Epicardial adipose tissue density, myocardial fibrosis, and heart failure with preserved ejection fraction in postmenopausal women: a mediation analysis

Background: Heart failure with preserved ejection fraction (HFpEF) predominantly affects postmenopausal women, but its underlying mechanisms remain unclear. Epicardial adipose tissue (EAT), a metabolically active fat depot adjacent to the myocardium, has been implicated in HFpEF. This study aimed to evaluate the associations of EAT volume and density with HFpEF in postmenopausal women and to determine whether myocardial fibrosis mediates this relationship.

Methods: In this retrospective cross-sectional study, we included 70 postmenopausal women with HFpEF and 70 age-matched controls (±3 years) who underwent cardiac computed tomography (CT). EAT volume and density were quantified from coronary artery calcium scoring images. Myocardial extracellular volume (ECV), derived from dual-energy CT, was used to quantify myocardial fibrosis. Multivariable regression analyses and mediation analyses were performed to evaluate the associations between EAT characteristics, ECV, and HFpEF.

Results: EAT volume index, density, and ECV were significantly higher in the HFpEF group than in controls (all P<0.05). After adjustment for cardiovascular risk factors and comorbidities, higher EAT density [per 1-Hounsfield unit (HU) increase; odds ratio (OR) =1.209; 95% confidence interval (CI): 1.073–1.362; P=0.002] and ECV (per 1% increase; OR =1.306; 95% CI: 1.104–1.510; P=0.001) remained independently associated with HFpEF. ECV mediated 47.7% of the relation between EAT density and HFpEF (effect =0.188; 95% CI: 0.094–0.296; P<0.05). EAT density was independently associated with ECV in the postmenopausal population (β =0.39, P<0.001).

Conclusions: EAT density is more strongly and independently associated with HFpEF in postmenopausal women than EAT volume. Myocardial fibrosis, measured as ECV, partially mediated the association between EAT density and HFpEF, supporting the concept of an EAT-myocardial fibrotic axis in the pathophysiology of HFpEF in this population.