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

© 2015 Dr. Tomos Evan Rhys WaltersAtrial 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