Abstract 13458: Obese Heart Failure With Preserved Ejection Fraction Demonstrates Impaired Myocardial Substrate Utilization

Abstract

Introduction: Myocardial fatty acid oxidation is impaired in heart failure with reduced ejection fraction (HFrEF) but increases with obesity with diabetes. HF with preserved EF (HFpEF) patients are often obese, but their myocardial metabolomic profiling compared to HFrEF is unknown. We hypothesized that HFpEF patients have distinctive metabolomics signatures from HFrEF. Methods: Plasma and endomyocardial biopsies were collected from HFpEF patients with clinical HF, LVEF≥50%, and consensus criteria for HFpEF (n=45). Most were obese (median BMI 39.8 kg/m 2 ). Data were compared to end-stage HFrEF (n=30) and unused donor controls (n=20). Liquid chromatography-mass spectrometry measured 97 metabolites (8 organic acids, 30 amino acids [AA], 59 acylcarnitines [AC]). Metabolites undetectable in ≥25% patients were excluded. Statistical analyses used one-way ANOVA with post-hoc Tukey test, and false discovery rate of 5% (Benjamini-Hochberg). Results: Myocardial metabolomics revealed HFpEF patients had greater pyruvate levels vs controls and HFrEF (2-2.5x, p<0.0001). Krebs cycle intermediates were reduced in HFpEF tissue vs controls (succinate, p=0.002; fumarate, p=0.009; malate, p=0.008), while myocardial branched chain AAs (isoleucine, leucine, valine) were greater than both controls (all p<0.0001) and HFrEF (p=0.048, <0.0001, <0.0001, respectively). Short chain ACs downstream of branched chain AA catabolism were reduced in HFpEF tissue vs Controls, whereas long chain ACs that reflect fatty acid oxidation were reduced in both HFpEF and HFrEF tissue vs controls, yet increased in HFrEF plasma. HFrEF had reduced tissue long chain ACs vs HFpEF. Plasma metabolomics replicated myocardial changes in only 11% of metabolites. Conclusions: HFpEF myocardium in obese patients displays metabolic signatures consistent with impaired utilization of fatty acids, glucose, and amino acids in a pattern quite distinct from HFrEF. This is not discerned from plasma metabolomics. These findings identify a unique metabolic phenotype in HFpEF in which obesity and associated insulin desensitization are coupled with compromised fat metabolism and alternate substrate utilization. This likely contributes to metabolic insufficiency in the HFpEF syndrome.