Abstract 14194: Dynamic Metabolite Profiles of Heart Failure and Central Hemodynamics

Abstract

Aim: Large-scale plasma metabolite profiling is garnering considerable interest for the discovery of therapeutic targets and facilitation of precision medicine across a range of conditions. Heart failure (HF) represents a particularly promising application of metabolite profiling for precision medicine. Here, we performed untargeted metabolite profiling of heart failure cases and healthy controls, and studied transplant dynamics and central hemodynamic correlates of identified metabolites. Methods and Results: Metabolite profiling was conducted with liquid chromatography-tandem mass spectrometry methods in two independent case-control samples: one sample with advanced HF patients undergoing right-heart catheterization (RHC, n=248) and healthy controls of matching age and sex (n=30), and one sample with HF outpatients (n=83) and controls from a population-based cohort (n=583). Metabolites associated with HF were identified based on multivariable-adjusted logistic regression models. In total, 93 of 1370 studied metabolites were significantly associated with HF in both cohorts with concordant directionality, after Bonferroni correction. A subset of the advanced HF patients underwent heart transplantation (n=28), after which a second sample was obtained at the routine 6 month follow up exam. In linear mixed-effects regression models, 17 metabolites (18%) returned significantly towards healthy control levels. Of these, 13 (76%) were associated with at least one of 14 central hemodynamic parameters. Most associations were with right atrial pressure (RAP, 10 metabolites), mixed venous oxygen saturation (12 metabolites) and left-ventricular stroke work index (9 metabolites). For example, vanillylmandelate, a catecholamine metabolite, was associated with stroke volume and cardiac index, while kynurenine, an immunomodulatory tryptophan metabolite mainly produced in the liver and previously associated with kidney function, was associated with higher left-sided (pulmonary arterial wedge pressure) and right sided (RAP) filling pressures. Conclusions: Here, we comprehensively identified metabolites associated with HF and describe the hemodynamic correlates and metabolite dynamics upon HF reversal by transplantation.