Independent and Inflammation-Linked Contribution of Fasting Plasma Glucose to Heart Failure Risk in Chronic Non-Rheumatic Aortic Regurgitation

Background Heart failure (HF) frequently complicates chronic nonrheumatic aortic regurgitation (CNRAR), yet the prognostic impact of fasting plasma glucose (FPG) and its inflammatory mechanisms remain unclear. We assessed whether FPG predicts HF in CNRAR and quantified inflammation-mediated effects. Methods We analyzed 13,200 CNRAR patients from Northwest China. The endpoint was new-onset HF. Post-discharge FPG was measured before an endpoint. Multivariable Cox models, competing-risk analysis, restricted cubic splines (RCSs), sensitivity analyses, inverse probability of treatment weighting (IPTW) and mediation analysis were performed. In addition, 13,200 CNRAR patients were 1:1 propensity matched to 2,774,530 general population participants to estimate relative hazard ratios (RHRs). External validation included 418 CNRAR or mixed aortic stenosis-regurgitation cases from the UK Biobank. Results During 535-day median follow-up, higher FPG demonstrated a dose-risk association. Compared with normoglycemia, FPG 6.1–7.0 and 7.0–16.7 mmol/L were associated with 17.1% (HR 1.171, 95% CI 1.026–1.337) and 26.2% (HR 1.262, 95% CI 1.102–1.446) higher HF risk; each 1.0 mmol/L increase conferred a 4.0% higher risk. White blood cells (WBC) accounted for 13.26% of the mediated effect on heart failure. Compared with the general population, CNRAR showed greater vulnerability at 6.1–7.0 mmol/L (RHR 1.270, 95% CI 1.037–1.555), while RHR at ≥ 7.0 mmol/L was non-significant (RHR 1.076, 95% CI 0.901–1.284). In UK Biobank, FPG ≥ 6.1 mmol/L was associated with higher HF risk (HR 1.713, 95% CI 1.044–2.808). Conclusions Elevated FPG independently predicts HF in CNRAR, partially through inflammation, supporting intensified glycemic and inflammatory risk management.