Medicine (RMH) - Theses

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    Mechanisms Driving Persistent Atrial Fibrillation: Insights from Endocardial-Epicardial Dissociation and Regional High-Density Mapping of the Human Atrium
    Parameswaran, Ramanathan ( 2020)
    Atrial fibrillation (AF) is an extremely common clinical problem with increasing global prevalence. Besides its frequent association with stroke, heart failure and increased mortality, recent data have shown the significant quality of life impairment and psychological distress that results from this arrhythmia. The clinical spectrum of AF can manifest as brief episodic paroxysmal AF or as a sustained arrhythmia in persistent AF in patients with progressive atrial disease. Mechanistically, paroxysmal AF is often triggered by rapidly firing impulses that originate in the pulmonary veins, allowing catheter-mediated elimination of sources, with clinical success rates of 70–85%. However, in persistent AF, the mechanism that sustains the arrhythmia remains incompletely understood and is a topic of ongoing debate. Recent advances in cardiac mapping and computational methods have suggested localised drivers and non-pulmonary vein triggers particularly from the left atrial appendage but there is also accumulating evidence that the atrium frequently functions electrically as a 3-dimensional structure and there exists endocardial-epicardial dissociation in activation during AF. The aims of this thesis are three-fold: Firstly, we review the evidence for the current and expanding indications for catheter ablation in AF and highlight some of the novel tools and technological advancements that have emerged in the recent years for achieving durable pulmonary vein isolation (PVI). Secondly, we investigate the role of some of the novel mechanisms that potentially sustain persistent AF. We addressed this first by systematically reviewing the evidence for a computational mapping technique thought to identify localised sources and then performed a series of cardiac mapping studies in humans. These high-density mapping studies characterised atrial endocardial-epicardial electrical dissociation in the presence of structural heart disease and explored the mechanistic role of localised sources in the left atrium and the left atrial appendage (LAA) in persistent AF. Finally, given the emerging evidence for the mental health effects from AF, we discuss the rationale and methodology of a randomised controlled study comparing catheter ablation with medical therapy on psychological distress and neurocognitive function in patients with AF. Chapter 1 summarizes several aspects of AF including the epidemiology, our current understanding of the classic and novel mechanisms of AF the mechanistic role of risk factors and their implications in remodelling and atrial cardiomyopathy. Chapter 2 reviews the role of catheter ablation in AF and highlights the recent technological advancements. Catheter ablation is a safe and effective rhythm control strategy for symptomatic patients who failed medical therapy or who prefer not to take medications and there is emerging evidence for its role in mortality reduction in AF patients with heart failure. Pulmonary vein isolation is the cornerstone approach and both radiofrequency and cryoablation have similar efficacy. Mounting evidence demonstrates the importance of risk factor management for improving ablation outcomes. In the era of high-density cardiac mapping, FIRM (focal impulse and rotor modulation) emerged as a novel computational mapping technique to identify rotors and focal sources that could potentially be targeted during catheter ablation. Despite early promising results, many studies that followed showed mixed outcomes and indeed, some others showed a pro-arrhythmic consequence. Chapter 3 presents a systematic review and meta-analysis of 11 observational studies and demonstrates the wide variability in the medium-term outcomes of FIRM guided ablation and explores the significant heterogeneity between published studies. Chapters 4 and 5 examine the characteristics of endocardial-epicardial dissociation (EED) in patients with structural heart disease. We performed high-density simultaneous endocardial-epicardial phase mapping of the right atrium in patients undergoing cardiac surgery to study this. In Chapter 3 we report the for the first time, functional EED based on observations of synchronous activation during sinus rhythm and EED in activation timing and wavefront propagation during pacing drive and premature extra-stimulation providing compelling evidence for the functional nature of the atrial substrate. Chapter 4 presents data of phase mapping prolonged persistent AF recordings. The results provide novel evidence for endocardial-epicardial wave front mismatch in AF along with marked EED with temporal heterogeneity. In Chapter 6 we sought to characterise the preferential 3-dimensional nature of sinoatrial conduction in humans using simultaneous endocardial-epicardial mapping of the sinus node region. In intact hearts of patients with structural heart disease, data confirmed the presence of multiple differential endocardial and epicardial sino-atrial exits and hence the redundant structure of the pacemaker complex. This is consistent with data from optical mapping of ex-vivo human hearts and demonstrates that clinical sinus node dysfunction only occurs in the setting of advanced atrial structural remodelling. Recently, data from cohort studies and a randomised controlled trial have shown that LAA isolation improves ablation outcomes in patients undergoing redo ablation for persistent AF. However, there have been concerning reports that such empirical ablation is associated with a heightened risk of LAA thrombus, even in patients who are anticoagulated. Furthermore, data from mapping studies have also shown mixed results on the potential role of LAA as a driver in persistent AF. In Chapter 7 we examine the role of localised sources in the left atrium particularly in the LAA by performing regional high-density mapping of persistent AF. In addition to finding infrequent drivers in the left atrium, this