Abstract Body: Background: Central obesity is a stronger determinant of cardiovascular diseases than body mass index (BMI), yet the biological mechanisms linking adiposity distribution to heart failure (HF) remain unclear. Recent evidence suggests that diabetes-associated HF is driven primarily by visceral adiposity rather than hyperglycemia. Whether systemic inflammation quantitatively mediates the relationship between central obesity and HF has not been well established.
Hypothesis: We hypothesized that systemic inflammation, indexed by high-sensitivity C-reactive protein (hs-CRP), mediates the association between central adiposity and incident HF.
Methods: We analyzed 1,998 adults from the Jackson Heart Study without HF at baseline. Adiposity indicators included weight, BMI, waist circumference (WC), and waist-to-height ratio (WHtR). hs-CRP was measured as a marker of systemic inflammation. Weibull accelerated failure time models estimated adjusted hazard ratios (HRs) for HF, and causal mediation analysis quantified the proportion of adiposity-related HF risk mediated through hs-CRP.
Results: Over a median follow-up of 6.9 years, elevated hs-CRP (≥ 1 mg/L) was associated with lower HF-free survival (log-rank p = 0.010). In adjusted models, WC (HR 1.31, 95% CI 1.06–1.62) and WHtR (HR 1.27, 95% CI 1.02–1.58) were independent predictors of HF, whereas BMI was not. Mediation analysis showed that hs-CRP accounted for 25.4% of the effect of WC and 28.5% of the effect of WHtR on HF risk, both with statistically significant indirect effects.
Conclusions: Systemic inflammation mediates approximately one quarter of the relationship between central obesity and incident HF, reinforcing the paradigm that visceral fat–driven inflammation is a key causal pathway linking obesity to HF. These findings underscore the importance of targeting adiposity-related inflammation in HF prevention strategies.