Aims Left ventricular diastolic dysfunction (LVDD) is common in obese subjects, and a relationship between epicardial adipose tissue (EAT), increased adipocytokines, and cardiovascular diseases has been reported. This study sought to examine as to whether the adipo-fibrokine activin A is a link between increased EAT, the metabolic syndrome (MetS), and LVDD in severely obese subjects. Methods and results In 236 obese subjects (empty set body mass index 39.8 +/- 7.9 kg/m(2) ) with a variable degree of the MetS and in 60 healthy non-obese controls (empty set body mass index 24.8 +/- 3.4 kg/m(2)), serum activin A levels were measured and correlated with parameters of the MetS, epicardial fat thickness (EFT), and echocardiographic parameters of LVDD. Activin A levels were higher in obese than in non-obese subjects (362 +/- 124 vs. 301 +/- 94 pg/mL, P = 0.0004), increased with the number of MetS components (from 285 +/- 82 with no MetS component, 323 +/- 94 with one or two MetS components, to 403 +/- 131 pg/ml with >= 3 MetS components, P < 0.0001) and correlated with EFT (r = 0.41, P < 0.001). Furthermore, activin A levels were related to several parameters of LVDD [e.g. left atrial size (382 +/- 117 vs. 352 125 pg/ml, P = 0.024), E/e' (394 +/- 108 vs. 356 +/- 127 pg/mL, P = 0.005)]. LVDD was highest in MetS obese subjects with high EFT (44.3%) compared with MetS obese subjects with low EFT (27.0%), non-MetS obese subjects with high EFT (24.2%), and non-MetS obese subjects with low EFT (10.6%, P < 0.0001). Conclusions In severe obesity, activin A was significantly related to EFT, MetS, and LVDD, implicating MetS-related alterations in the secretory profile of EAT in the pathogenesis of obesity-related heart disease.