Histological Determinants of Atrial Dysfunction in Patients With Atrial Fibrillation

Background Atrial fibrillation (AF) is associated with diverse histological abnormalities, but their contributions to atrial dysfunction and functional recovery remain unclear. Methods In a discovery cohort of 375 patients with nonvalvular AF undergoing catheter ablation, atrial biopsy samples were quantitatively analyzed for fibrosis, intercellular space expansion, myofibrillar loss, myocardial nuclear density, and amyloid deposition. Left atrial reservoir strain (LASr) was assessed as a measure of atrial function during sinus rhythm (Group 1) or AF (Group 2) at the time of echocardiography. Functional recovery was defined as the change in LASr 12 months after ablation. Findings were validated in an independent cohort of 191 patients with AF. A subset of samples was additionally analyzed for DNA damage markers, poly(ADP‐ribose), and phosphorylated histone H2A.X. Results LASr improved significantly after ablation in Group 2 but not in Group 1. Multivariable analyses identified greater fibrosis, reduced myocardial nuclear density, and advanced amyloid deposition as significant determinants of impaired atrial function in both groups and of limited postablation functional recovery in Group 2 (all P <0.01). Amyloid deposition was also significantly associated with adverse clinical outcomes. Decision‐tree models incorporating LASr accurately identified advanced amyloid deposition in both cohorts (accuracy, 94%–96%). DNA damage markers were inversely associated with myocardial nuclear density and positively associated with cardiomyocyte hypertrophy. Conclusions Fibrosis, DNA damage–associated reduction in myocardial nuclear density, and advanced atrial amyloidosis are key determinants of atrial dysfunction and impaired postablation functional recovery in patients with AF. LASr enables noninvasive identification of advanced atrial amyloidosis.