Abstract 17979: Global Metabolomic Profiling in Heart Failure With Preserved Ejection Fraction Identifies Markers of Myocardial Dysfunction
Background: Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous disease felt to be distinct from heart failure with reduced ejection fraction (HFrEF). We hypothesized that metabolomic profiling would reveal molecular phenotypes and biomarkers unique to this disease.
Methods: Subjects were identified from the CATHGEN biorepository of patients undergoing cardiac catheterization. All cases had diastolic dysfunction (grade ≥ 1) and heart failure (HF); HFpEF (n=282) had left ventricular ejection fraction (LVEF) ≥ 45%, and HFrEF (n=278) had LVEF < 45%. No-HF controls (n=190) had LVEF ≥ 45%, normal diastolic function and no HF. Mass spectrometry-based metabolomic profiling was performed in frozen fasting plasma samples. Metabolites were tested for association with case-control status using ANCOVA models adjusted for age, sex, race, smoking, body mass index, diabetes, hypertension, hyperlipidemia, glomerular filtration rate and number of diseased coronary arteries.
Results: After Bonferroni correction (p<2.4x10-4) of 210 unambiguously identified metabolites, 31 were associated with HFpEF/HFrEF/no-HF status. These small molecules report on mitochondrial metabolic pathways, including 12 acylcarnitine species (min p=1.1x10-10), 7 dicarboxylic acids (min p=4.5x10-10), and 5 tricarboxylic acid (TCA) cycle intermediates (min p=5.1x10-14). For all, the mean metabolite concentration was highest in HFrEF cases, intermediate in HFpEF cases and lowest in the no-HF control group.
Conclusions: Using a global metabolomic profiling approach, we identified circulating metabolites differentially expressed among HFpEF, HFrEF and no-HF groups. Interestingly, these metabolites were highest in HFrEF and intermediate in HFpEF. This suggests that they are markers of global metabolic impairments associated with heart failure that worsen in severity with declining LVEF. Thus, these metabolites could serve as more granular markers of metabolic impairments in HF patients who have not yet developed structural damage detectable via changes in LVEF. These results suggest that HFpEF and HFrEF are on a continuum of disease pathology, and these metabolic biomarkers could be used as early markers of myocardial dysfunction.
Author Disclosures: L.C. Kwee: None. W.G. Hunter: None. R.W. McGarrah: None. J.P. Kelly: None. D. Craig: None. P. Shipkova: Employment; Significant; Bristol-Myers Squibb. M. Reily: Employment; Significant; Bristol-Myers Squibb. J. Chen: Employment; Significant; Bristol-Myers Squibb. S. Chasalow: Employment; Significant; Bristol-Myers Squibb. S. Hnatyshyn: Employment; Significant; Bristol-Myers Squibb. J. Thompson: Employment; Significant; Bristol-Myers Squibb. P. Gargalovic: Employment; Significant; Bristol-Myers Squibb. A.F. Hernandez: Research Grant; Significant; AstraZeneca, Amgen, Bayer, Novartis. Honoraria; Modest; AstraZeneca. Honoraria; Significant; Novartis. G.M. Felker: None. E.J. Velazquez: Research Grant; Significant; NHLBI, Amgen, Novartis, Pfizer, Alnylam. Consultant/Advisory Board; Modest; Amgen, Merck, Expert Exchange. Consultant/Advisory Board; Significant; Novartis. W.E. Kraus: None. S.H. Shah: None.
- © 2016 by American Heart Association, Inc.