Although atrial fibrillation (AF) is the most common sustained arrhythmia, its pathophysiology is complex and remains poorly understood. Most episodes of AF are initiated by ectopic beats originating from the pulmonary veins (PVs). It has been suggested that the distinct electrophysiological properties of the PVs and their rich innervation by noradrenergic sympathetic fibres contribute to the susceptibility of this region to ectopic activity. This study aimed to determine whether the cellular electrophysiological responses to noradrenaline (NA) of card iomyocytes isolated from the PVs differed to those isolated from the left atrium (LA).

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Tntroduction. The [alpha]-subunit (KCNQl) and auxiliary [beta]-subunit (KCNEl) form the slow delayed rectifier potassium channel (IKs)' Although the IKs current is considered to be involved in repolarisation of the cardiac action potential the exact role of IKs in cardiac physiology is still unclear. Recent studies have suggested that IKs is involved as a repolarisation reserve. However, inherited mutations in KCNQl and KCNEI genes suggest that IKs has a prominent role in normal cardiac repolarisation. Understanding the role of IKs in human cardiac physiology may lead to improvements in the treatment of arrhythmias. The aim of this project was to assess the extent to which the cardiac IKs current is involved in excitation-contraction coupling and whether modification of the IKs CUlTent can be of therapeutic benefit in treatment of ventricular arrhythmias.

Background The effects of meat reduction on markers of cardiovascular health A growing body of literature suggests that there are several benefits to plant-based nutrition, which include both health and environmental effects. However, there are various barriers that could prevent a transition to a diet which incorporates a variety of plant foods, while minimizing meat-based products. This PhD investigated those barriers, while attempting to aid a student population in reducing meat-intake successfully. Methods This research project comprised three studies: Study 1, a critical review compiled 13 studies related to vegetarianism and CVD. Study 2 involved 334 university students who submitted dietary data and completed a questionnaire related to the Vegetarian diet. 100 participated in a plant-based intervention. Study 3 included 25 healthy students who participated in a 4-week intervention, which aimed to reduce meat intake by 50%. Results The primary finding of the critical review was that significant reductions were recorded for primary CVD risk factors as a result of consuming a vegetarian diet. The results of Study 2 suggest that the enjoyment of meat and the family/friend influence has had the greatest impact on preventing a potential transition to vegetarianism. Vegetarian students reported lower levels in caloric intake, protein, total fat and carbohydrates with a greater intake of calcium, iron and fibre. Study 3 found that there was no significant effects of reducing meat intake on BMI or % Body Fat and that total plasma and LDL cholesterol and triacylglycerol were significantly reduced. No significant effect of the intervention was seen on HDL cholesterol. Conclusion The outcome of the combined studies suggests that a well-planned vegetarian diet can reduce the risk of developing cardiovascular disease risk factors and that with sustained support, a group of healthy individuals can reduce meat intake by a minimum of 50% without impacting body weight or composition or negatively effecting well-being.

Cardiovascular (CV) disease is the commonest cause of mortality in CKD. CV mortality is not entirely explained by traditional CV risk factors and therefore systemic inflammation and vitamin D deficiency are thought to play a major role in CKD. Vitamin D [25 (hydroxy vitamin D; 25(OH)D] modulates adaptive immune responses and 25(OH)D deficiency is associated with CV mortality. Vascular endothelial dysfunction is a surrogate marker of atherosclerotic CV disease and related to systemic inflammation in CKD. However, the role of vitamin D on inflammation and endothelial function in CKD is largely unknown, which I aimed to investigate.

BACKGROUND Cardiac resynchronisation therapy (CRT) implant rates continue to escalate but device optimisation is rarely performed despite being routinepractice in the CRT trials. This thesis seeks to address the uncertainties contributing to failure of uptake of atrioventricular (AV) optimisation, and examines best management of the patient following CRT. METHODS AND RESULTS Echocardiographic iterative AV delay optimisation was used in both rest and exercise studies. A significant drop in NT-proBNP (median fall 474 pg/ml) was seen within 7 days of optimisation compared with patients requiring AV adjustment. The larger the change in AV delay made (>50ms change), the greater the reduction in NT-proBNP levels. During exercise the majority of patients [94%] demonstrated a marked reduction in optimal AV delay. With rate adaptive AV delay activated (adaptive shortening of AV delay with exercise), a 10% improvement in peak V02 and exercise duration was seen. 77 patients were followed over a median 16.3 months, revealing that more than a third of patients required further AV delay readjustment. Multivariate analysis shows the degree of reverse remodelling post CRT dictated the requirement for repeat optimisation. The additional benefits of the CRT optimisation clinic resulting in a multifaceted patient assessment via simultaneous clinical, echocardiographic and device interrogation are demonstrated. Finally, using remote monitoring device diagnostic data, patients with atrial high rate event (AHRE) burden >3.8 hours/day were 9 times more likely to develop thromboembolic complications and 4 times more likely to experience the composite endpoint of death from cardiovascular cause, thromboembolic events and admissions for heart failure or atrial fibrillation. CONCLUSION AV delay device optimisation at both rest and exercise provides additional benefits for the patient over that with CRT implant alone. The setting of the optimisation clinic facilitates a 3600 appraisal of the patient with additional benefits over that of AV delay optimisation alone. Ongoing remote monitoring helps to detect, risk assess and manage patients most at risk from HF decompensation, death and thromboembolic events. The concept of CRT as an isolated procedure is evolving into that of a remotely monitorable, adjustable component of a complex long term condition.

