Direct current transthoracic cardioversion is a well-established treatment for atrial fibrillation (AF). Significant changes in the device technology have taken place since the procedure was first described. Since then there has been a constant quest to improve the efficacy of the device by optimising various parameters that affect the success of cardioversion. Particular waveforms used in different models of defibrillators determine the energy used and efficacy of defibrillators. The technique of internal cardioversion was developed to treat patients in whom transthoracic cardioversion was unsuccessful. The aims of this thesis was to address issues surrounding optimisation of internal cardioversion. Data from this thesis will help. in developing a novel atrial defibrillator. Commercially available internal and external cardioversion devices use a capacitor based exponential energy. A unique radiofrequency energy powered defibrillator was developed at the Royal Victoria Hospital in collaboration with the Centre for Advanced Cardiovascular Research (University of Ulster). This device was extensively studied both in animal models and clinical studies at the Royal Victoria Hospital, Belfast. In this study, I compared the safety and efficacy of a novel radiofrequency low tilt monophasic waveform with a low tilt biphasic waveform for internal cardioversion of persistent AF. All the persistent AF patients had a previous history of failed external cardioversion. I also compared the waveforms in patients who inadvertently go into AF during electrophysiological studies. In both the studies, significant proportion of patients were successfully cardioverted to sinus rhythm with low energy. The radiofrequency powered defibrillator was safely used for transvenous cardioversion of atrial fibrillation. In this thesis, I have discussed about cardioversion, internal cardioversion, atrial defibrillators, various waveforms used for cardioversion, development of radiofrequency defibrillator and the concept of novel atrial defibrillator. Data from my work will add to the development of a novel radiofrequency atrial defibrillator. This device will eventually contain a passive implantable atrial defibrillator that is powered by an externally transmitted pulse of RF energy.

Atrial fibrillation is the commonest clinical arrhythmia and places a considerable burden on health services, patient wellbeing and survival. Many strategies have been implemented to treat this condition using such diverse approaches as pharmacological, device, ablative and hybrid therapies. However, as yet there is no panacea for this heterogeneous condition and thus there is active on-going research in each of these fields. The aim of this thesis is to investigate the potential benefits of selected device therapies in the management of symptoms in patients with atrial fibrillation. This thesis commences with a historical review of device therapy for atrial fibrillation. A methodological chapter discusses pacemaker analytical processes and the development of echocardiographic tools for assessing ventricular synchrony during exercise. Original work using third generation anti-AF preventive pacIng algorithms and their impact on disea'se and symptoms is examined. This IS followed by an assessment of the sensing accuracy of modern pacemakers. The device-derived electrophysiological factors are then compared to patient symptoms to isolate predictors of symptomatic status for individual atrial fibrillation episodes. The confounding problem of ventricular pacing is examined for an adverse effect on paroxysmal atrial fibrillation. The next chapter examines the use of an impedance-based rate response sensor in the right ventricular high septum. The final study describes an assessment of right ventricular apical versus high septal pacing in 'ablate and pace' patients with persistent AF uSIng cardiopulmonary and symptomatic assessments. The thesis concludes with the principal findings and a discussion on directions for future research in this field.

The QT interval is a representation of the cardiac ventricular repolarization process on the electrocardiogram. QT interval varies as a function of age, sex, heart rate, genetic variation and cardiac and non-cardiac drugs. Some individuals may have "normal" QT intervals, but are more susceptible to cardiac arrhythmias, potentially caused by genetic factors underlying QT variability in the general population. A twin study was conducted in which the genetic and environmental influences on QT and corrected QT interval were compared, based on different adjustment formulae. The current report provided evidence that corrected QT interval heritability estimates depend on the specific correction formula applied, as well as that approximately a quarter of the uncorrected QT interval heritability is due to genes specific to QT interval, while the remainder is shared with genes for heart rate. This thesis also aimed to show the penetrance of mutations occurring in the KCNQ1, KCNH2, SCN5A, KCNE1 and KCNE2 cardiac ion channel genes in clinically '. , diagnosed Long QT Syndrome (LQTS) cases. This study showed that the overall detection rate for mutations in the five defined LQTS genes was approximately 31%. Interestingly, a KCNH2 protein linked C terminal mutation was found to produce a prematurely truncated KCNH2 channel and protein defective trafficking using functional analysis. Page 3 •

SCN5A is the gene encoding the a subunit of the cardiac voltage-gated sodium channel, hNav1.5. The ionic current through this channel, which is responsible for the upstroke of the cardiac action potential, plays an important role in normal cardiac rhythm in the heart. Genetic defects of SCN5A have been linked with several cardiac arrhythmic disorders including sick sinus syndrome (SSS).

The aim of this thesis is to investigate the role of both conventional and contemporary mapping techniques and novel ablative modalities to map and to treat these difficult arrhythmias. We investigated the use of a range of mapping systems in examining the substrates for these arrhythmias including body surface 12-lead ECG mapping in patients with a Fontan circulation, contact Halo tricuspid annular activation assessment for right free wall accessory pathways, non-contact mapping in atrial fibrillation, and cryomapping in peri-nodal arrhythmias.  We hypothesised that insights into the arrhythmia substrates will facilitate the design of preventative strategies for Fontan associated arrhythmias as well as enhancing the safety and effectiveness of ablative therapy in the other atrial arrhythmias. Atrial fibrillation is the commonest sustained arrhythmia in humans and is widely acknowledged as the area in electrophysiology in which significant advancements are awaited to improve the efficacy and safety of ablative procedures.  Therefore, the last two chapters were dedicated to investigation of the role of alternative sources of ablative energies and catheter designs in the treatment of atrial fibrillation.  We tested the hypotheses that cryoablation and the focused ultrasound balloon catheter may have distinct advantages over conventional radiofrequency catheters in performing electrical isolation of pulmonary veins for the treatment of patients with atrial fibrillation. In conclusion I synthesize our experience with these cutting edge techniques and place our contribution in the context of the prevailing knowledge of these difficult to treat arrhythmias, undoubtedly the new frontier in cardiac electrophysiology.

