Abstract Body: Background: Heart failure (HF) is a leading cause of morbidity and mortality. Modifiable health behaviors and factors influence HF development, but pathways linking cardiovascular health to HF remain incompletely understood. The American Heart Association’s Life’s Essential 8 (LE8) score captures cardiovascular health across eight components: diet, physical activity, nicotine exposure, sleep, body mass index, blood lipids, blood glucose, and blood pressure, integrating both behavioral and clinical factors.

Hypothesis: We hypothesize that higher LE8 scores are associated with lower HF risk through metabolite-mediated pathways that differ by race and sex.


Methods: Complete LE8 scores (scaled 0-100) were calculated at baseline for 12,775 (30% Black; 56% female) Reasons for Geographic and Racial Differences in Stroke (REGARDS) study participants. Incident HF events (n=746) were ascertained over a median 14.8 years. Cox models adjusted for age, sex, race, income, and education estimated LE8-HF associations. Metabolomics quantified 358 metabolites in 2,435 participants. Causal mediation analyses (using bootstrap confidence intervals) evaluated the extent to which metabolites explained the association of LE8 (composite or components) with incident HF. Analyses were further stratified by race and sex. We report metabolites with plausible effect estimates and significant natural indirect effects (p<0.05).

Results: Each 10-unit higher overall LE8 score was associated with a 26% lower risk of HF (hazard ratio=0.74, 95% CI: 0.70-0.78). This effect was consistent across sex and race, with hazard ratios ranging from 0.63 to 0.76. Cotinine, a nicotine exposure marker, mediated ~20% of the overall LE8-HF association, and 41% and 33% of the LE8-HF association in men and White participants, respectively. Lysophosphatidylethanolamine (LPE 18:2) isomers mediated 13%-25% of the LE8-HF association. Among LE8 components, dimethylguanidino valeric acid mediated 14% of the blood glucose-HF association in Black participants.

Conclusions: Higher LE8 scores consistently predict lower HF risk across multiple metabolic pathways, regardless of sex or race. Nicotine exposure-, glucose-, and lipid-related metabolites partially explain the protective association between cardiovascular health, as measured by LE8, and HF. These circulating metabolites may serve as intermediate biomarkers linking lifestyle and clinical factors to HF, reinforcing LE8 as a comprehensive target for prevention.