project also showed paucity of triggers from the LAA providing further evidence of its passive role rather than an active driver in persistent AF. Besides physical symptoms that patients with AF experience, recent data has shown the enormity of mental health effects that AF can have that is often underappreciated by clinicians. More importantly, preliminary data from observational studies show the benefits of catheter ablation to improve mental health. Chapters 8 and 9 present the methodology and rationale of a multicentre, randomised controlled trial that assesses the impact of catheter ablation on psychological distress and neurocognitive function in patients with AF. The study has completed recruitment and successfully enrolled 100 participants across the Royal Melbourne and Alfred Hospitals and completion of analysis is expected by March 2022. Chapters 10 and 11 conclude by summarizing the key findings of the studies and their clinical implications. Further, it paves the way for future work that might progress our understanding of AF, especially in light of novel mechanisms
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    Novel Personalised Determinants of Atrial Substrate in Atrial Fibrillation
    Wong, Geoffrey Ren Quan ( 2019)
    Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia encountered in clinical practice in developed countries, with a rising incidence reaching epidemic proportions. Beyond adverse impacts on quality of life, AF is associated with significant morbidity, heart failure, stroke and a markedly higher risk of mortality. Current understanding incorporates contributions from focal triggers and remodelled atrial substrate, however the precise interactions between these mechanisms remain incompletely understood. The paradigm of AF management over the last decade has evolved to a more lifestyle directed and holistic approach rather than basic pharmacological rate versus rhythm control measures. However, the AF disease process is multifactorial and the optimal treatment of particularly persistent forms of AF continues to be elusive. This thesis aims to evaluate novel mechanisms and influences on electroanatomic atrial substrate contributing to AF which may form the basis for emerging strategies in personalised AF therapy. Initially, we assess the genetic predisposition to AF by effects on atrial substrate and post AF ablation outcomes. We explore the impact of novel pacing strategies and sex-differences on atrial substrate in patients with AF. Finally, we define the influence of AF on sinus node and crista terminalis characteristics. Chapter 1 delineates the role of genetics in AF, a rapidly progressive area in cardiovascular medicine. We then explore the evolving understanding of pathogenesis of the AF mechanism with an emphasis on the impact and importance of atrial substrate, sex-differences and sinus node remodelling. Chapter 2 investigates the impact of genetic susceptibility in patients with AF to electrical and structural remodelling and outcomes. Chapter 2 is a prospective cohort study of 102 patients undergoing AF ablation who undergo genetic sequencing for a 4q25 single nucleotide variant (SNV) and high-density electroanatomical mapping of their left atria. The genetic aspects were completed under the supervision of Prof Diane Fatkin’s Inherited Heart Diseases Laboratory at the Victor Chang Cardiac Research Institute. We document long-term outcomes 2 years post ablation utilising high intensity monitoring including insertable loop recorders and regular Holter monitors. We compare carriers and non-carriers to determine whether there are differences in electrophysiological and conduction properties between groups. We conclude that the 4q25 variants is associated with adverse atrial remodelling characterised by greater conduction heterogeneity and presence of complex fractionated signals with poorer long-term outcomes. Chapter 3 and 4 examine the impact of pacing strategies on electroanatomic atrial substrate in patients with AF. Chapter 3 describes rate-dependent conduction differences in maps created at different cycle-lengths in 56 patients with a history of AF. It observes globally greater atrial substrate at a faster cycle-length across multiple electrophysiologic parameters including voltage, conduction velocity and complex signals. Chapter 4 then evaluates the impact of direction-dependent conduction in 17 patients with AF when pacing from the pulmonary vein. It concludes a highly regional increase in atrial substrate posteriorly. Together, these data suggest the dynamic nature of atrial substrate maps with marked variation according to changes in pacing rate and direction. Chapter 5 focusses on the comparison of electrophysiologic properties underpinning sex-based differences in AF as despite having a lower incidence of AF compared with men, women carry higher risks of stroke and adverse AF-related outcomes. We perform a cross-sectional electroanatomic mapping study of 93 patients with AF and 45 control patients with SVT. Interestingly, in both patients with and without AF, women have a greater degree of atrial substrate when compared with men. Coupled with these substrate differences, we demonstrate that women had higher single and multi-procedure arrhythmia-recurrence following AF ablation. Chapter 6 presents an ultra high-density mapping study investigating the characteristics of the sinus node and anatomically-determined regions of right atrial substrate in relation to AF. We conduct a mapping study on 25 patients with AF and 25 age-matched controls undergoing SVT ablation. Key findings included more significant sinus node remodelling in patients with AF and persistent forms of AF in particular characterised by progressive caudal shifts in sinus node activation, loss of multicentricity, lower sinus node voltage and greater ‘latent’ substrate at the crista terminalis. Chapter 7 concludes the thesis by summarising the pertinent translational findings and implications for the clinical outlook of each study. Moreover, the future directions of novel mechanisms of AF may help pave the way for personalised AF strategies to better treat AF.
