Central Adiposity, Systemic Inflammation, and Incident Heart Failure: A Causal Mediation Analysis From the Jackson...

Obesity and systemic inflammation have each been independently associated with an increased risk of heart failure (HF). However, whether inflammatory pathways mediate the association between obesity and the development of heart failure remains unclear.

We analyzed data from a community-based cohort of 1998 participants to evaluate multiple adiposity indicators in relation to incident HF. hs-CRP (high-sensitivity C-reactive protein) was examined as a mediator using causal mediation analysis to quantify the contribution of systemic inflammation. Kaplan-Meier analyses and multivariable Weibull accelerated failure time models were applied to estimate hazard ratios (HRs) for HF occurrence.

Over a median follow-up of 6.9 years, individuals with elevated hs-CRP levels showed significantly lower HF-free survival (log-rank P=0.010). In multivariable accelerated failure time models, indicators of central obesity and hs-CRP-but not BMI-were significantly associated with higher HF risk (eg, waist circumference: HR=1.30 [95% CI: 1.05-1.61], P=0.017; hs-CRP: HR=1.25 [1.05-1.51], P=0.013). Mediation analysis revealed that hs-CRP accounted for 26.5% of the effect of waist circumference and 32.4% of the effect of waist-to-height ratio on HF risk, with statistically significant indirect effects for both.

Our findings build upon recent conceptual advances by demonstrating that central obesity contributes to HF largely through inflammation. By quantifying the proportion of HF risk attributable to systemic inflammation, this study reinforces the rationale for prioritizing both anti-obesity and anti-inflammatory strategies in HF prevention.