Atrial structural remodeling and atrial fibrillation substrate: A histopathological perspective

Atrial fibrillation (AF) substrate progresses with the advancement of atrial structural remodeling, resulting in AF perpetuation and recurrence. Although fibrosis is considered a hallmark of atrial structural remodeling, the histological background has not been fully elucidated because obtaining atrial specimens is difficult, especially in patients not undergoing open-heart surgery. Bipolar voltage reduction evaluated using electroanatomic mapping during AF ablation is considered a surrogate marker for the progression of structural remodeling; however, histological validation is lacking. We developed an intracardiac echocardiography-guided endomyocardial atrial biopsy technique to evaluate atrial structural remodeling in patients undergoing catheter ablation for nonvalvular AF. The histological factors associated with a decrease in bipolar voltage were interstitial fibrosis, as well as an increase in myocardial intercellular space preceding fibrosis, myofibrillar loss, and a decrease in cardiomyocyte nuclear density, which is a surrogate marker for cardiomyocyte density. Cardiomyocyte hypertrophy is closely associated with a decrease in cardiomyocyte nuclear density, suggesting that hypertrophic changes compensate for cardiomyocyte loss. Electron microscopy also revealed that increased intercellular spaces indicated the leakage of plasma components owing to increased vascular permeability. Additionally, amyloid deposition was observed in 4 % of biopsy cases. Only increased intercellular space and interstitial fibrosis were significantly higher for long-standing persistent AF than for paroxysmal AF and associated with recurrence after AF ablation, suggesting that this interstitial remodeling is the AF substrate. An increase in intercellular space that occurs early in AF formation is a therapeutic target for the AF substrate, which prevents irreversible interstitial degeneration due to collagen accumulation. This endomyocardial atrial biopsy technique will allow the collection of atrial tissue from a wide variety of patients and significantly facilitate the elucidation of the mechanisms of atrial cardiomyopathy, structural remodeling, and AF substrates.