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Atrial fibrillation (AF) is the commonest cardiac arrhythmia. Ageing and heart failure are both independent risk factors for the development of AF. In an ageing society the prevalence of AF will undoubtedly increase and become a burden on the economy. T'he aims of my thesis were to establish why the atria itself is predisposed to more arrhythmias than the ventricle and whether independently ageing and heart failure predispose the atria to an AF-like phenotype.

Atrial fibrillation (AF) is the most common heart rhythm disturbance. Once AF is initiated, dynamic alterations of atrial electrophysiological properties occur invoking, in turn, AF inducibility. In patients for whom AF persists for long-term periods (persAF), identification of critical areas for successful ablation remains a challenge. Improving our understanding of the underlying AF behaviour is a key factor to contribute towards improving patient outcome. In this research, spectral analysis of simultaneous high density non-contact unipolar intracardiac atrial electrograms (AEGs) recorded from the left atrium (LA) of persAF patients (AF duration 34±25 months) was applied after a coherent strategy of cancellation of the ventricular influence on the AEGs. Three-dimensional dominant frequency (DF) maps with 2048 measurement points from AEGS were generated over consecutive frames of up to 1 minute (windows of 4s with 50% overlap). The results of this thesis showed a lack of DF spatiotemporal stability, demonstrating that AF mapping would be preferable performed using simultaneous multipolar recordings. Although DF is not stable, a certain degree of DF reappearance was observed, mostly within 10 s. The spatiotemporal analysis of areas thought to be playing a role in AF maintenance, highest DF areas (HDFAs), revealed presence of three distinct patterns with predominance of cyclic behaviour (61.2±12.4 % of the time) followed by local (27.0±8.6 %) and irregular behaviour (11.9±9.1 %), mostly concentrated in the LA roof and the pulmonary veins. Independently of the trajectory of the HDFAs, the regions located next to the HDFAs’ core presented higher DF organisation than areas by the HDFAs’ periphery (p=0.0061) providing further insight into the potential mechanisms of persAF. The research has demonstrated the importance of DF mapping as an auxiliary tool contributing to the investigation of persAF patients and would help clinicians to better understand the AF mechanisms. Real-time implementation was shown to be feasible with the use of Graphic Processing Units, where the processing time was 15 times faster than real time, representing an innovation that could have considerable impact on clinical practice, as part of the decision making process for persAF treatment.

The technological advances made over the last century have afforded the clinician an array of sophisticated tests to aid the diagnostic process. Much of the knowledge gained on the pathophysiology of cardiac disease has been from invasive assessment, often in animals, but also in human subjects. Application of this knowledge to patient care is limited by the need for invasive studies that present some risk of harm to the patient. Non-invasive assessment reduces risk of harm significantly whilst providing information equivalent to invasive assessment. The best example of this is the insight delivered by technological advances in imaging of the heart. Ultrasound echocardiography, radio-isotope imaging, computerised tomography and magnetic resonance imaging have all excelled expectations in delivering accurate anatomic and functional information non-invasively. Assessment of electrophysiologic function began non-invasively with the recording of surface potentials by Augustus D Waller1 and the development of the electrocardiogram (ECG) by William Einthoven2 (who was later awarded the Nobel Prize in 1924 for his endeavours). Recognition of pathology from the surface ECG was hypothesis generating. In order to explore the heart's electrical system further electrophysiological assessment was made invasively to supplement the information obtained from the surface ECG. This information proved favourable and when combined with pacing stimulus protocols provided the clinician with detailed information on conduction properties that could be measured in a reproducible and reliable way to reflect the impact of drugs or disease in detail that the surface ECG could not. Moreover, the invasively measured properties could be linked with changes at the cellular level and thus the effect of changes in ion channel density, for example, on electrophysiologic properties could be predicted. It would obviously be beneficial to somehow gather the information non-invasively, but this has proved more challenging. Firstly, much of the information obtained invasively is the product of pacing protocols that cannot be reproduced non-invasively. Secondly, the detailed assessment of cardiac electrophysiology from surface electrograms is hampered by multiple factors pertaining to the intervening tissue, i.e. body habitus and electrical interference (noise). Given these factors the expectations of non-invasive assessment of cardiac electrophysiology must be limited and cannot be compared to imaging. The utility of non-invasive tests must be in the 'broad stokes' rather than the fine detail. However it is not beyond expectations to provide useful insights that may be employed in the investigation of disease trends and or the impact of intervention. The trade off for lack of detailed information is the safety, low cost and general applicability to a large patient population. The difficulty in gathering further information from the surface ECG has been alluded to briefly above. Digital techniques are used to overcome some of the difficulties such as amplification and noise reduction. Digital applications are then often used to analyse the data gathered. It is useful to be familiar with some of the concepts involved in digital signal processing as it pertains to cardiac signals and thus a brief outline is presented in appendix 1. This thesis begins with a detailed review of the surface P wave in health and disease, and a review of atrial fibrillation (AF) - the most common arrhythmia encountered in clinical practice.

