Autonomic Function in Atrial Fibrillation

Abstract

At the population level, the prevalence of Atrial fibrillation (AF) is escalating. AF burden also increases in individuals, due its self-perpetuating, progressive nature. While AF itself has been implicated in its self-maintenance, mechanisms responsible are not fully determined. The efferent arm of the Autonomic nervous system (ANS) alters atrial electrophysiology, triggering AF. At the population-level, imbalances of autonomic tone are prospectively associated with AF. Whilst it is well known that cardiovascular risk factors promote AF, how they interact is uncertain, though there is a potential role of the ANS. AF itself, causes autonomic dysfunction, altering atrial innervation and heightening efferent sympathetic activity. Thus, a bidirectional relationship is likely between AF and the ANS. Whilst considerable effort was placed on the efferent arm of the ANS, the role of the afferent, regulatory arm in AF pathophysiology is unknown. Especially cardiovascular reflexes regulating blood pressure and volume. Interestingly, blood-volume regulating (low-pressure) baroreceptors are co-located in pulmonary vein-atrial tissue, which contain drivers for AF. This thesis undertakes a series of studies that delineate the role of the afferent arm of the ANS in AF. Using a systematic review and meta-analysis, we demonstrate that AF is independently associated with falls and syncope in older adults. AF can cause orthostatic intolerance (a clinical manifestation of autonomic dysfunction). Next, we examined low-pressure baroreceptor function in paroxysmal or persistent AF patients, studied in sinus rhythm (SR), identifying novel blood volume regulating reflex abnormalities using Low-level Lower Body Negative Pressure (LBNP). Then, we performed a series of autonomic reflex tests to delineate the function of lowpressure volume regulating (LBNP), high-pressure blood pressure regulating baroreceptors (Valsalva) and both (Isometric handgrip reflex, IHR). Testing cardiovascular reflexes in the presence of AF is challenging, however, we utilised continuous beat-beat haemodynamic monitoring and venous occlusion plethysmography to evaluate these in patients with AF studied in-AF, and in SR. We demonstrated dysfunction of the volume-regulating LBNP reflex in-AF, for the first time and confirmed diminished LBNP reflexes in-SR. IHR was diminished in-AF, however blood pressure baroreflexes were preserved. In subsequent studies, we proceeded to show that cardioversion improved LBNP reflex abnormality, as did LLTS (low-level vagal nerve stimulation) a novel neuromodulating technique (LLTS), aiding localisation to the afferent level. Further, we tested whether catheter ablation of AF might further destroy such afferent receptors in pulmonary veins, not having found evidence for this. Given loss of homeostasis (blood-volume dysregulation) in-AF, we propose an intersect between autonomic and anatomic remodelling (atrial dilatation), possibly representing a mechanism behind AF progression. In the last study, we tested the interplay between anatomic and autonomic remodelling in Postural tachycardia syndrome (POTS), a known dysautonomia, where the heart is thought normal. We present new evidence of cardiac remodelling, utilising electrocardiogram markers (also associated with AF). AF has several sequelae; falls, syncope, dementia, and heart failure, notwithstanding, its own progression, all of which, increase morbidity and all-cause mortality. We open a new scientific avenue to explore mechanisms for these and highlight the role of rhythm management and neuromodulation to treat AF.