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    A multi-faceted approach to atrial fibrillation: from lifestyle factors to invasive therapies
    Voskoboinik, Aleksandr ( 2019)
    Atrial fibrillation (AF) is a leading epidemic of cardiovascular disease in developed countries, owing to an ageing population and the Western lifestyle. In addition to effects on quality of life and economic burden on the health system, AF is associated with heart failure, stroke and a higher risk of mortality. The focus of AF management over the last decade has shifted from anticoagulation and rate control to a more a more holistic and multi-faceted approach. This encompasses attention to potentially modifiable lifestyle factors and adoption of novel invasive strategies such as catheter ablation to maintain rhythm control. The aim of this thesis is to explore these emerging strategies in AF management, with a focus on rhythm control. Initially, we assess the impact of lifestyle related factors on AF and cardiovascular disease. The emphasis initially is on the effects of habitual alcohol consumption on the atria and ventricles and the impact of abstinence in the AF population. We explore novel strategies for cardioversion of persistent AF, focussing on improving success rates in obese patients. Finally, we explore the evolution of catheter ablation as an increasingly utilized rhythm control strategy. Chapter 1 details our evolving understanding of AF pathogenesis, and the impact of common lifestyle factors on arrhythmogenesis, with a focus on alcohol, caffeine, diet and obesity. We then explore the evidence base for rhythm control strategies, including role of anti-arrhythmics, cardioversion and catheter ablation. Chapter 2 and 3 explore the impact of regular alcohol consumption on the atrium to determine whether there is an association with electrical and structural remodelling. Chapter 2 is a prospective observational study of 75 patients undergoing novel high-density electroanatomical mapping of their left atria at the time of AF ablation. We compare non-drinkers, mild drinkers and moderate drinkers to determine whether there are differences in voltage and conduction properties between the three groups. Chapter 3 is a prospective observational study of 160 AF patients comparing atrial size, mechanical and reservoir function based on degree of alcohol intake utilizing high-definition cardiac magnetic resonance imaging (CMR). We conclude that moderate-to-heavy levels of consumption are associated with adverse atrial remodelling, characterised by reduction in voltage, slowing of atrial conduction, atrial dilatation and impaired mechanical function suggestive of progressive fibrosis. Chapter 4 is a randomized controlled trial of 140 moderate habitual drinkers with a history of AF. We examine the impact of 6 months of abstinence on risk of AF recurrence, AF burden, symptom scores, blood pressure, weight and atrial structure / function. Key findings include reduction in AF recurrence rates, with small but significant reductions in systolic blood pressure and weight. This is the first randomized trial to demonstrate the benefits of abstinence from alcohol in the AF population. Chapter 5 examines the paradox between adverse effects of moderate alcohol consumption on the atrium and AF with widely reported benefits of light-to-moderate habitual alcohol consumption with respect to cardiovascular disease, heart failure and mortality. We undertook a cross-sectional study of 165 stable outpatients comprising of lifelong non-drinkers and regular drinkers. Participants underwent cardiac MRI T1 mapping, a novel imaging sequence that examines markers of ventricular fibrosis. Interestingly, light-to-moderate drinkers displayed lower markers of fibrosis. The clinical implications of this finding require further investigation. Chapter 6 focusses on novel and improved treatment strategies for persistent AF in obese patients. We undertook a randomized controlled trial of 125 obese patients undergoing cardioversion for AF (as well as an observational sub-study of morbidly obese patients). Key findings included higher success rates with the use of hand-held paddles, manual pressure augmentation and higher energies (up to 360 Joules biphasic). Chapter 7 also focuses on improving outcomes for cardioversion in persistent AF, looking at the strategy of early presentation for cardioversion in the emergency department. We report a retrospective cohort study of 150 patients and conclude that compared to (delayed) elective cardioversion, earlier restoration of sinus rhythm prevented adverse atrial remodelling, delaying onset of next AF recurrence and improving quality of life. Chapter 8 examines our evolving understanding of ablation strategies for persistent AF. Recent studies highlight that adjunctive substrate modification beyond pulmonary vein isolation (PVI) may not offer additional benefit and may in fact be pro-arrhythmic. We perform a meta-analysis of 14 studies reporting outcomes from PVI alone in this patient population. We conclude that with current technology, acceptable arrhythmia-free survival can be achieved without additional substrate modification. Chapters 9 and 10 report observational data from our institution with the aim of critically assessing key performance measures for catheter ablation of AF over time. Chapter 9 demonstrates a significant reduction in radiation exposure over time for both operator and patient, and examines the factors responsible. Chapter 10 focuses on procedural safety over time through the prism of increasing patient complexity, greater operator experience and technological advances over time. We conclude that at a high-volume centre, catheter ablation is an acceptable strategy that can be performed safely in a large majority of patients.