Purpose: Atrial fibrillation (AF) is the most common heart arrhythmia and is associated with an increased risk of stroke. Stroke risk is commonly treated with oral anticoagulation (OAC) with a narrow therapeutic range (INR 2.0 to 3.0); which is poorly controlled in practice. Barriers to adherence include poor knowledge, and inaccurate perceptions surrounding illness and medications. Trial registration: ISRCTN93952605. Systematic review: Seven trials of educational, self-monitoring and decision aid interventions were included in a systematic review. Pooled analysis suggested education OR, 95% CI 7.89 (5.54-10.24) and self monitoring OR (95% CI) 5.47(2.55-8.39) significantly improve TTR; whereas decision aids are no more effective in reducing decision conflict than usual care, OR (95% CI) -0.10 (-0.17 to -0.02). Intervention development: The intervention was theoretically-driven (utilising the common sense and beliefs about medication models) and developed with expert patient feedback. Described using behavioural change techniques, the one-off group session included an educational booklet, ‘expert-patient’ focussed DVD, and worksheet. Methods: Ninety seven warfarin-naïve AF patients were randomised to receive the intervention (n=43), or usual care (n=54). The primary endpoint was time within therapeutic range (TTR), secondary endpoints included knowledge, quality of life (AF-QoL-18), beliefs about medication (BMQ), illness perceptions (IPQ-B), and anxiety and depression (HADS). Results: Intervention group had significantly higher TTR than usual care (78.5% vs. 66.7%; p=0.01). Knowledge changed significantly across time (F (3, 47) = 6.4; p<0.01), but not between groups (F (1, 47) = 3.3; p = 0.07). At six months knowledge predicted TTR (r=0.245; p=0.04). Illness concern negatively correlated with TTR (r= - 0.199; p=0.05). General Harm scores at one month predicted TTR (F (1, 72) = 4.08; p=0.048). There were significant differences in emotional representations (F (3, 49) = 3.3 (3, 49); p= 0.03), anxiety (F (3, 46) = 25.2; p<0.01) and depression (F (3, 46) = 37.7; p<0.01) across time. Conclusion: A theory-driven educational intervention can improve TTR in AF patients and potentially reduce the risk of adverse clinical outcomes. Improving education provision for AF patients is essential to ensure efficacious treatment.

The sudden death of a' child is a risk that families with Long O'T syndrome face. Preliminary research has shown that young people and their families with both Long O'T syndrome and asymptomatic Long O'T syndrome are at risk of developing psychological difficulties. To date however, the psychological processes that mediate the challenges associated with Long O'I syndrome within the context of adolescent development have not been fully explored. The present study conducted in-depth individual interviews with five young people aged between 12 and 15 years with a diagnosis of asymptomatic Long O'T syndrome and one of their parents/carers. The cross sectional research employed a qualitative approach, using Interpretative Phenomenological Analysis (IPA) to make sense of the lived experiences of young people and their parents/carers . . The analysis of the parent/carer data yielded four main themes: A Horror Story, Loss, Living with Risk and Coping and Getting on with it. Two themes emerged from the young people's data: Multi-faceted Identity and Loss. Both young people and their parents appear to find challenging; negotiating autonomy and independence in the context of the associated risk with Long O'T syndrome. The difficulties young people and their parents faced appeared to persist in the period following diagnosis. Participants expressed that, whilst able to express some hope for the future, the associated risks with Long O'T syndrome remained a mediating factor as ultimately these parents/carers are being confronted with the possible- mortality of their children. The current study facilitated the exploration of how living with the condition and the associated risks affects the lives of young people their parents, mediates their relationship and in turn affects the developmental process. The current study 3 highlighted the distressing impact of the condition for parents and the long term global consequences the condition has upon the entire system. The study states relevant clinical implications and makes suggestions for future research. 4

Atrial Fibrillation (AF) is the most common sustained arrhythmia, affecting approximately 1 % of the population. In its treatment, pharmacological inhibition of repolarising potassium channel currents prolongs the atrial action potential (AP) and refractoriness, but due to a lack of atrial-selectivity the majority of existing drugs can have unwanted proarrhythmic side effects in the ventricles. Small-conductance calcium-activated potassium (SK) channels have been proposed as a promising atrial-selective drug target. However, data in the field are controversial. Although some discrepancies may be due to species differences there are nevertheless direct contradictions. The aim of this study was to confirm the presence of SK channels in the mouse atrium and resolve their functional role in the mouse heart. Three subtypes of SK channels have been cloned (SKI, SK2 and SK3). The presence of SK2 protein in mouse atrial myocytes was confirmed using confocal immunofluorescence microscopy. Whole-cell patch-clamp recordings revealed an outward current in mouse atrial myocytes that was partially inhibited by the SK inhibitors apamin, UCLI684 or NS8593. The effect of NS8593 was unlike that of apamin or UCL1684. Furthermore, NS8593 blocked other heterologously expressed cardiac channels, indicating multichannel block. Apamin inhibited the current in atrial myocytes with an ICso of 118 pM, close to reported values for homomeric SK2 channels. UCLI684 prolonged the AP duration (APD) in isolated mouse atrial myocytes and in the intact atrium. However, UCLI684 prolonged APD significantly more than did apamin, suggesting that there is an apamin-insensitive population of SK channels activated during an action potential. Co-expression of SK2 and SK3 channels in HEK293 cells produced a current with a pharmacology that matched that observed during atrial action potentia Is, suggesting the presence of heteromeric SK2-SK3 channels. Finally, UCLI684 increased beat-to-beat variability in repolarisation raising the possibility that SK inhibition may be pro-arrhythmic.