title: Validation of the association between a branched chain amino acid metabolite profile and extremes of coronary artery disease in patients referred for cardiac catheterization.
abstract: OBJECTIVE
  To validate independent associations between branched-chain amino acids (BCAA) and other metabolites with coronary artery disease (CAD).
  
  
  METHODS
  We conducted mass-spectrometry-based profiling of 63 metabolites in fasting plasma from 1983 sequential patients undergoing cardiac catheterization. Significant CAD was defined as CADindex ≥ 32 (at least one vessel with ≥ 95% stenosis; N = 995) and no CAD as CADindex ≤ 23 and no previous cardiac events (N = 610). Individuals (N = 378) with CAD severity between these extremes were excluded. Principal components analysis (PCA) reduced large numbers of correlated metabolites into uncorrelated factors. Association between metabolite factors and significant CAD vs. no CAD was tested using logistic regression; and between metabolite factors and severity of CAD was tested using linear regression.
  
  
  RESULTS
  Of twelve PCA-derived metabolite factors, two were associated with CAD in multivariable models: factor 10, composed of BCAA (adjusted odds ratio, OR, 1.20; 95% CI 1.05-1.35, p = 0.005) and factor 7, composed of short-chain acylcarnitines, which include byproducts of BCAA metabolism (adjusted OR 1.30; 95% CI 1.14-1.48, p = 0.001). After adjustment for glycated albumin (marker of insulin resistance [IR]) both factors 7 (p = 0.0001) and 10 (p = 0.004) remained associated with CAD. Severity of CAD as a continuous variable (including patients with non-obstructive disease) was associated with metabolite factors 2, 3, 6, 7, 8 and 9; only factors 7 and 10 were associated in multivariable models.
  
  
  CONCLUSIONS
  We validated the independent association of metabolites involved in BCAA metabolism with CAD extremes. These metabolites may be reporting on novel mechanisms of CAD pathogenesis that are independent of IR and diabetes.
authors.affiliation: Duke Global Health Institute, Durham, NC, USA; Duke Institute of Molecular Physiology, Durham, NC, USA. Electronic address: sayanti.bhattacharya@duke.edu.
authors.forename: Sayanti
authors.initials: S
authors.lastname: Bhattacharya
authors.affiliation: Division of Cardiovascular Medicine, Duke University School of Medicine, Durham, NC, USA; Duke Clinical Research Institute, Durham, NC, USA. Electronic address: christopher.granger@duke.edu.
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Granger
authors.affiliation: Duke Institute of Molecular Physiology, Durham, NC, USA. Electronic address: damian.craig@duke.edu.
authors.forename: Damian
authors.initials: D
authors.lastname: Craig
authors.affiliation: Duke Institute of Molecular Physiology, Durham, NC, USA. Electronic address: carol.haynes@duke.edu.
authors.forename: Carol
authors.initials: C
authors.lastname: Haynes
authors.affiliation: Duke Institute of Molecular Physiology, Durham, NC, USA. Electronic address: james.bain@duke.edu.
authors.forename: James
authors.initials: J
authors.lastname: Bain
authors.affiliation: Duke Institute of Molecular Physiology, Durham, NC, USA. Electronic address: rdjestev@duke.edu.
authors.forename: Robert D
authors.initials: RD
authors.lastname: Stevens
authors.affiliation: Duke Institute of Molecular Physiology, Durham, NC, USA. Electronic address: elizabeth.hauser@duke.edu.
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Hauser
authors.affiliation: Duke Institute of Molecular Physiology, Durham, NC, USA. Electronic address: newga002@mc.duke.edu.
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Newgard
authors.affiliation: Duke Institute of Molecular Physiology, Durham, NC, USA. Electronic address: william.kraus@duke.edu.
authors.forename: William E
authors.initials: WE
authors.lastname: Kraus
authors.affiliation: Division of Cardiovascular Medicine, Duke University School of Medicine, Durham, NC, USA; Duke Clinical Research Institute, Durham, NC, USA. Electronic address: kristin.newby@duke.edu.
authors.forename: L Kristin
authors.initials: LK
authors.lastname: Newby
authors.affiliation: Duke Global Health Institute, Durham, NC, USA; Duke Institute of Molecular Physiology, Durham, NC, USA; Division of Cardiovascular Medicine, Duke University School of Medicine, Durham, NC, USA; Duke Clinical Research Institute, Durham, NC, USA. Electronic address: svati.shah@duke.edu.
authors.forename: Svati H
authors.initials: SH
authors.lastname: Shah
mesh_terms: D000368:Aged; D000418:Albumins / Q000737:chemistry; D000597:Amino Acids, Branched-Chain / Q000737:chemistry*; D006328:Cardiac Catheterization; D016022:Case-Control Studies; D017023:Coronary Angiography; D003324:Coronary Artery Disease / Q000097:blood* / Q000628:therapy; D003920:Diabetes Mellitus / Q000097:blood*; D005260:Female; D006801:Humans; D007333:Insulin Resistance; D016014:Linear Models; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D015999:Multivariate Analysis; D016017:Odds Ratio; D010641:Phenotype; D025341:Principal Component Analysis
chemical_list: D000418:Albumins; D000597:Amino Acids, Branched-Chain
keywords: Branched chain amino acids; Coronary artery disease; Metabolism