TY - JOUR
T1 - Heart Failure, Female Sex, and Atrial Fibrillation Are the Main Drivers of Human Atrial Cardiomyopathy
T2 - Results From the CATCH ME Consortium
AU - Winters, Joris
AU - Isaacs, Aaron
AU - Zeemering, Stef
AU - Kawczynski, Michal
AU - Maesen, Bart
AU - Maessen, Jos
AU - Bidar, Elham
AU - Boukens, Bas
AU - Hermans, Ben
AU - van Hunnik, Arne
AU - Casadei, Barbara
AU - Fabritz, Larissa
AU - Chua, Winnie
AU - Sommerfeld, Laura
AU - Guasch, Eduard
AU - Mont, Luis
AU - Batlle, Montserrat
AU - Hatem, Stephane
AU - Kirchhof, Paulus
AU - Wakili, Reza
AU - Sinner, Mortiz
AU - Stoll, Monica
AU - Goette, Andreas
AU - Verheule, Sander
AU - Schotten, Ulrich
N1 - Funding Information: Solutions Inc. (Switzerland), and Johnson & Johnson Medical Limited (United Kingdom). Dr Schotten is cofounder and shareholder of YourRhythmics BV, a spin-off company of the University Maastricht. Dr Fabritz has received institutional research grants and nonfinancial support from the European Union, DFG, British Heart Foundation, Medical Research Council (UK), NIHR, and several biomedical companies. Drs Fabritz and Kirchhof are listed as inventors of 2 patents held by the University of Birmingham (Atrial Fibrillation Therapy, WO 2015140571; Markers for Atrial Fibrillation, WO 2016012783). The remaining authors have no disclosures to report. Funding Information: This study was supported by grants of the Netherlands Heart Foundation (CVON2014-09, RACE V Reappraisal of Atrial Fibrillation: Interaction between hyperCoagulability, Electrical remodeling, and Vascular Destabilization 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), and 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. Publisher Copyright: © 2023 The Authors.
PY - 2023/11/21
Y1 - 2023/11/21
N2 - BACKGROUND: Atrial cardiomyopathy (atCM) is an emerging prognostic factor in cardiovascular disease. Fibrotic remodeling, cardiomyocyte hypertrophy, and capillary density are hallmarks of atCM. The contribution of etiological factors and atrial fibrillation (AF) to the development of differential atCM phenotypes has not been quantified. This study aimed to evaluate the association between histological features of atCM and the clinical phenotype. METHODS AND RESULTS: We examined left atrial (LA, n=95) and right atrial (RA, n=76) appendages from a European cohort of patients undergoing cardiac surgery. Quantification of histological atCM features was performed following wheat germ agglutinin/CD31/vimentin staining. The contributions of AF, heart failure, sex, and age to histological characteristics were determined with multiple linear regression models. Persistent AF was associated with increased endomysial fibrosis (LA: +1.13±0.47 μm, P=0.038; RA: +0.94±0.38 μm, P=0.041), whereas total extracellular matrix content was not. Men had larger cardiomyocytes (LA: +1.92±0.72 μm, P<0.001), while women had more endomysial fibrosis (LA: +0.99±0.56 μm, P=0.003). Patients with heart failure showed more endomysial fibrosis (LA: +1.85±0.48 μm, P<0.001) and extracellular matrix content (LA: +3.07±1.29%, P=0.016), and a higher capillary density (LA: +0.13±0.06, P=0.007) and size (LA: +0.46±0.22 μm, P=0.044). Fuzzy k-means clustering of histological features identified 2 subtypes of atCM: 1 characterized by enhanced endomysial fibro-sis (LA: +3.17 μm, P<0.001; RA: +2.86 μm, P<0.001), extracellular matrix content (LA: +3.53%, P<0.001; RA: +6.40%, P<0.001) and fibroblast density (LA: +4.38%, P<0.001), and 1 characterized by cardiomyocyte hypertrophy (LA: +1.16 μm, P=0.008; RA: +2.58 μm, P<0.001). Patients with fibrotic atCM were more frequently female (LA: odds ratio [OR], 1.33, P=0.002; RA: OR, 1.54, P=0.004), with persistent AF (LA: OR, 1.22, P=0.036) or heart failure (LA: OR, 1.62, P<0.001). Hypertrophic features were more common in men (LA: OR=1.33, P=0.002; RA: OR, 1.54, P=0.004). CONCLUSIONS: Fibrotic atCM is associated with female sex, persistent AF, and heart failure, while hypertrophic features are more common in men.
AB - BACKGROUND: Atrial cardiomyopathy (atCM) is an emerging prognostic factor in cardiovascular disease. Fibrotic remodeling, cardiomyocyte hypertrophy, and capillary density are hallmarks of atCM. The contribution of etiological factors and atrial fibrillation (AF) to the development of differential atCM phenotypes has not been quantified. This study aimed to evaluate the association between histological features of atCM and the clinical phenotype. METHODS AND RESULTS: We examined left atrial (LA, n=95) and right atrial (RA, n=76) appendages from a European cohort of patients undergoing cardiac surgery. Quantification of histological atCM features was performed following wheat germ agglutinin/CD31/vimentin staining. The contributions of AF, heart failure, sex, and age to histological characteristics were determined with multiple linear regression models. Persistent AF was associated with increased endomysial fibrosis (LA: +1.13±0.47 μm, P=0.038; RA: +0.94±0.38 μm, P=0.041), whereas total extracellular matrix content was not. Men had larger cardiomyocytes (LA: +1.92±0.72 μm, P<0.001), while women had more endomysial fibrosis (LA: +0.99±0.56 μm, P=0.003). Patients with heart failure showed more endomysial fibrosis (LA: +1.85±0.48 μm, P<0.001) and extracellular matrix content (LA: +3.07±1.29%, P=0.016), and a higher capillary density (LA: +0.13±0.06, P=0.007) and size (LA: +0.46±0.22 μm, P=0.044). Fuzzy k-means clustering of histological features identified 2 subtypes of atCM: 1 characterized by enhanced endomysial fibro-sis (LA: +3.17 μm, P<0.001; RA: +2.86 μm, P<0.001), extracellular matrix content (LA: +3.53%, P<0.001; RA: +6.40%, P<0.001) and fibroblast density (LA: +4.38%, P<0.001), and 1 characterized by cardiomyocyte hypertrophy (LA: +1.16 μm, P=0.008; RA: +2.58 μm, P<0.001). Patients with fibrotic atCM were more frequently female (LA: odds ratio [OR], 1.33, P=0.002; RA: OR, 1.54, P=0.004), with persistent AF (LA: OR, 1.22, P=0.036) or heart failure (LA: OR, 1.62, P<0.001). Hypertrophic features were more common in men (LA: OR=1.33, P=0.002; RA: OR, 1.54, P=0.004). CONCLUSIONS: Fibrotic atCM is associated with female sex, persistent AF, and heart failure, while hypertrophic features are more common in men.
KW - atrial cardiomyopathy
KW - atrial fibrillation
KW - endomysial fibrosis
KW - heart failure
UR - http://www.scopus.com/inward/record.url?scp=85178400341&partnerID=8YFLogxK
U2 - https://doi.org/10.1161/JAHA.123.031220
DO - https://doi.org/10.1161/JAHA.123.031220
M3 - Article
C2 - 37982389
SN - 2047-9980
VL - 12
JO - Journal of the American Heart Association
JF - Journal of the American Heart Association
IS - 22
M1 - e031220
ER -