BACKGROUND: Sudden arrhythmic death syndrome (SADS) describes sudden, premature and unexpected deaths, which remain unexplained despite autopsy. Approximately one-third of SADS relates to inherited conditions such as Brugada syndrome (BrS), long QT syndrome (LQT) and catecholaminergic polymorphic ventricular tachycardia (CPVT). AIMS: We aimed to evaluate clinical utility for novel histopathological and genetic molecular investigation following SADS. METHODS: SADS cases were investigated by: [1] morphometric analysis of picrosirius-red histological myocardial staining; [2] a novel enrichment (Fluidigm Access Array) for BrS, LQT and CPVT risk-genes with next generation sequencing (NGS); [3] NGS of risk-genes in an international cohort; [4] genotyping putative functional exomic variants (Illumina BeadChip); 5) whole exome sequencing in a family. RESULTS: [1] Regression analysis demonstrated that BrS cases have a 42% excess in interstitial fibrosis over age and gender-matched non-cardiac deaths (P=0.026, n=6). No association was seen between BrS and intramyocardial fat distribution (P=0.133). [2] Optimisation of bioinformatics of NGS resulted in a sensitivity of 80.72% and specificity of 99.99% for genetic variation on molecular autopsy of 46 British SADS cases; all disease-causing mutations were identified correctly (6.4%). [3] Diagnostic yield ofNGS molecular autopsy was established as 13.2% (95% CI: 7.8-18.9%) by replication in 151 additional multi-ethnic SADS cases. [4] Exomic genotyping of 82 British SADS cases and 376 ethnically-matched controls revealed 8 significantly SADS-associated genes, though none were known cardiac risk-genes. The reported association of rs1559040 (chromosome 2) with cardiac arrest in coronary disease was replicated. [5] Four possible risk-genes for SADS were implicated from 46 candidates using co-segregation analysis and subsequent prioritisation following whole exome sequencing in a multi-generational pedigree. D ISCUSSION: We report here on fibrotic features of BrS, screening utility of NGS molecular autopsy following SADS and novel potential risk-genes for further study.

The measurement of the cardiac troponins has produced a paradigm shift in the management of cardiac disease. Elevation of cTn without acute myocardial infarction (AMI) also occurs in non-cardiac patients including those with chronic kidney disease (CKD). Cardiovascular disease accounts for 50% of mortality in CKD. In this thesis, the prognostic value of cTn elevation in CKD was investigated by meta-analysis of published data and recruitment of a CKD cohort. The relationship between elevated cTn and cardiac imaging; the involvement of inflammation, oxidative stress and platelet activation were investigated. The difference in cTn pre and post haemodialysis was investigated. The forms of cTn released into the circulation in CKD was investigated and compared to the forms released following AMI. CKD patients positive for cTn are three times more likely to die than cTn negative patients. Elevated cTn was not associated with extent of cardiac pathology but rather the presence of diffuse global ischemia. Elevated cTn in CKD is associated with increased C-reactive protein but not other markers of inflammation, oxidative stress or platelet activation. cTn, CRP and interleukin-6 were predictive of all-cause mortality. Following dialysis, cTnl but not cTnT adsorbs to the membrane within the vascular compartment. Intact cTnT and cTnl were observed in CKD patient serum by Western blotting, which is similar to the cTn forms of observed following myocardial infarction. Some lower molecular weight fragments are demonstrable but their presence is method dependent and heterogeneous between patients. Elevated cTn is of prognostic value in CKD and reflects the high incidence of cardiovascular disease and cardiac death. Elevated cTn is not a false positive. The mechanism of cTn release in CKD remains to be understood. The clinical challenge is for the renal physician to translate the potential for cardiovascular disease monitoring conferred by cTn into improved patient management.

Joint European Society of Cardiology and European Association for Cardiothoracic Surgery (ESC/EACTS) Guidelines on Myocardial Revascularisation advocate Heart Team discussion of all patients with severe coronary artery disease. Furthermore, incomplete revascularisation is known to increase morbidity and mortality following intervention. The guidelines suggest that patients with left main stem, proximal LAD or three vessel disease (3VD) should be discussed with a surgeon prior to percutaneous coronary intervention (PCI). The aim of this project is to assess the impact of the guidelines on referral patterns to the Heart Team and myocardial revascularisation outcomes in the United Kingdom. Methods All patients undergoing revascularisation at three major cardiothoracic centres in London were studied. Patients undergoing PCI were identified from the British Cardiovascular Intervention Society Database. Data was collected prospectively from January to June 2010, prior to the guidelines and January to June 2012 following its publication. Heart team discussion or direct referral for surgery, for all patients with surgical disease, was determined from database and electronic patient records. Primary outcomes were Heart Team discussion and method of revascularisation. Results In 2010, 621 patients underwent elective PCI before the guidelines, of which 224 had potentially surgical disease. Of these, only 37 (15%) were discussed by the Heart Team prior to intervention. Furthermore, 41 (18%) of patients had three vessel coronary disease and only 10 (25%) of these were discussed. In 2012, following introduction of the guidelines, 686 elective PCI were performed, of which 272 had surgical disease. Again only 47 (17%) were discussed by the Heart Team prior to intervention (p = NS). Similarly, 43 (16%) had three vessel disease and only 16 (37%) were discussed. Of those patients undergoing elective PCl for severe coronary disease in 2010, only 98 (44%) were fully revascularised. In 2012, 133 (48%) received complete revascularisation. However, of those with 3VD, in 2010 only 7 (17%) were fully revascularised. Similarly, in 2012 only 4 (11 %) received full revascularisation. Conclusion Despite joint ESC/EACTS guidelines and attention given to this subject by the professional bodies, a significant number of patients with severe coronary artery disease who would clearly benefit from surgical revascularization are not being discussed by the Heart Team and receiving optimal treatment.