unclear. This thesis consists of three studies using local (Northern Irish) data, national data (from the National Diabetes Audit) and international data (combined as part of a multi-centre collaborative meta-analysis). Its aims were to assess the survival of Northern Irish diabetic patients with CKD, examine the prevalence and associations of diabetes-related CKD in the UK National Diabetes Audit and to assess the association between glycosylated haemoglobin (HbA1c) and survival in diabetic haemodialysis patients.

Aims: The project is designed to investigate the effects of exposure to airborne pollution on cardiovascular health. Many studies have identified an association between exposure to elevated levels of airborne pollution and increases in morbidity and mortality associated with acute myocardial infarction, heart failures and coronary heart disease. The project investigates the occurrence of these diseases in a low pollution scenario and investigates plausible biomedical causes of the observed increases. The study investigates the composition of airborne particles in the city, as one hypothesis is that particle composition may be as important as the total mass of respired particles. The project investigates the aetiology of myocardial infarction and heart failure in the city, associated with exposure to air pollution and variations in meteorological conditions. The study aimed to identify to what degree these diseases are affected by changes in environmental conditions. Variations in the composition of the blood were investigated as a possible mediator in the association between air pollution, meteorology and MI and HF. In one study an epidemiological approach was used to investigate changes in the concentrations of blood coagulation factors. The second study used blood obtained from healthy volunteers on high pollution days and low pollution days, accounting for meteorological changes. The samples were analysed for several non-blood coagulation factors, with the capability of adversely altering MI and HF aetiology. Primary results: The study identified that no significant association is observed between exposure to airborne pollution and morbidity and mortality associated with acute myocardial infarction of heart failure. The gaseous pollution levels in the city were identified as too low to have a significant effect on cardiovascular health, however decreases in outdoor temperature were seen to have a significant detrimental effect on myocardial infarction and heart failure. However air pollution levels were observed to be significantly associated with deaths arising from respiratory disease. The composition of the collected particulate matter was identified as the primary reason of the lack of any association between airborne particulate matter and acute myocardial infarction of heart failure. Daily variations in outdoor temperature are identified as the most significant environmental parameter affecting the occurrence of morbidity and mortality associated with acute myocardial infarction of heart failure. There was no significant association between exposure to elevated levels of air pollution or decreased temperature and variations in blood coagulation factors. There was also no significant association between changes in non-coagulation blood factors and changes in meteorological and air pollution factors. Two possible explanations exist to explain these results, either air pollution levels are too low to effect blood composition, or the association between air pollution and MI and HF is not mediated through the studied parameters. Several significant associations were identified between exposure to airborne pollution and changes in non-coagulation blood parameters. These changes, including a variety of changes in white blood cells, the haematocrit and plasma viscosity, all suggest mechanisms by which exposure to airborne pollution may exacerbate myocardial infarction and heart failures. These findings indicate that exposure to airborne pollution has more than a statistical association with MI and HF. Conclusions: In the city and county of Cardiff levels of primary airborne pollutants is at a much lower level than many other study areas. As a consequence of these differences in air pollution dynamics there is a significant difference in the disease aetiology, particularly associated with MI and FIF. However even in this low pollution environment adverse health effects are noted, including elevation in deaths associated with respiratory disease. The pollution levels identified in Cardiff were associated with changes in several blood parameters, which in other studies are associated with adverse health effects, including exacerbation of MI and HF.

The policies of the Welsh Assembly Government (WAG) regarding the health of the Welsh population are underpinned by a social marketing approach. This is where the individual is supported in their efforts to take personal responsibility for their health. Atherogenic cardiovascular disease (CVD) is a prevalent health problem for women who can take preventative steps through attention to major modifiable risk factors for the disease. There is a paucity of information about the experience of preventing CVD from the perspective of Welsh women and this was the stimulus for this project involving a profiling of apparently healthy women aged between 25 and 79 years living in the Vale of Glamorgan. The thesis consisted of three exploratory studies the first of which utilised a 27-item questionnaire developed by the primary investigator to ascertain knowledge of CVD, preferred sources of health information, physical activity levels, prevalence of overweight and obesity, smoking status, perceptions of risk, and health screening behaviours of 724 women aged between 25 and 65 years. The second study of women aged between 25 and 65 years (n = 58) utilised a Chester Step test to measure women‘s aerobic fitness facilitating comparison with thresholds of CVD risk identified in the literature, and comparison of self-perceptions of aerobic fitness with measured aerobic fitness. Additionally, measured body-weight and stature enabled estimation of body mass index and this together with measured waist circumference allowed comparison with risk thresholds identified in the literature. The third study investigated and compared perceptions of exercise benefits and barriers of women aged between 25 and 79 years (n = 128) utilising an Exercise Benefits and Barriers Scale (Sechrist et al., 1987). Participants for the three studies were obtained by convenience sampling and this took place in various localities where women were known to meet for leisure or employment. The results of study one highlighted gaps in women‘s knowledge base of CVD, a concerning prevalence of overweight and obesity, low levels of physical activity, poor uptake of screening for cholesterol and blood pressure, and misperceptions of personal CVD risk. Preferred sources of information about CVD were magazines and television and only 10.0% of women reported discussing CVD prevention with their General Practitioner. The results of study two suggested that women were moderately accurate regarding self-perception of their aerobic fitness and 75.8% reported partially meeting recommendations for physical activity. Fifty-seven percent were overweight or obese and 50.0% were over thresholds advised by the National Institute for Health and Clinical Excellence (2006) for risk of CVD and other long-term illness. Nineteen percent had an increased risk of all-cause mortality and cardiovascular events based on failure to achieve an aerobic threshold of 7.9 METs suggested by Kodama et al. (2009). The results of study three demonstrated that women in the sample perceived more exercise benefits than barriers. Physical performance and psychological outcome benefits were the most agreed with exercise benefits in women aged between 25 and 65 years but in women aged between 66 and 79 years social interaction was the most important. Preventative health benefits were not ranked highly across the age spectrum. The most agreed with barrier in women aged between 25 and 79 years was that of exercise as tiring or fatiguing, and restrictions caused by time and family responsibilities also ranked highly. The overall results indicated that interventions to increase exercise participation in women must account for possible negative perceptions of exercise as tiring and fatiguing and efforts to increase participation should focus on enjoyment. Furthermore, account should be taken of the time restrictions faced by women, and exercise opportunities should be easily accessible and convenient. The prevention of CVD entails attention to major modifiable risk factors. The overall results of this thesis suggested that women might more readily take responsibility for CVD prevention if gaps in their knowledge base were addressed, they were supported in efforts at maintaining xviii a healthy body-weight, were engaged in talking with health professionals about prevention, and if more attention was paid to their perceptions of exercise benefits and barriers. Further research could capitalise on these findings adding to what is known about women and the prevention of CVD, particularly with regard to interventions to increase physical activity and for the management of body-weight.