Abstract 4371466: Epicardial and Visceral Adiposity Define High-Risk Obesity Phenotypes for Cardiovascular Disease: A Harmonized Analysis of Multi-Cohort Imaging and Biomarker Data

Abstract

Background: Obesity is heterogeneous, with cardiovascular disease (CVD) risk driven by ectopic fat distribution rather than total adiposity. Epicardial Adipose Tissue (EAT) and Visceral Adipose Tissue (VAT) are key mediators of cardiometabolic risk through pro-inflammatory pathways. Despite this, clinical risk stratification relies on body mass index (BMI), which fails to differentiate high-risk obesity phenotypes. We assessed whether EAT and VAT identify distinct obesity phenotypes with differing CVD risk profiles and quantified the role of systemic inflammation in mediating this risk. Hypothesis: We hypothesized that individuals with concurrently high EAT and VAT represent a high-risk obesity phenotype with significantly greater CVD risk compared to Metabolically Healthy Obesity (MHO), and that systemic inflammation mediates ≥30% of this increased risk. Methods: We analyzed 47,091 participants from three cohorts: Framingham Heart Study (N=3,489), Dallas Heart Study (N=3,072), and UK Biobank (N=40,530). EAT volume and VAT area were measured by CT/MRI. Systemic inflammation biomarkers (hs-CRP, IL-6) were assayed. Obesity phenotypes were defined as: High-risk (EAT ≥125 cm3 and VAT ≥75th percentile); MHO (VAT ≥75th percentile and insulin resistance); and MHO (BMI ≥30 kg/m2 and low EAT/VAT [below high-risk thresholds]). Multivariable Cox models (adjusted for age, sex, race, diabetes, smoking, SES) Estimated Hazard Ratios (HRs) for incident CVD (MI, stroke, or HF). Mediation used the product-of-coefficients method. Results: High EAT (≥125 cm3) was associated with a 2.1-fold higher CVD risk (95% CL: 1.6–2.8; p<0.001). Concurrently high EAT and VAT conferred a 4.5-fold increased heart failure risk (95% CL: 2.8–7.3; p<0.001). MUO demonstrated a 3.8-fold higher CVD risk versus MHO (95% CL: 3.1–4.6; p<0.001), while MHO showed no significant risk elevation (HR 1.1; 95% CL: 0.9–1.4; p=0.32). Systemic inflammation mediated 38% of the EAT–CVD association (p<0.001) and 42% of the EAT–heart failure association (p<0.001). Conclusion: EAT and VAT identify high-risk obesity phenotypes with markedly elevated CVD and heart failure risk, whereas metabolically healthy obesity confers no excess risk. Systemic inflammation explains over one-third of the EAT/VAT–CVD relationship. These findings advocate for integrating EAT/VAT imaging into clinical risk stratification, prioritizing anti-inflammatory therapies in high-risk populations, and expanding access to advanced imaging.