title: Metabolomic Profiling Identifies Novel Circulating Biomarkers of Mitochondrial Dysfunction Differentially Elevated in Heart Failure With Preserved Versus Reduced Ejection Fraction: Evidence for Shared Metabolic Impairments in Clinical Heart Failure.
abstract: Metabolic impairment is an important contributor to heart failure (HF) pathogenesis and progression. Dysregulated metabolic pathways remain poorly characterized in patients with HF and preserved ejection fraction (HFpEF). We sought to determine metabolic abnormalities in HFpEF and identify pathways differentially altered in HFpEF versus HF with reduced ejection fraction (HFrEF).
  
  
  
  We identified HFpEF cases, HFrEF controls, and no-HF controls from the CATHGEN study of sequential patients undergoing cardiac catheterization. HFpEF cases (N=282) were defined by left ventricular ejection fraction (LVEF) ≥45%, diastolic dysfunction grade ≥1, and history of HF; HFrEF controls (N=279) were defined similarly, except for having LVEF <45%. No-HF controls (N=191) had LVEF ≥45%, normal diastolic function, and no HF diagnosis. Targeted mass spectrometry and enzymatic assays were used to quantify 63 metabolites in fasting plasma. Principal components analysis reduced the 63 metabolites to uncorrelated factors, which were compared across groups using ANCOVA. In basic and fully adjusted models, long-chain acylcarnitine factor levels differed significantly across groups (P<0.0001) and were greater in HFrEF than HFpEF (P=0.0004), both of which were greater than no-HF controls. We confirmed these findings in sensitivity analyses using stricter inclusion criteria, alternative LVEF thresholds, and adjustment for insulin resistance.
  
  
  
  We identified novel circulating metabolites reflecting impaired or dysregulated fatty acid oxidation that are independently associated with HF and differentially elevated in HFpEF and HFrEF. These results elucidate a specific metabolic pathway in HF and suggest a shared metabolic mechanism in HF along the LVEF spectrum.
authors.affiliation: Duke University School of Medicine, Durham, NC Department of Medicine, Duke University School of Medicine, Durham, NC.
authors.forename: Wynn G
authors.initials: WG
authors.lastname: Hunter
authors.affiliation: Division of Cardiology, Department of Medicine, Duke University School of Medicine, Durham, NC Duke Clinical Research Institute, Durham, NC.
authors.forename: Jacob P
authors.initials: JP
authors.lastname: Kelly
authors.affiliation: Division of Cardiology, Department of Medicine, Duke University School of Medicine, Durham, NC Duke Molecular Physiology Institute, Durham, NC.
authors.forename: Robert W
authors.initials: RW
authors.lastname: McGarrah
authors.affiliation: Division of Cardiology, Department of Medicine, Duke University School of Medicine, Durham, NC.
authors.forename: Michel G
authors.initials: MG
authors.lastname: Khouri
authors.affiliation: Duke Molecular Physiology Institute, Durham, NC.
authors.forename: Damian
authors.initials: D
authors.lastname: Craig
authors.affiliation: Duke Molecular Physiology Institute, Durham, NC.
authors.forename: Carol
authors.initials: C
authors.lastname: Haynes
authors.affiliation: Duke Molecular Physiology Institute, Durham, NC.
authors.forename: Olga
authors.initials: O
authors.lastname: Ilkayeva
authors.affiliation: Duke Molecular Physiology Institute, Durham, NC.
authors.forename: Robert D
authors.initials: RD
authors.lastname: Stevens
authors.affiliation: Duke Molecular Physiology Institute, Durham, NC.
authors.forename: James R
authors.initials: JR
authors.lastname: Bain
authors.affiliation: Duke Molecular Physiology Institute, Durham, NC.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Muehlbauer
authors.affiliation: Division of Cardiology, Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC Department of Medicine, Duke University School of Medicine, Durham, NC Duke Molecular Physiology Institute, Durham, NC.
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Newgard
authors.affiliation: Division of Cardiology, Department of Medicine, Duke University School of Medicine, Durham, NC Duke Clinical Research Institute, Durham, NC.
authors.forename: G Michael
authors.initials: GM
authors.lastname: Felker
authors.affiliation: Division of Cardiology, Department of Medicine, Duke University School of Medicine, Durham, NC Duke Clinical Research Institute, Durham, NC.
authors.forename: Adrian F
authors.initials: AF
authors.lastname: Hernandez
authors.affiliation: Division of Cardiology, Department of Medicine, Duke University School of Medicine, Durham, NC Duke Clinical Research Institute, Durham, NC.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Velazquez
authors.affiliation: Division of Cardiology, Department of Medicine, Duke University School of Medicine, Durham, NC Duke Molecular Physiology Institute, Durham, NC.
authors.forename: William E
authors.initials: WE
authors.lastname: Kraus
authors.affiliation: Division of Cardiology, Department of Medicine, Duke University School of Medicine, Durham, NC Duke Clinical Research Institute, Durham, NC Duke Molecular Physiology Institute, Durham, NC svati.shah@duke.edu.
authors.forename: Svati H
authors.initials: SH
authors.lastname: Shah
mesh_terms: D000368:Aged; D000704:Analysis of Variance; D015415:Biomarkers / Q000378:metabolism; D016022:Case-Control Studies; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D006333:Heart Failure / Q000378:metabolism* / Q000503:physiopathology; D006801:Humans; D008297:Male; D008659:Metabolic Diseases / Q000378:metabolism* / Q000503:physiopathology; D055432:Metabolomics; D008875:Middle Aged; D008929:Mitochondria, Heart / Q000378:metabolism; D028361:Mitochondrial Diseases / Q000378:metabolism* / Q000503:physiopathology; D020097:Natriuretic Peptide, Brain / Q000378:metabolism; D010084:Oxidation-Reduction; D010446:Peptide Fragments / Q000378:metabolism; D013318:Stroke Volume / Q000502:physiology
chemical_list: D015415:Biomarkers; D005227:Fatty Acids; D010446:Peptide Fragments; C109794:pro-brain natriuretic peptide (1-76); D020097:Natriuretic Peptide, Brain
keywords: fatty acid oxidation; heart failure; metabolism; metabolomics; mitochondrial dysfunction