Introduction Atrial fibrillation AF is the
Atrial fibrillation (AF) is the most common arrhythmia in adults and the most common cause of embolic stroke. AF affects approximately 0.8 million patients in Japan alone, and its incidence is expected to grow exponentially [1–3]. However, the electrophysiological mechanisms of the initiation and maintenance of AF remain poorly understood. Pathophysiological changes in atrial structure and function occur as AF progressively advances from an acute to a chronic stage. These alterations include electrophysiological remodeling and fibrosis, [4–6] which give rise to the diverse mechanism of AF pathogenesis. In 1998, Haïssaguerre et al. [7,8] reported for the first time that paroxysmal AF is triggered by focal discharges localized at the pulmonary vein (PV) and that catheter-based procedures that ablate focal triggers effectively terminate up to 90% of cases of paroxysmal AF. Subsequently, many research investigations confirmed Haïssaguerre\'s results. As a consequence, PV isolation is widely accepted as a standard therapy for patients with paroxysmal AF, particularly for those without underlying structural withaferin a disease. However, the success rate of PV isolation in patients with persistent AF is limited, and multiple procedures and the continuation of anti-arrhythmic drug therapy are often required for patients with chronic AF. Furthermore, limitations related to the long duration of the ablation procedure and the occurrence of important side effects renders this approach altogether impractical for the vast majority of AF patients. In addition, one of the major limitations of the currently available ablation techniques is the difficulty of visualizing electrical activity with sufficient spatial resolution to accurately determine the location of potential AF sources. In animal experiments, however, the exploration of the mechanisms linking myocardial stretch, remodeling, and fibrosis to AF [9,10] has benefited from advances in high-resolution electrical and/or optical mapping. In this review article, we summarize recent studies in sheep hearts and discuss the dynamics of wave propagation during AF and its mechanistic link to ionic and structural properties of the atria.
AF mechanisms: multiple wavelets and mother rotors Despite many years of research, the precise mechanisms underlying AF initiation and maintenance are far from being understood. In the early 1900s, the two most prevalent explanations for such mechanisms were the “circus movement reentry” and the “ectopic focus” hypotheses . Subsequently, in 1962, Moe et al. [12,13] postulated the “multiple wavelet hypothesis” for AF maintenance, in which disorganized activity of AF may be the consequence of random propagation of multiple independent wavelets (more than 20 wavelets) in a heterogeneous medium of dispersed refractoriness. Later, Allessie et al.  provided experimental support for Moe\'s hypothesis in a dog model of AF induced in the presence of acetylcholine. In that study, several apparently independent wavelets propagated simultaneously throughout both atria. However, unlike Moe\'s prediction that AF required a minimum number of 26 wavelets to be maintained, Allessie provided a critical number of 4 to 6 wavelets. To our knowledge, this discrepancy has never been resolved. Nevertheless, support for the multiple wavelet hypothesis came also in the form of the so-called surgical maze procedure, in which the highly compartmentalized atria were unable to sustain multiple, randomly propagating wavelets . Thus, the multiple wavelet theory has been widely accepted by most clinical electrophysiologists. In a landmark article published by Haïssaguerre et al. in 1998,  credence was given to rapid spontaneous focal activity in the PV area as the main mechanism of paroxysmal AF initiation and/or maintenance. Since then, PV isolation by radiofrequency ablation has become the gold standard for the treatment of paroxysmal AF. This, however, is no longer true for persistent AF. Electrical isolation of PV foci is frequently insufficient and additional linear ablation and/or ablation targeting complex fractionated atrial electrograms (CFAEs), which frequently result in the destruction of vast portions of the left atrium, are required . Therefore, the simplistic explanation of such differing outcomes is that focal activity plays a predominant role in paroxysmal AF, whereas persistent AF is maintained by multiple wavelets.