No description available.

In this thesis a coupled model of cardiac electromechanical activity is presented, using the finite element method to model both electrophysiology and mechanics within a deforming domain. The efficiency of the electrical model was improved using adaptive mesh refinement and the mechanical system performance was improved with the addition of preconditioning. Unstructured triangular meshes were used throughout. The electrophysiology model uses the ten Tusscher-Panfilov 2006 detailed cellular model, and includes anisotropic diffusion, uses a semi-implicit time stepping scheme, stores data in an efficient sparse storage format and applies a Reverse Cuthill-McKee ordering algorithm to reduce the matrices’ bandwidths. Linear elements were used to approximate the transmembrane voltage and spatial and temporal convergence tests were undertaken. Local mesh adaptivity is added to the electrical component of the model and improvements to the performance and efficiency gained by this technique were investigated. Two different monitor functions were utilised and these demonstrated that by targeting adaptive mesh refinement at the front of the electrical wave significant efficiency and performance benefits could be achieved. The cardiac mechanical model is based on finite deformation elasticity theory, enforces the incompressibility of the tissue and incorporates anisotropic tension to simulate fibre orientation. This uses isoparametric quadratic elements for deformation, linear elements for pressure, was integrated with numerical quadrature and the resulting non-linear system solved with the iterative Newton method. Preconditioning was added to the mechanical component of the model and improvements in the performance of the solver due to this were investigated. An ILUT (Incomplete Lower Upper factorisation with drop Tolerance) preconditioner was implemented and this demonstrated performance improvements of up to 27 times on the meshes tested. The resulting cardiac electromechanical solver was then used to consider how known changes in cardiac electrophysiology, which are manifest in end-stage heart disease, affect the stability of the electrical wave. Specifically, investigations were undertaken into the introduction of fibrotic regions (with different sizes and concentrations) and electrical remodelling caused by end-stage cardiac disease. These were modelled on both static and deforming domains to consider whether deformation can alter the stability of a spiral wave. These simulations demonstrated that fibrotic regions and tissue deformation can have significant disruptive effects on the stability of a re-entrant spiral wave and that remodelling the electrophysiology stabilises the wave.

No description available.

In this thesis, a method for studying the electrophysiological consequences of acute regional ischaemia in rabbit heart was established using a combination of a novel snare technique and optical mapping. The purpose of this approach was to discover the mechanistic link between acute coronary infarction and the occurrence of arrhythmias. The electrophysiology of the epicardial surface of isolated hearts was examined using the voltage sensitive dye RH237 and optical action potentials were recorded from a 13x13mm area of left ventricular epicardium using a 16x16 element Hamamatsu photodiode array. Contraction motion artefacts were practically eliminated with blebbistatin (5µM). An alternative mechanical uncoupler, BDM, was found to be not suitable for the study of arrhythmic behaviour associated with ischaemia. After occlusion of the left coronary artery, a progressive reduction in action potential duration (APD), and slowing of upstroke was observed in an area of the left ventricle anterior surface, accompanied by ECG S-T segment elevation. These effects were reversed when the coronary artery occlusion was released. Ligation (duration 12-15mins) caused a decrease in APD50 (APD at 50% repolarisation), in the zone of reduced perfusion, from 141±5.2ms to 53.3±9.3ms (mean±SEM, n=10 hearts, P<0.001). After ligation was reversed and full perfusion restored, APD50 returned to normal values (149±7.0ms, n.s.). Trise (action potential rise time from 10-90% depolarisation) increased from 7.2±1.0ms to 15.8±2.8ms (P<0.01). In the non-infarcted area of myocardium, no significant changes in APD50 (147±7.0ms vs. 147±8.1ms) or Trise (6.4±0.4ms vs 8.8±1.4ms) were observed during occlusion. T-wave alternans behaviour was observed frequently during local ischaemia and associated with alternans of optical action potentials (OAPs) in the ischaemic border zone (BZ) and in ischaemic zone (IZ). T-wave alternans amplitude was not maintained during local ischaemia but OAPs continued to show alternating behaviour. Arrhythmias (VT and VF) were common when conduction block occurred at the interface between the normal and ischaemic zone, but arrhythmias were absent when conduction into the IZ was retained. This observation suggests that the conduction block was the crucial precipitating event for the generation of arrhythmias. Acute local ischaemia was also imposed in a heart with an existing infarct scar to examine the effects of pre-existing ischaemic damage. The incidence of arrhythmias was similar to that observed in the absence of an infarct scar indicating that pre-existing damage did not predispose the heart to arrhythmias. Global ischaemic challenges, both low flow and zero flow produced similar reductions in APD and rise time and were followed by arrhythmias, but the associated changes in the ECG were complex and could not be easily interpreted. Significant temporal variability in electrophysiology was observed in global ischaemia, but absent in the local ischaemic challenge. The underlying mechanisms of these temporal flucuations in cardiac electrophysiology may be dictated by either cellular metabolism or fluctuations in coronary flow. Long-term local ischaemia (~60mins) did not reveal a second phase of arrhythmias after 40-45mins as observed in other animal models, and nor were there signs of significant further electrophysiological changes as a consequence of the additional period of local ischaemia.

No description available.