Pathophysiology of atrial fibrillation: From initiation to maintenance

Atrial fibrillation (AF) is the most common arrhythmia in adults; it affects approximately 0.8 million patients in Japan alone. Yet despite many years of basic and clinical research, the exact mechanisms underlying the initiation and maintenance of AF remain poorly understood. In this review article, we summarize recent high-resolution optical mapping studies in isolated sheep hearts, which have provided new insights into the dynamics and mechanisms of AF. We focus on 3 models of AF. First, we discuss results from experiments on AF induced by atrial stretch that revealed the presence of spatio-temporally organized waves emerging from the posterior wall of the left atrium. In the presence of adreno-cholinergic stimulation and stretch, AF was governed by evolving interactions between reentry and spontaneous focal discharges. Next, we outline the results obtained from a persistent AF model (average AF duration: 21.3 day) induced by intermittent rapid atrial pacing. By using simultaneous optical mapping of epicardial and endocardial activation patterns, we demonstrated that AF in this model was maintained by 3-dimensional scroll waves with I-shaped filaments anchored to junctions between thin and thick myocardium. Numerical simulation results predicted that wall thickness-dependent activation of stretch-activated channels and the filament tension dynamics were sufficient to explain the specific localization of the I-shaped filament. In a final set of studies discussed herein, we investigated AF in sheep with tachypacing-induced heart failure and found that micro-reentry in the left atria was a major mechanism of AF maintenance, although focal discharges at the pulmonary vein area also played a role. Large fibrotic patches in failing hearts may serve as potential anchoring sites for micro-reentry in this model. Thus, the 3 different experimental results in isolated sheep hearts presented here clearly suggest that self-sustained rotors do exist in the atria and that such rotors are in fact the high frequency sources that determine the complex patterns of activation that characterize AF.