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    Radiological, clinical and genetic markers of ischaemic stroke outcome
    Naylor, Jillian Jane ( 2018)
    Acute ischaemic stroke is caused by a blocked blood vessel in the cerebral circulation. It is the most common form of stroke worldwide and a major cause of disability and death. Over the past 20 years, major advances in acute stroke treatment and management have led to a reduction in stroke-related mortality, and thus an unavoidable side effect has been the concomitant rise in survivors living with life-changing disability, requiring ongoing clinical management and care. However, stroke outcome is not entirely represented as mortality rates and level of disability – there are a range of neurological sequelae that contribute an important additional burden to patients. Up to 13% of patients who have suffered an ischaemic stroke will develop seizures within 2 years. For clinicians the development of seizures represents a clinical challenge to manage, is difficult to predict and treat, and associated with poorer patient quality of life. However, at present no indications for antiepileptic drugs in preventing post stroke seizures and epilepsy exist and to date, no blood biomarkers and only few genetic biomarkers have been identified as being associated with an increased risk of post stroke seizure development. This multicentre (China, Brazil and Australia), multidisciplinary thesis examines novel imaging, genetic and clinical markers as methods for identifying patients at higher risk of developing seizures. Reperfusion therapies with thrombolysis and, more recently, endovascular thrombectomy have transformed outcomes for patients. This body of research targeted patient groups treated with modern cerebrovascular stent devices and revascularization techniques, in order to assess the implications of these novel stroke interventions, particularly in terms of the development of post stroke seizures. Multiple advanced neuroimaging techniques were used to determine capacity to identify patients at the highest risk of developing post stroke seizures. Results from these investigations showed that the Alberta Stroke Program Early CT Score on non-contrast CT, cortical involvement on CT perfusion parameters and extent of haemorrhagic transformation on non-contrast CT, can be used as radiological markers for stroke outcome, including the identification of higher risk patients for post stroke seizure development. Additionally, unlike previous work, international sites were included along with Australian sites, allowing the interrogation of whether ethnicity and environment influences the development of post stroke seizures. Results from this investigation revealed that, not only does occurrence of seizures differ across populations from different countries, but certain clinical markers, such as presence and treatment of atrial fibrillation, may influence seizure occurrence across populations. Our exploratory study assessing the genetic influence on the development of post stroke seizures has also laid important groundwork in developing genetic biomarkers for future studies and results from this thesis have identified potential genetic variants warranting further investigation. The results presented in this thesis have the potential to guide identification of individuals at higher risk of developing post stroke seizures and represent a step towards personalised medicine. In the future, if antiepileptogenic drugs become available, these results may inform the selection of an enriched population for trials and guide recruitment for biomarker studies of epileptogenesis.
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    Stroke and atrial fibrillation: better detection, effects on infarct evolution and outcome
    Tu, Hans ( 2018)
    Ischemic stroke is the commonest stroke and a leading cause of disability and death worldwide. Atrial fibrillation (AF) is the most frequent persistent cardiac arrhythmia and a preventable cause of ischemic strokes. The incidence and prevalence of AF have progressively increased over the last few decades and will likely continue to rise, due to the aging population and ongoing growth in other AF risk factors such as obesity, hypertension, diabetes mellitus, heart failure, coronary artery disease and sleep apnea. The social and economic costs associated with the increasing AF burden represent a mounting public health challenge, leading many to consider AF an evolving epidemic in the twenty-first century. Ischemic strokes related to AF usually result from cardioembolism of a large cerebral artery, therefore tend to be larger, more frequently fatal or associated with greater disability than strokes from other causes. However, the pathophysiological mechanisms underlying this association remain unclear. Analysis of serial multimodal magnetic resonance brain imaging in a cohort of acute hemispheric ischemic stroke patients revealed that patients with AF had greater volumes of more severely hypoperfused brain tissue at 3-6 hours following stroke onset, higher infarct growth and larger final infarcts. These findings were best explained by poorer collateral circulation in patients with AF, supporting further investigation of acute stroke therapy that improve cerebral collateral circulation. Analysis of clinical data in a separate large cohort of acute ischemic stroke patients emphasized that serious cardiac adverse events (SCAE) including acute coronary syndrome, symptomatic heart failure, life threatening cardiac arrhythmias, cardiopulmonary arrest and cardiac death were common and occurred early following stroke. SCAEs were significantly more frequent in patients with AF, contributing to the association between AF and higher mortality following stroke, in addition to greater neurological impairment. Given that most SCAEs are potentially remediable, these results highlight the need for more rigorous surveillance of SCAEs following stroke, particularly in patients with AF. CHADS2 and CHA2DS2-VASc scores are validated and clinically useful tools for assessing stroke risk in patients with AF. Both scores have also been associated with a number of short and long term outcomes following stroke, suggesting potential utility in stroke prognosis. However, both scores had very modest precision in estimating the probability of mortality, functional outcome and SCAEs within 3 months following ischemic stroke in a large cohort of acute ischemic stroke patients with and without AF. Pre-stroke CHA2DS2-VASc score did have high negative predictive value for SCAE and high specificity for poor functional outcome, suggesting that it could be used for identifying patients at lower risk of poor outcomes and SCAEs within 3 months following ischemic stroke in patients with and without AF. AF can be persistent or paroxysmal and is frequently asymptomatic, therefore are hard to detect. However, the stroke risk and benefit from validated prevention therapy do not significantly differ between persistent and paroxysmal AF. There is strong evidence that current standard testing paradigm such as 24-hour Holter monitoring following ischemic stroke misses a large proportion of patients with paroxysmal AF. A pilot study in a prospective cohort of 20 cryptogenic stroke patients confirmed previous findings that a significant proportion has paroxysmal AF undetected by 24-hour Holter monitoring. However, longer monitoring with 28-day Holter monitoring was poorly tolerated and still insufficiently sensitive. Further studies are urgently needed to elucidate the optimal timing, method and duration of cardiac rhythm monitoring following ischemic stroke.
