Heart failure, female sex and atrial fibrillation are the main drivers of human atrial cardiomyopathy: results from the CATCH ME consortium

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. However, the contribution of various 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 sampled 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 a multivariate model. K-means clustering of 6 histological features was performed to identify different types of atCM. Results In both LA and RA, persistent AF was associated with increased endomysial fibrosis (LA:+1.07±0.41µm,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±0.41µm,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±0.23µm,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:+3.35µm,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:+1.20µm,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.