Abstract Body (Do not enter title and authors here): Introduction: Heart failure (HF) disproportionately affects Black adults. Despite therapeutic advancements, symptom burden remains a major driver of healthcare utilization and reduced quality of life. Metabolic dysregulation may underlie HF symptomatology, particularly in populations with high comorbidity. Metabolomics offers new insight into pathways linked to symptom burden. We performed untargeted metabolomics to identify metabolic signatures associated with HF symptoms in Black adults.

Hypothesis: We hypothesized metabolic dysregulation is associated with HF symptom severity of in Black adults.

Methods: We conducted a cross-sectional analysis using untargeted liquid chromatography-mass spectroscopy (positive and negative ion modes) and the Heart Failure Somatic Perception Scale (HFSPS), including total and subscale scores. Associations between metabolite intensity and symptom scores were tested using mummichog (V1.0.10) adjusting for age, sex, BMI, LVEF.

Results: The sample included 37 Black adults with HF (mean age 57±11 years, 66% female, 49% college-educated. Total HFSPS score (18.2±9.4). After covariate adjustment, 499 features were associated (p<0.05) with total HFSPS score. For the dyspnea subscale, 556 features were linked (p<0.05) to enriched pathways including vitamin C and A metabolism, arginine/proline metabolism, and amino acid metabolism. Early symptoms were associated with 560 features, enriched for vitamin B6, porphyrin, and prostaglandin pathways. Edema symptoms were linked to enriched in bile acid biosynthesis and the urea cycle. Chest symptoms were associated with 957 features (22 FDR-significant), all positively correlated with symptom severity. Eighteen pathways were significantly enriched most featuring positively associated metabolites.

Discussion: Findings suggest metabolic signatures are linked to HF symptom severity in Black adults. Key pathways involved mitochondrial function, oxidative stress, and amino acid metabolism. Enrichment of TCA cycle and pyruvate metabolism pathways supports the role of metabolic dysfunction in symptomatic HF. Antioxidant-related pathways (e.g., vitamin C and retinol) highlight the contribution of redox imbalance. TheChest symptoms showed the strongest associations, with FDR-significant features and consistent enrichment patterns.

Conclusion: Untargeted metabolomics identified multiple pathways associated with HF symptom burden, especially chest-related symptoms, in Black adults.