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    Atrial fibrillation and systolic heart failure: the role of myocardial fibrosis and catheter ablation
    Prabhu, Sandeep ( 2017)
    Atrial fibrillation and systolic dysfunction are both emerging epidemics in the developed world and both frequently co-exist. Each condition, both individually and in combination, are associated with significantly worsened morbidity and mortality. Both share pathophysiological mechanisms and may promote the progression of each other. Traditional pharmacological therapies for AF have limited efficacy, which is also the case in patients with concurrent systolic dysfunction. Catheter ablation has emerged as an effective treatment for AF with superior outcomes compared to pharmacological rhythm control, the current standard of care. An increasing body of evidence has shown that catheter ablation is feasible and effective in patients with systolic dysfunction. Nonetheless, identifying those patients with systolic impairment likely obtain the greatest benefit from catheter ablation remains a evolving challenge. Additionally, the electrophysiological and structural changes associated with the co-morbid AF and systolic dysfunction is yet to be fully elucidated. The central aim of this thesis is to comprehensively evaluate the role of catheter ablation as a treatment for systolic dysfunction. Following a comprehensive review of the relevant existing literature in this area in Chapter 1, Chapters 2, 3 and 4, of this thesis seek to clinically evaluate the effectiveness of catheter ablation in selected patients with systolic impairment and AF, with a particular focus on utilising advanced imaging techniques such as cardiac magnetic resonance imaging (CMR), as a tool to optimise patent selection, and evaluate treatment outcomes. Secondly in Chapters 5 to 8, this thesis seeks to characterise the electrophysiological and structural characteristics of patients with AF in the setting of systolic impairment and additionally to highlight the limitations and challenges of catheter ablation in persistent AF, with a focus on pulmonary vein electrical activity and the role of intra-procedural adenosine.
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    Mechanisms, predictors and treatment of lethal cardiac arrhythmias and sudden cardiac death
    Wong, Michael Chun-Gee ( 2015)
    Lethal cardiac arrhythmias are fatal heart rhythm disturbances commonly seen in patients with conditions including cardiomyopathy and chronic kidney disease (CKD). Cardiovascular disease (CVD) is the leading cause of death in Australia consistently accounting for over 30% of all reported deaths. SCD remains a high priority public health problem leading to significant mortality and health care expenditure. Tachyarrhythmic SCD attributable to potentially reversible VT or VF remains a major cause of SCD in the general population. However, the emerging importance of non-VF SCD is beginning to become apparent with a proportional increase in cases presenting with non-VF rhythms (pulseless electrical activity [PEA] and asystole). Accurate risk stratification in patients at high risk of SCD is of critical importance to facilitate clinical decision-making and provide direction when prescribing costly preventative therapies and reduce mortality. Pre-emptive identification of those at high SCD risk remains an ongoing challenge to the clinician due to several reasons: 1) approximately half of all deaths attributable to heart disease are diagnosed as SCD; 2) approximately 50% of all SCDs are the first recognized cardiac event and 3) only a minority of those who suffer out of hospital cardiac arrest will survive. Apart from left ventricular ejection fraction, there remains a paucity of cardiac risk markers that can help identify those at highest risk of SCD. Furthermore, improving the understanding of PEA mechanisms and development of new approaches for its prevention and management are warranted. Current traditional risk factors for sudden cardiac death (SCD) in the general population do not accurately predict outcomes in CKD patients. The risk of arrhythmic death is very high and remains poorly understood. This thesis examines the use of a combination of novel invasive/non-invasive risk assessment techniques to investigate the alarmingly high SCD risk faced by the CKD population. Using these techniques, we comprehensively demonstrated that: 1) CKD patients experience a significant burden of serious arrhythmias contributing to SCD; 2) lethal bradycardia is the terminal rhythm, in contrast to the prevailing traditional paradigm that ventricular arrhythmias were the main cause of sudden death in CKD; and 3) a significant proportion of arrhythmias occur during the longer break in-between dialysis sessions. Ventricular tachycardia (VT) and ventricular fibrillation (VF) are the most prevalent heart rhythm disturbances seen in patients with cardiomyopathy. Studies have identified differences in arrhythmia