Abstract Body: Introduction: Metabolomic biomarkers have enhanced heart failure (HF) prediction in addition to clinical risk factors. However, urine metabolites related to incident HF have not been studied.
Hypothesis: Novel urine metabolites, as well as uremic toxins, are associated with an increased risk of HF.
Methods: Metabolomic profiling was performed in the Atherosclerosis Risk in Communities (ARIC) study at visit 5 using urine samples. Urine metabolite levels were probabilistic quotient normalized prior to the analyses, and 914 known urine metabolites were evaluated with incident HF using Cox proportional hazard regression. Replication analyses were performed on 3,431 participants, including 172 HF cases (mean age=58) from the German Chronic Kidney Disease (GCKD) study (100% Whites).
Results: During an average of 7 years of follow-up, 226 incident HF events occurred among 1,242 ARIC participants (54.3% Whites, mean age= 76). After adjusting for clinical risk factors and eGFR, ten urine metabolites were associated with incident HF (FDR p-value <0.05). Guanosine-3',5'-cyclic monophosphate (cGMP), a biologic marker reflecting renal activities of natriuretic peptides, was associated with an increased risk of HF (HR=1.40, 95% CI= 1.21-1.63). Sucrose, a disaccharide composed of glucose and fructose, was also associated with an increased effect on HF (HR=1.30, 95% CI= 1.12-1.50), and the effect persisted with further adjustment of fasting glucose levels. The associations of urine cGMP and sucrose with HF were replicated in GCKD (HR_cGMP=1.40, 95% CI= 1.24-1.56; HR_sucrose= 1.19, 95% CI= 1.03-1.35, Figure). Additional analyses revealed that cGMP was more strongly associated with HF with reduced (HFrEF) than with preserved ejection fraction (HFpEF), while sucrose was more strongly associated with HFpEF than HFrEF.
Conclusions: Urinary metabolites associated with incident HF and its subtypes were identified, providing complementary insights into the molecular mechanism of the development of HF.