Abstract 13276: Metabolic Pathways and Risk Biomarkers for Incident Heart Failure

Abstract

Introduction: Metabolomic profiling provides important information about heart failure (HF) risk. Metabolites reporting on muscle fuel substrate including branched-chain amino acids (BCAAs) and ketones have been implicated in HF pathogenesis and as circulating biomarkers of risk. We sought to identify the role of these known metabolites and identify novel metabolites and related pathways associated with incident HF in a large population-based cohort. Methods: Metabolomic profiling has been performed in the UK Biobank cohort using the Nightingale NMR platform. Principal component analysis (PCA) was used for dimensionality reduction and to identify shared metabolic pathways. Cox proportional hazard models were used to test the association between each PCA factor, and of individual metabolites heavily loaded on significant factors, with time to incident HF. Results: Of n=118,021 participants with metabolomic profiling data, n=3,865 (3.3%) developed incident HF (mean [SD] follow-up: 12.5 [1.3] years). The 107 metabolite biomarkers clustered into 12 PCA factors (Table 1). Nine factors were associated with incident HF in adjusted models. Factor 5 (BCAAs, aromatic acids) was not associated with incident HF in adjusted models. However, higher levels of each individual BCAA were associated with decreased risk of incident HF, with valine as the most protective (HR 0.91 [CI 0.88-0.95], q = 3x10 -6 ). Factors 2 (large HDL) and 6 (ketones) were associated with increased risk of incident HF, while factors 4 (small HDL) and 9 (omega-3 fatty acids) were associated with decreased risk of incident HF. Conclusions: In a large population-based cohort, we found that higher baseline levels of ketones and large HDL were associated with increased risk of incident HF, while higher levels of BCAAs, small HDL, and omega-3 fatty acids were associated with decreased risk of incident HF. These results highlight known and new metabolic pathways and related circulating biomarkers of HF risk.