substrate between patients with ischemic or nonischemic cardiomyopathy (i.e. ICM or NICM) who do or do not have VT. However, patients with VF are less clear. Ventricular scarring alters electrical conduction properties and has been attributed to the development of VT/VF in these patients. Further work emanating from this thesis evaluates new percutaneous cardiac catheter ablation technology to treat these malignant tachyarrhythmias which has very important clinical implications to manage high-risk patients and intervene early to reduce the risk of SCD. Collectively, this thesis systematically evaluates and reports on the mechanisms, predictors and newer treatment techniques for malignant and lethal arrhythmias in humans incorporating the vast body of basic research from animal experimental studies, clinical information from human clinical trials and novel findings from our work which question and challenge prevailing paradigms published over the last four decades. The work presented characterizes the burden and entire spectrum of cardiac arrhythmias contributing to the excessive cardiovascular burden (including sudden cardiac death) in chronic kidney disease patients as well as examining the utility of new and novel cardiac ablation catheter therapy using contact force sensing technology in an open beating heart animal model.
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    Mechanisms and consequences of atrial fibrillation: insights into the electrical mechanisms sustaining atrial fibrillation, the drivers of underlying atrial remodeling, and the factors governing symptom severity and quality of life
    Walters, Tomos Evan Rhys ( 2015)
    Atrial fibrillation (AF) exists on a clinical spectrum from paroxysmal to persistent and eventually permanent AF. Progression through this spectrum is well described, but is not universal. Mechanistically, paroxysmal AF is driven by fast electrical triggers most commonly located in the myocardial sleeves of the pulmonary veins, whilst persistent AF is dependent on perpetuating electrical mechanisms rooted in an abnormal atrial substrate. The nature of these mechanisms remains a subject of debate, with recent evidence pointing towards rotors, a form of functional reentry, providing a driving source for human persistent AF. Various studies have ascribed quite different properties to these rotors. More severe abnormalities in the electroanatomic properties of the left atrium (LA) have been demonstrated in persistent than in paroxysmal AF, and improvement in such properties has been described after catheter ablation of AF, but there is little data describing the rate of deterioration in LA properties with ongoing AF, or the key drivers of change. Finally, it is recognized that AF is frequently associated with significant quality of life impairment, but there is a wide spectrum of clinical severity and the factors governing this variation are incompletely understood. Chapters 2 and 3 of this thesis examine the atrial substrate. The extent of remodeling of the LA is a key determinant of the success of catheter ablation, and so non-invasive techniques with which to assess remodeling are keenly sought. In chapter 2, the association between the extent of LA electroanatomic remodeling and the fibrillatory cycle length derived from lead V1 of the surface electrocardiogram during AF is characterized. It is demonstrated that a longer AF cycle length in lead V1 is associated with more advanced LA remodeling, specifically slower atrial conduction and more extensive electrogram fractionation. Given that gender-based differences in clinical behaviour of multiple cardiac arrhythmias are well described, the presence of systematic gender-based differences in the pulmonary vein and atrial substrate is examined in chapter 3. No such between-gender differences were observed, either in those with or without a history of AF, and with a similar prevalence of AF-related comorbidities seen in both male and female groups. Chapters 4, 5 and 6 move to an exploration of the electrical mechanisms underlying AF, through detailed epicardial mapping studies of the LA and its junction with the pulmonary vein (PV-LA junction). Chronic stretch is fundamental to atrial remodeling in human AF, and conditions associated with acute stretch are recognized triggers for episodes of AF. In chapter 4 the response of the PV-LA junction to acute stretch was characterized, with the observation that acute stretch results in conduction slowing across the PV-LA junction and a greater degree of signal complexity, providing conditions suitable for reentry. Chapters 5 and 6 involved epicardial mapping in patients with longstanding persistent AF, with the aim of determining the spatiotemporal stability of the AF cycle length and of atrial activation patterns, including the stability of any demonstrated rotors, over a 10 minute period. This is a time period much in excess of that over which detailed mapping has previously ben performed. It was