Abstract Body: Introduction
Metabolic dysregulation is recognized in heart failure (HF). A comprehensive assessment of circulating metabolites, specifically on HF subtypes, in multi-ethnic populations is limited.

Hypothesis
We hypothesize that circulating metabolites are significantly associated with the risk of HF and have differential effects on HF subtypes.

Methods
Circulating metabolites from seven studies in the Trans-Omics for Precision Medicine Program were analyzed among 21,398 HF-free participants (58% non-Whites, 58% women), from which 1,160 incident HF, 373 HF with reduced (HFrEF), and 439 HF with preserved ejection fraction (HFpEF) events were ascertained with an average of 11.5 years of follow up. Cox proportional hazard regressions were applied by the study, followed by random-effect meta-analyses, to produce metabolite HF associations. Over-representation analyses were performed to identify relevant metabolite pathways.

Results
Out of 1,015 metabolites analyzed, 54 were significantly associated with incident HF (Bonferroni corrected p<0.05) after accounting for clinical risk factors. Eleven metabolic pathways were mapped; pentose and glucuronate interconversions and pyrimidine metabolism demonstrated over-representation (FDR<0.05). Most identified metabolites (93%) were positively associated with HF, and the strength of the associations persisted with further adjustment of kidney function. Thirteen metabolites showed consistent effects from all participating studies, and subtype analyses indicated that most metabolites were more strongly associated with HFpEF than HFrEF (Figure). For example, N-acetylputrescine, a precursor of γ-aminobutyric acid (GABA), and 4-acetamidobutanoate, a derivative of GABA, were associated with an increased risk of HFpEF but not HFrEF.

Conclusions
We identified circulating metabolites associated with the risk of HF in multi-ethnic populations, highlighting the need to better understand the differential metabolic etiology of HFpEF compared to HFrEF.