Abstract 11443: Metabolic Profile Signature of Obesity in Heart Failure With Preserved Ejection Fraction

Abstract

Introduction: Heart failure (HF) affects an estimated 6.2 million people in the US, with at least 50% of patients having HF with preserved ejection fraction (HFpEF). Obesity is a risk factor for HFpEF, however the association of obesity with metabolic signatures in HFpEF remains unclear. We aimed to identify unique metabolic profile of obesity among patients with HFpEF. Methods: A total of 41 participants from the Metabolomics, Oxidative Stress and Vascular Function (MOV) in HF study formed the discovery cohort, and 40 participants from the Atlanta Cardiomyopathy Consortium (TACC) study formed the validation cohort. All patients had HFpEF with left ventricular ejection fraction ≥ 50%. Untargeted high-resolution plasma metabolomic profiling identified 1,986 metabolic features. Partial least squares-discriminant analysis (PLS-DA) was performed separately in two cohorts to find the differently expressed metabolic features among obese (body mass index [BMI] ≥ 30 kg/m 2 ) vs. non-obese (BMI < 30 kg/m 2 ) patients with HFpEF. Variable Importance in Projection (VIP) score > 1 was used for feature selection. Annotation was performed by matching to an in-house library of previously confirmed metabolites. All features with VIP > 1 were used to explore pathway enrichment using Mummichog. Results: The MOV and TACC cohorts included 68.3% and 42.5% obese patients, respectively. The PLS-DA identified 23 metabolic features with confirmed annotations associated with obesity in the MOV, and 9 metabolic pathways were represented. Ten metabolites were validated in TACC, including 2,6-dihydroxypyridine, l-proline, taurine, l-methionine, guanine, 4-coumarate/phenylpyruvate, pyridoxamine, 1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline, ll-2,6-diaminoheptanedioate, and linoleate. One metabolic pathway, di-unsaturated fatty acid beta-oxidation, was validated. Conclusions: In two cohorts of HFpEF patients, by comparing the metabolic profiles of obese vs. non-obese patients, we identified alterations in amino acids, fatty acids, alkaloids, and vitamins. Moreover, pathway analysis confirmed alterations in the metabolic pathway of beta-oxidation of unsaturated fatty acids such as linoleate are also associated with obesity.