title: Diastolic Left Ventricular Function in Relation to Circulating Metabolic Biomarkers in a General Population.
abstract: BACKGROUND
  The metabolic signature associated with subclinical diastolic left ventricular (LV) dysfunction in the population remains ill defined.
  
  
  RESULTS
  In 711 randomly recruited Flemish (50.8% women; mean age, 50.8 years), we assessed echocardiographic Doppler indexes of diastolic LV function in relation to 44 circulating metabolites determined by nuclear magnetic resonance spectroscopy. In multivariable-adjusted regression analysis with Bonferroni correction of significance levels applied, peak a' decreased (P≤0.048) and e'/a' increased (P≤0.044) with circulating tyrosine, high-density lipoprotein apolipoproteins, glucose+glutamine, and an unidentified molecule. Effect sizes expressed per 1-SD increment in the metabolite ranged from -0.277 to -0.203 cm/s for peak a' and from +0.047 to +0.054 for e'/a'. In addition, peak a' decreased (P≤0.031) with glucose+2-aminobutyrate (-0.261 cm/s) and glucose+2-phosphoglycerate (-0.209 cm/s). In partial least square discriminant analysis (PLS-DA), metabolites associated with normal diastolic LV function (n=538) included glucose+glutamine, glucose+2-aminobutyrate, and glucose+2-phosphoglycerate, whereas those siding with abnormal function encompassed 4-aminobutyrate, 4-hydroxybutyrate, creatinine, and phosphocholine. In receiver operating characteristics plots, adding 3 latent factors identified by PLS-DA to prohormone brain natriuretic peptide increased (P<0.0001) the area under the curve from 0.64 (95% CI, 0.58-0.68) to 0.73 (0.68-0.78).
  
  
  CONCLUSIONS
  In a general population, circulating metabolites indicative of energy substrate utilization and protection against oxidative stress differentiated normal from abnormal diastolic LV function. These findings improve our understanding of the pathophysiology underlying deterioration of diastolic LV function and potentially point to new targets for prevention and treatment of this condition.
authors.affiliation: Studies Coordinating Centre, Research Unit Hypertension and Cardiovascular Epidemiology, KU Leuven Department of Cardiovascular Sciences, University of Leuven, Belgium.
authors.forename: Zhen-Yu
authors.initials: ZY
authors.lastname: Zhang
authors.affiliation: Metabolomic and Molecular Image Laboratory, Fundación Investigatión Clínico de Valencia (INCLIVA), Valencia, Spain.
authors.forename: Vannina G
authors.initials: VG
authors.lastname: Marrachelli
authors.affiliation: Studies Coordinating Centre, Research Unit Hypertension and Cardiovascular Epidemiology, KU Leuven Department of Cardiovascular Sciences, University of Leuven, Belgium.
authors.forename: Lutgarde
authors.initials: L
authors.lastname: Thijs
authors.affiliation: Studies Coordinating Centre, Research Unit Hypertension and Cardiovascular Epidemiology, KU Leuven Department of Cardiovascular Sciences, University of Leuven, Belgium.
authors.forename: Wen-Yi
authors.initials: WY
authors.lastname: Yang
authors.affiliation: Studies Coordinating Centre, Research Unit Hypertension and Cardiovascular Epidemiology, KU Leuven Department of Cardiovascular Sciences, University of Leuven, Belgium.
authors.forename: Fang-Fei
authors.initials: FF
authors.lastname: Wei
authors.affiliation: Metabolomic and Molecular Image Laboratory, Fundación Investigatión Clínico de Valencia (INCLIVA), Valencia, Spain.
authors.forename: Daniel
authors.initials: D
authors.lastname: Monleon
authors.affiliation: Studies Coordinating Centre, Research Unit Hypertension and Cardiovascular Epidemiology, KU Leuven Department of Cardiovascular Sciences, University of Leuven, Belgium.
authors.forename: Lotte
authors.initials: L
authors.lastname: Jacobs
authors.affiliation: Centre for Environmental Sciences, University of Hasselt, Diepenbeek, Belgium Research Unit Environment and Health, KU Leuven Department of Public Health and Primary Care, University of Leuven, Belgium.
authors.forename: Tim
authors.initials: T
authors.lastname: Nawrot
authors.affiliation: Centre for Molecular and Vascular Biology, KU Leuven Department of Cardiovascular Sciences, University of Leuven, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: Verhamme
authors.affiliation: Research Unit Cardiology, KU Leuven Department of Cardiovascular Sciences, University of Leuven, Belgium.
authors.forename: Jens-Uwe
authors.initials: JU
authors.lastname: Voigt
authors.affiliation: Studies Coordinating Centre, Research Unit Hypertension and Cardiovascular Epidemiology, KU Leuven Department of Cardiovascular Sciences, University of Leuven, Belgium.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Kuznetsova
authors.affiliation: Metabolomic and Molecular Image Laboratory, Fundación Investigatión Clínico de Valencia (INCLIVA), Valencia, Spain Hypertension Unit, Division of Internal Medicine, Hospital Clinico, University of Valencia, Spain Centro de Investigación Biomédica de la Fisiopatología de la Obesidad y la Nutrición (CIBERObn), Madrid, Spain Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Josep
authors.initials: J
authors.lastname: Redón
authors.affiliation: Studies Coordinating Centre, Research Unit Hypertension and Cardiovascular Epidemiology, KU Leuven Department of Cardiovascular Sciences, University of Leuven, Belgium R & D Group VitaK, Maastricht University, Maastricht, The Netherlands jan.staessen@med.kuleuven.be ja.staessen@maastrichtuniversity.nl.
authors.forename: Jan A
authors.initials: JA
authors.lastname: Staessen
mesh_terms: D000328:Adult; D000368:Aged; D019540:Area Under Curve; D015415:Biomarkers / Q000097:blood*; D003971:Diastole; D016002:Discriminant Analysis; D015150:Echocardiography, Doppler; D004734:Energy Metabolism; D005260:Female; D006801:Humans; D016018:Least-Squares Analysis; D016014:Linear Models; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D055432:Metabolomics / Q000379:methods; D008875:Middle Aged; D015999:Multivariate Analysis; D018384:Oxidative Stress; D011237:Predictive Value of Tests; D011379:Prognosis; D012372:ROC Curve; D018487:Ventricular Dysfunction, Left / Q000097:blood* / Q000000981:diagnostic imaging / Q000503:physiopathology; D016277:Ventricular Function, Left
chemical_list: D015415:Biomarkers
keywords: biomarker; diastolic left ventricular function; metabolomics; nuclear magnetic resonance spectroscopy; population science