observed that atrial activation patterns are spatiotemporally stable over this time scale, with clear anatomic determinism, and that in the great majority of patients transient rotors can be demonstrated. These appear to last only a median of 3 cycles, usually develop due to perpendicular wavefront-wavetail interaction, and are commonly anchored on a region of short cycle electrical activity. Such activity, however, is highly non-specific for rotor localization, more often being the result of passive wavefront collision. The frequency of atrial activation appears much more variable over 10 minutes, but there was clear inter-dependence between left and right atrial cycle lengths during mapping of anatomically disparate regions, and within each region the relative distribution of locations with faster and slower activation frequencies was highly conserved. These observations, indicating significant underlying spatiotemporal organization, are consistent with the presence of focal drivers such as rotors governing global atrial activation. Chapter 7 returns to the issue of atrial remodeling, with the aim of defining the magnitude and the predictors of change in the extent of LA electroanatomic remodeling over 12 months of high burden AF. Using measures of atrial myocardial deformation characteristics derived from strain imaging to of the atrial wall and P-wave characteristics as non-invasive biomarkers of remodeling, ongoing high burden AF was found to be associated with measurable progression in the extent of LA remodeling even over a 12 month period, whilst after AF ablation in a similar cohort results there was significant reversal of existing remodeling. These data may have implications for timing of ablative intervention. Finally, chapter 8 addresses the key determinants of AF symptom severity and quality of life. It is demonstrated that a high proportion of patients with AF experience significant psychological distress and even thoughts of self-harm. Clinical variables including age, body mass index and the burden of AF influence the perceived severity of the AF syndrome, with key differences between patients with intermittent and continuous forms of AF. The influence of organic cardiac variables, however, is subsumed by the dominant influence of personality style, with a predisposition to perceive life events as stressful and a chronic tendency to anxiety and negativity particularly powerful. Effective rhythm control through AF ablation was found to lead to marked improvements in AF symptom severity, quality of life and levels of psychological distress, suggesting that psychological distress is a consequence of the arrhythmia itself interacting with a vulnerable personality style.
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    Atrial fibrillation and heart failure: the impact of atrial fibrillation on cardiac remodeling
    LING, LIANG-HAN ( 2013)
    Atrial fibrillation (AF) and heart failure (HF) are common cardiovascular conditions that individually are associated with significant morbidity and mortality. Each has a tendency to promote the other, with grave outcomes resulting when they occur in combination. Despite the prevalence of concurrent AF-HF, pathophysiologic interactions between the two conditions remain to be well understood due in part to their complex and dynamic nature. Utilizing a wide range of complementary laboratory methods in the experimental setting, as well as start-of-the-art imaging and electrophysiologic techniques in a series of clinic studies, this thesis explores the relationship between AF and HF, focusing in particular on the influence of AF on left ventricular remodeling. Two highly novel findings include the following: (i) the irregular ventricular rhythm associated with AF has an adverse impact on ventricular calcium handling and contractile function independent of rate-related effects, and (ii) diffuse ventricular fibrosis resulting from tachycardia-mediated cardiomyopathy persists long after resolution of tachycardia and appears to correlate with AF burden, suggesting that fibrosis may be cumulative with successive periods of poor rate control. These results imply that a strategy of rate-control alone in the management of combined AF-HF is insufficient to protect the left ventricle from the adverse influence of AF, and add weight to the argument for early rhythm control. Further major findings relating to clinical management of combined AF-HF include the following: (i) the pattern of ventricular fibrosis as assessed by cardiac magnetic resonance (CMR) imaging is useful in selecting patients most likely to recovery LV function following catheter-based therapy for AF, and (ii) post-contrast CMR T1 mapping identifies changes in atrial myocardial tissue that parallel electrophysiologic remodeling and are suggestive of atrial fibrosis. Thus, CMR imaging may have a key role in individualizing therapy for patients with combined AF-HF, and place its routine use in clinical practice on the horizon.
