Background: Atrial cardiomyopathy (AtCM) is emerging as an independent prognostic factor in cardiovascular disease. Fibrotic remodeling, cardiomyocyte hypertrophy, and capillary density are histological hallmarks of atCM. The contribution of etiological factors and atrial fibrillation (AF) to the development of differential atCM phenotypes has not been robustly quantified. We aimed to evaluate the association between histological features of atCM and the clinical phenotype. Methods: We examined left (LA,n=95) and right (RA,n=76) atrial appendages from a European cohort of patients undergoing cardiac surgery. Quantification of histological atCM features was performed using the JavaCyte algorithm, following staining with agglutinin (WGA), CD31 and vimentin. The contributions of AF, heart failure (HF), sex and age to histological characteristics were determined in multivariate models. K-means clustering of histological features was performed to identify different types of atCM. Results: In both atria, persistent AF was associated with increased endomysial fibrosis (LA:+1.07±0.41μ m,p=0.01; RA:+0.89±0.43μm,p=0.032), whereas total extracellular matrix (ECM) content was unchanged in AF. Men had larger cardiomyocytes (LA:+1.87±0.72μm,p=0.012), while women had a higher degree of endomysial fibrosis (LA:+0.99±0.51μm,p=0.048). Heart failure patients showed more endomysial fibrosis (LA:+1.79±0.41μ m,p<0.001) and ECM content (LA:+2.93±1.15%, p=0.014), and a higher capillary density (LA:+0.14±0.06,p=0.032) and size (LA:+0.48±0.23μ m,p=0.041; RA:+0.31±0.16μm,p=0.047). Clustering of samples based on structural features identified 2 distinct atCM phenotypes; one characterized by enhanced endomysial fibrosis (LA:+3.35μ m,p<0.001; RA:+1.88μm,p<0.001), ECM content (LA:+5.68%,p<0.001; RA:+7.78%,p<0.001), and a higher fibroblast density (LA:+4.79%,p<0,001) and one characterized by cardiomyocyte hypertrophy (LA:+1.20μ m,p=0.009; RA:+2.95μm ,p<0.001). Patients with fibrotic atCM were more often female (LA:OR=1.31,p=0.003; RA:OR=1.55,p=0.003), had more often persistent AF (LA:OR=1.23,p=0.031) or heart failure (LA:OR=1.62,p<0.001) whereas hypertrophic features were more common in men (LA:OR=1.31,p=0.031; RA:OR= 1.55,p=0.003). Conclusions: AtCM phenotypes vary with patient characteristics. Fibrotic atCM is associated with female sex, persistent AF and heart failure, while hypertrophic features are more common in men.

This study has been supported by grants of the Netherlands Heart Foundation (CVON2014-09, RACE V Reappraisal of Atrial Fibrillation: Interaction between hyperCoagulability, Electrical remodeling, and Vascular Destabilisation in the Progression of AF) and the European Union (ITN Network Personalize AF: Personalized Therapies for Atrial Fibrillation: a translational network, grant number 860974; CATCH ME: Characterizing Atrial fibrillation by Translating its Causes into Health Modifiers in the Elderly, grant agreement number 633196; MAESTRIA: Machine Learning Artificial Intelligence Early Detection Stroke Atrial Fibrillation, grant agreement number 965286; AFFECT-EU, grant agreement number 847770, REPAIR: Restoring cardiac mechanical function by polymeric artificial muscular tissue, grant number 952166), the British Heart Foundation, CH/12/3/29609. The Institute of Cardiovascular Research, University of Birmingham, has received an Accelerator Award by the British Heart Foundation AA/18/2/34218.

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