Epicardial fat remodeling in end-stage heart failure with reduced ejection fraction

Abstract Background Epicardial adipose tissue (EAT) transformation in heart failure with reduced ejection fraction (HFrEF) is poorly understood, which limits its potential as a therapeutic target and prognostic factor. The aim of our study was to characterize EAT in patients with HFrEF at the histological, computed tomography (CT) imaging and radiomic level to better understand its transformation in HFrEF. Methods We enrolled 70 patients with HFrEF who were scheduled for implantation of a left ventricular assist device (LVAD) or orthotopic heart transplantation (OHT). Fifty non–heart failure (HF) subjects served as controls. All participants underwent contrast- or non-contrast-enhanced chest CT imaging for EAT analysis. Left ventricular myocardial cones with overlying EAT were obtained from LVAD patients during surgery, from explanted OHT hearts, and from 20 unused healthy donor hearts for histological analysis. Results While total EAT volume did not differ between non-HF and HFrEF subjects, its density assessed in CT images, was higher in HFrEF. Moreover, periventricular EAT exhibited density gradient, with the densest voxels immediately adjacent to the myocardium (over up to 1 mm). This density gradient was extended to almost 3 mm in LV EAT in HFrEF patients. Histological analysis showed that adipocytes also exhibited a characteristic cell size gradient, with smaller cells adjacent to the myocardium, more pronounced than in non-HF subjects; moreover, median LV EAT adipocyte size was smaller in HFrEF vs. non-HF patients. However, EAT fibrosis and blood vessel density did not differ between non-HF and HFrEF subjects. Both histological analysis and radiomic analysis of CT images revealed that EAT was more heterogeneous in HFrEF than in non-HF subjects. These changes were most pronounced in LV EAT, but other EAT depots (RV and periatrial) were also affected. Conclusions LV EAT in HFrEF contains smaller adipocytes and has higher density in CT images, exhibits pronounced cell size/density gradient and is more heterogeneous than in non-HF subjects. Thus LV EAT undergoes complex remodeling in HFrEF. Further studies are needed to elucidate the mechanisms driving this remodeling, determine whether it can be therapeutically targeted, and assess which parameters may have prognostic value in patients with HFrEF.