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    Insights into mechanisms and effects of omega-3 polyunsaturated fatty acid supplementation in human atrial fibrillation
    KUMAR, SAURABH ( 2012)
    Atrial fibrillation (AF) is the most common cardiac arrhythmia in humans, causing significant morbidity, mortality and health care expenditure. Anti-arrhythmic drugs are the cornerstone of AF management but are limited in their efficacy, side effects and potential for pro-arrhythmia. A concordance of in vivo and in vitro animal experimental studies have demonstrated that omega-3 polyunsaturated fatty acids (ω-3 PUFAs) in fish oils may have anti-arrhythmic and anti-fibrillatory effects. However, definitive demonstration of the efficacy of fish oils in human AF has remained elusive. This thesis systematically evaluates the mechanisms and effects of ω-3 PUFAs in human AF incorporating the vast body of pre-clinical information from animal experimental paradigms, information on ω-3 PUFA dosing, duration of supplementation, kinetics of membrane incorporation and the importance of form of administration. The thesis characterises the effects of ω-3 PUFAs on human atrial electrical and mechanical function and examines the efficacy of ω-3 PUFAs on clinical AF endpoints. Chapter 1 describes the current state of knowledge about AF mechanisms in the absence and presence of structural heart disease, mechanisms of action and efficacy of contemporary anti-arrhythmic and anti-remodeling drugs and the pre-clinical and clinical evidence for ω-3 PUFAs in cardiac arrhythmias. Chapter 2 assesses the use of AF inducibility as a metric for future experimental chapters and its appropriateness for use as a clinical endpoint after electrical isolation of the pulmonary veins for AF. This study demonstrates that in the absence of structural heart disease or clinical AF, inducible and sustained AF occurs at a similar frequency to that noted in patients with a history of AF. It highlights the criticality of the induction protocol, inducibility definitions and number of inductions on rates of AF inducibility and persistence. Chapter 3 and 4 are the first randomised human studies of their kind to examine the effects of long-term ω-3 PUFA supplementation (>30 days) on human atrial electrophysiology in the absence of confounders such as structural heart disease or a history of clinical AF or flutter (Chapter 3) and on pulmonary vein and left atrial electrophysiology in the presence of paroxysmal AF (Chapter 4). Both studies showed that long-term supplementation results in chronic incorporation of ω-3 PUFA in plasma phospholipids. This results in significant prolongation of right, left atrial and pulmonary venous refractoriness. Long-term oral ω-3 PUFAs had no effect on atrial or pulmonary venous conduction. Most importantly, both studies showed a significant reduction in vulnerability toward and persistence of AF, an effect attributed to refractory period prolongation. Together, these studies provide mechanistic insights into the anti-fibrillatory effects of long-term oral ω-3 PUFA exposure. Chapter 5 examines the effects of long-term ω-3 PUFA supplementation on human atrial mechanical function after reversion of persistent atrial arrhythmias to sinus rhythm. Reversion of persistent atrial arrhythmias to sinus rhythm is associated with transient depression of left atrial mechanical function, a phenomenon known as atrial mechanical stunning. Stunning is implicated in the heightened risk of thromboembolic complications such as stroke, failure of improvement in cardiac output and exercise tolerance, and increased risk of recurrence atrial arrhythmias. The main finding was that patients randomised to fish oils, compared to controls, had markedly reduced incidence of atrial mechanical stunning. This study provides insights into how fish oils can attenuate adverse atrial remodeling in response to persistent atrial arrhythmias. Chapter 6 is a randomised clinical trial examining the efficacy of long-term fish oils in the prevention of persistent AF recurrence post electrical cardioversion in a high risk population. Patients were randomised to control or fish oil groups; the latter was commenced >1 month prior to cardioversion and continued till return of AF or maximum of 1 year. The main finding was that fish oil patients had higher rates of pharmacological reversion, and a significantly lower risk of persistent AF recurrence compared to controls at 1 year. These effects were seen in the presence or absence of concurrent anti-arrhythmic drugs. This study shows the critically of long-duration, high dose supplementation to allow sufficient time for maximal myocardial incorporation and for the all expected electrophysiologic, anti-remodeling and anti-inflammatory mechanisms of ω-3 PUFA to take effect before assessment of clinical endpoints, an approach rarely used in previous clinical studies. Chapter 7 is a prospective randomised study examining if long-term ω-3 PUFA supplementation (6 or 12 months) reduces burden of paroxysmal atrial tachycardia/fibrillation (AT/AF) in a high risk population of elderly patients with sinus node dysfunction, implanted dual chamber pacemakers and a history of the same arrhythmias. The main findings were that whilst fish oils did not suppress AT/AF burden per se, they significantly attenuated temporal progression of AT/AF burden over time that was seen in controls over 18 months of follow up. There was no demonstrable effect on arrhythmia triggers, but significantly shorter episodes of AF were seen suggesting that the predominant effect of fish oils are on atrial substrate. This study demonstrates that long-term ω-3 PUFA supplementation reduces paroxysmal atrial arrhythmia burden likely mediated by effects on atrial structural remodeling. Chapter 8 is the first human study of its kind examining the effects of acute, intravenously delivered, high dose ω-3 PUFAs on human atrial electrophysiology. The main findings were that when given intravenously, fish oils are predominantly present as free ω-3 PUFAs, with little or no membrane incorporation. Free ω-3 PUFAs predominantly caused atrial conduction slowing with minimal effects on atrial refractoriness which was in contrast to the previous observations that incorporated ω-3 PUFAs had no effect on atrial conduction, but prolonged atrial refractoriness. Moreover, free ω-3 PUFA reduced AF inducibility and persistence, organised inducible AF into atrial flutter and significantly increased the inducibility of atrial flutter in patients with no clinical history of this arrhythmia. This study provides novel insights into the complex effects of incorporated versus free ω-3 PUFAs on atrial electrophysiology and provides evidence for a future clinical study examining the efficacy of high dose IV fish oil on acute AF termination.