Regional fat distribution as a determinant of mortality in populations with left ventricular systolic dysfunction: challenging the obesity paradox

Abstract Aims Obesity and regional fat distribution are associated with adverse cardiovascular outcomes, yet the prognostic significance of specific adiposity phenotypes in individuals with left ventricular systolic impairment remains incompletely defined. Body mass index (BMI) incompletely captures fat distribution and may underestimate metabolically adverse adiposity. Methods and results Participants from the community-based UK Biobank Imaging Enhancement Programme who underwent cardiac magnetic resonance (CMR) imaging were evaluated. Individuals with CMR-defined left ventricular systolic impairment [left ventricular ejection fraction <50%] were identified, while participants with prevalent heart failure at baseline were excluded. Adiposity was assessed using BMI, waist circumference (WC), waist-to-hip ratio (WHR), body fat percentage, and total fat mass. Associations between adiposity measures (per 1 SD increase) and all-cause and cardiovascular (CV) mortality were evaluated using Cox proportional hazards models adjusted for age, sex, hypertension, diabetes mellitus, hypercholesterolaemia, and smoking. Left ventricular (LV) impairment aetiology was classified as ischaemic or non-ischaemic using International Classification of Diseases, 10th Revision codes or self-reported prior myocardial infarction. All analyses were performed using R 4.4.0 within the UK Biobank Research Analysis Platform. Among 5615 participants with CMR-defined LV systolic impairment (mean age 56.7 ± 7.4 years; 52% male), 290 all-cause and 76 CV deaths occurred over a median follow-up of 13.5 years. In fully adjusted analyses, BMI was associated with increased all-cause [hazard ratio (HR) 1.19, 95% confidence interval (CI) 1.05–1.34] and CV mortality (HR 1.37, 95% CI 1.11–1.69). Central adiposity measures demonstrated stronger associations with outcomes, particularly WC (all-cause HR 1.25; CV HR 1.49) and WHR (all-cause HR 1.30; CV HR 1.52). Compared with a BMI-based reference model (C-statistic 0.67 for all-cause and 0.71 for CV mortality), inclusion of WC and WHR resulted in modest but statistically significant improvements in discrimination (ΔC up to +0.008 for all-cause and +0.012 for CV mortality), whereas general adiposity measures, including body fat percentage and total fat mass, did not meaningfully improve incremental discrimination. Conclusion In this large imaging-defined cohort of individuals with LV systolic impairment, central adiposity measures, particularly WC and WHR, were more strongly associated with CV mortality than BMI, body fat percentage, or total fat mass. These findings suggest that fat distribution, rather than overall adiposity alone, provides important prognostic information in individuals with LV systolic impairment. Registration Biobank Project ID 55469