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

Total EAT volume did not differ between HFrEF patients and non-HF controls despite significant structural remodeling.

• 70 patients with HFrEF scheduled for LVAD implantation or orthotopic heart transplantation were enrolled
• 50 non-heart failure subjects served as controls
• All participants underwent contrast- or non-contrast-enhanced chest CT imaging for EAT volume analysis
• Total EAT volume was preserved in HFrEF despite other measurable changes in EAT characteristics

EAT density assessed by CT imaging was higher in HFrEF patients compared to non-HF subjects.

• CT-derived density was used as a surrogate measure of EAT composition
• Higher density in HFrEF suggests a shift away from lipid-dominant tissue toward a denser tissue composition
• Density differences were most pronounced in left ventricular EAT depots
• Other EAT depots (RV and periatrial) were also affected, though changes were most pronounced in LV EAT

Periventricular EAT exhibited a density gradient with densest voxels immediately adjacent to the myocardium, which was more extended in HFrEF.

• In non-HF subjects, the density gradient extended over up to approximately 1 mm adjacent to the myocardium
• In HFrEF patients, the LV EAT density gradient was extended to almost 3 mm
• This gradient was identified using CT voxel-level density analysis of periventricular EAT
• The extended gradient in HFrEF suggests greater remodeling at the myocardium-EAT interface

Histological analysis revealed smaller adipocytes in LV EAT in HFrEF compared to non-HF subjects.

• Tissue samples were obtained from left ventricular myocardial cones with overlying EAT from LVAD patients during surgery and from explanted OHT hearts
• 20 unused healthy donor hearts provided control tissue for histological comparison
• Median LV EAT adipocyte size was smaller in HFrEF vs. non-HF patients
• Adipocyte size reduction was most pronounced in LV EAT but changes were also observed in RV and periatrial depots

EAT adipocytes exhibited a characteristic cell size gradient with smaller cells adjacent to the myocardium, more pronounced in HFrEF than in non-HF subjects.

• A gradient of adipocyte cell size was identified histologically in periventricular EAT in both groups
• Smaller adipocytes were located immediately adjacent to the myocardium in both HFrEF and non-HF subjects
• This gradient was more pronounced in HFrEF patients than in non-HF subjects
• The cell size gradient paralleled the CT-derived density gradient observed in imaging analysis

EAT fibrosis and blood vessel density did not differ between HFrEF and non-HF subjects.

• Histological analysis was performed on tissue samples from LVAD patients, OHT explanted hearts, and 20 healthy donor hearts
• Despite significant changes in adipocyte size and heterogeneity, fibrosis levels were not significantly different between groups
• Blood vessel density in EAT was also comparable between HFrEF and non-HF subjects
• These null findings suggest that the remodeling in HFrEF is not primarily driven by fibrotic or vascular changes

EAT was more heterogeneous in HFrEF than in non-HF subjects as revealed by both histological and radiomic analyses.

• Radiomic analysis of CT images was used to quantify EAT texture and heterogeneity at the imaging level
• Histological analysis independently confirmed greater cellular heterogeneity in HFrEF EAT
• Heterogeneity was most pronounced in LV EAT but was also detected in RV and periatrial EAT depots
• Convergent findings from two independent analytical methods (radiomics and histology) support the robustness of the heterogeneity finding