OBJECTIVE: Obesity is a well-known heart failure (HF) risk factor, yet the biological pathways linking adiposity indices to HF remain unclear. This study aimed to identify proteomic mediators for five novel indices-waist circumference (WC), waist-to-hip ratio (WHR), waist-to-height ratio (WHTR), body roundness index (BRI), weight-adjusted waist index (WWI), and translate mechanistic differences into clinical practice. METHODS: Using UK Biobank data, we applied Cox regression and linear regression to identify proteins associated with both HF and each index, followed by mediation and GO enrichment analyses. RESULTS: All five indices were associated with HF, with WHR and WHTR showing the strongest links. Shared pathways included angiogenesis and cardiac development. Each index occupied a distinct position along a pathological continuum: BRI (cell surface-related) as the upstream driver of early adipose dysfunction; WHR (inflammatory-fibrotic cascade) and WHTR (developmental-metabolic-inflammatory-hormonal) as intermediate downstream markers; WWI (vascular development) and WC (extracellular matrix remodeling) as terminal downstream markers of established organ damage. CONCLUSIONS: Each indicator occupies a distinct position in HF progression, offering unique mechanistic insights into its onset, and thus enabling individualized risk assessment and mechanism-based interventions for obese patients.