Abstract P272: Association of Small Molecule Metabolic Intermediates that Predict Cardiovascular Mortality with Peak VO2 in a Heart Failure Population

Abstract

Blood-borne small metabolic intermediates have been associated with disease severity and major adverse coronary events (MACE), including mortality alone, in a cardiovascular disease population. Specifically, short chain dicarboxylacylcarnitines (SCDC), long chain dicaboxylacylcarnitines (LCDC) and long neutral amino acids (LNAA) have been the strongest and most consistent diagnostic and predictive metabolic markers in our CATHGEN cohort. HF-ACTION was a randomized controlled trial of exercise training versus usual care in patients with chronic heart failure (HF) due to left ventricular systolic dysfunction (n=2331). In the study, baseline peak VO 2 was the most significant predictor of mortality in the this population ( X 2 =153). We hypothesized that small molecule blood-borne metabolic intermediates would be associated with peak VO 2 in HF-ACTION. Peak VO 2 was measured using a standard protocol across 82 centers and quality control was ensured in a core laboratory. We measured 15 amino acids and 45 acylcarnitines from baseline plasma samples in 447 individuals in the Duke Stedman Metabolomics Laboratory. The 60 metabolites were reduced into 13 independent factors using principal components analysis that accounted for a total of 43.8% of the total variance in these sample analytes. We assessed the ability of metabolite factors to predict baseline peak VO 2 in the presence of covariates modeled as significant predictors in previous published work in this population (age, gender, race, region, BMI, diabetes, PVD, NYHA Class, LVEF, ventricular conduction and test modality—bicycle or treadmill). Five metabolite factors were significant predictors of peak VO 2 , the three strongest being SCDC (estimate in SD factor score per mL/kg/min (VO 2 ) = -1.004; p-value=0.002), LNAA (0.583; p=0.003); and LCDC (-0.903; p=0.008). The direction of change with increased peak VO 2 (related to decreased mortality in HF-ACTION) were consistent with the relation of metabolites to decreased mortality in CATHGEN. Thus, three classes of metabolic intermediates that are associated with MACE in a cardiovascular cohort study also were associated with functional capacity (peak VO 2 ). To the best of our knowledge this is the first description of molecular metabolic biomarkers that independently related, even with our strongest clinical variables in the model, to functional capacity in HF. These metabolic intermediates may be functionally related to the reductions in functional capacity in HF and therefore serve as potential targets for new diagnostics or therapeutic interventions.