Atrial fibrillation (AF) is the most frequent arrhythmia, and its initiation and persistence are associated with the progression of atrial structural remodeling. We evaluated the reduction of atrial voltage, a marker of atrial structural remodeling, during catheter ablation for AF, revealing that atrial structural remodeling is not a localized process but a diffuse process. Histological evaluation of atrial structural remodeling has been limited so far due to the difficulty in obtaining atrial tissue, however, we have developed an intracardiac echo-guided catheter atrial biopsy and confirmed that the extent of histological fibrosis in the atria is inversely correlated with the bipolar voltage both at the biopsy site and in the whole left atrium. Although fibrosis has been considered the primary histological factor associated with structural remodeling, we have demonstrated that histological correlates associated with atrial structural remodeling include not only fibrosis progression but also increased intercellular space, myofibrillar loss, decreased myocardial nuclear density,a surrogate marker for cardiomyocyte number, and amyloid deposition. Among the histological factors associated with structural remodeling, we showed that fibrosis progression and increased intercellular space were associated with persistence and recurrence of AF, suggesting that interstitial remodeling is the histological substrate for AF persistency. Electron microscopic evaluation of the atrial ultrastructure showed leakage of plasma components due to increased vascular permeability in the increased intercellular space. We also observed the presence of immature collagen in the increased intercellular spaces, suggesting that the increase of intercellular space is a histological change preceding fibrosis. In addition, the space with decreased myofibrils was replaced by proliferated mitochondria. Further studies will elucidate the mechanism of atrial remodeling and explore therapeutic targets for AF and atrial cardiomyopathy.