title: Effect of Metformin on Metabolites and Relation With Myocardial Infarct Size and Left Ventricular Ejection Fraction After Myocardial Infarction.
abstract: BACKGROUND
  Left ventricular ejection fraction (LVEF) and infarct size (ISZ) are key predictors of long-term survival after myocardial infarction (MI). However, little is known about the biochemical pathways driving LV dysfunction after MI. To identify novel biomarkers predicting post-MI LVEF and ISZ, we performed metabolic profiling in the GIPS-III randomized clinical trial (Glycometabolic Intervention as Adjunct to Primary Percutaneous Intervention in ST Elevation Myocardial Infarction). We also investigated the metabolic footprint of metformin, a drug associated with improved post-MI LV function in experimental studies.
  
  
  RESULTS
  Participants were patients with ST-segment-elevated MI who were randomly assigned to receive metformin or placebo for 4 months. Blood samples were obtained on admission, 24 hours post-MI, and 4 months post-MI. A total of 233 metabolite measures were quantified using nuclear magnetic resonance spectrometry. LVEF and ISZ were assessed 4 months post-MI. Twenty-four hours post-MI measurements of high-density lipoprotein (HDL) triglycerides (HDL-TG) predicted LVEF (β=1.90 [95% confidence interval (CI), 0.82 to 2.98]; P=6.4×10-4) and ISZ (β=-0.41 [95% CI, -0.60 to -0.21]; P=3.2×10-5). In addition, 24 hours post-MI measurements of medium HDL-TG (β=-0.40 [95% CI, -0.60 to -0.20]; P=6.4×2×10-5), small HDL-TG (β=-0.34 [95% CI, -0.53 to -0.14]; P=7.3×10-4), and the triglyceride content of very large HDL (β=-0.38 [95% CI, -0.58 to -0.18]; P=2.7×10-4) were associated with ISZ. After the 4-month treatment, the phospholipid content of very large HDL was lower in metformin than in placebo-treated patients (28.89% versus 38.79%; P=7.5×10-5); alanine levels were higher in the metformin group (0.46 versus 0.44 mmol/L; P=2.4×10-4).
  
  
  CONCLUSIONS
  HDL triglyceride concentrations predict post-MI LVEF and ISZ. Metformin increases alanine levels and reduces the phospholipid content in very large HDL particles.
  
  
  BACKGROUND
  URL: https://clinicaltrials.gov/ct2/show/NCT01217307. Unique Identifier: NCT01217307.
authors.affiliation: From the Department of Cardiology (R.N.E., E.L., D.J.v.V., P.v.d.H.), Department of Endocrinology (R.P.F.D.), Department of Critical Care (I.C.C.v.d.H.), University of Groningen, University Medical Center Groningen, The Netherlands; Division of Heart and Lungs, Department of Cardiology (D.K., F.W.A.), Julius Center for Health Sciences and Primary Care (G.W.D.), University Medical Center Utrecht, The Netherlands; Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, Utrecht (F.W.A., P.v.d.H.); and Institute of Cardiovascular Science, Faculty of Population Health Sciences, University College London, United Kingdom (F.W.A.).
authors.forename: Ruben N
authors.initials: RN
authors.lastname: Eppinga
authors.affiliation: From the Department of Cardiology (R.N.E., E.L., D.J.v.V., P.v.d.H.), Department of Endocrinology (R.P.F.D.), Department of Critical Care (I.C.C.v.d.H.), University of Groningen, University Medical Center Groningen, The Netherlands; Division of Heart and Lungs, Department of Cardiology (D.K., F.W.A.), Julius Center for Health Sciences and Primary Care (G.W.D.), University Medical Center Utrecht, The Netherlands; Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, Utrecht (F.W.A., P.v.d.H.); and Institute of Cardiovascular Science, Faculty of Population Health Sciences, University College London, United Kingdom (F.W.A.).
authors.forename: Daniel
authors.initials: D
authors.lastname: Kofink
authors.affiliation: From the Department of Cardiology (R.N.E., E.L., D.J.v.V., P.v.d.H.), Department of Endocrinology (R.P.F.D.), Department of Critical Care (I.C.C.v.d.H.), University of Groningen, University Medical Center Groningen, The Netherlands; Division of Heart and Lungs, Department of Cardiology (D.K., F.W.A.), Julius Center for Health Sciences and Primary Care (G.W.D.), University Medical Center Utrecht, The Netherlands; Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, Utrecht (F.W.A., P.v.d.H.); and Institute of Cardiovascular Science, Faculty of Population Health Sciences, University College London, United Kingdom (F.W.A.).
authors.forename: Robin P F
authors.initials: RP
authors.lastname: Dullaart
authors.affiliation: From the Department of Cardiology (R.N.E., E.L., D.J.v.V., P.v.d.H.), Department of Endocrinology (R.P.F.D.), Department of Critical Care (I.C.C.v.d.H.), University of Groningen, University Medical Center Groningen, The Netherlands; Division of Heart and Lungs, Department of Cardiology (D.K., F.W.A.), Julius Center for Health Sciences and Primary Care (G.W.D.), University Medical Center Utrecht, The Netherlands; Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, Utrecht (F.W.A., P.v.d.H.); and Institute of Cardiovascular Science, Faculty of Population Health Sciences, University College London, United Kingdom (F.W.A.).
authors.forename: Geertje W
authors.initials: GW
authors.lastname: Dalmeijer
authors.affiliation: From the Department of Cardiology (R.N.E., E.L., D.J.v.V., P.v.d.H.), Department of Endocrinology (R.P.F.D.), Department of Critical Care (I.C.C.v.d.H.), University of Groningen, University Medical Center Groningen, The Netherlands; Division of Heart and Lungs, Department of Cardiology (D.K., F.W.A.), Julius Center for Health Sciences and Primary Care (G.W.D.), University Medical Center Utrecht, The Netherlands; Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, Utrecht (F.W.A., P.v.d.H.); and Institute of Cardiovascular Science, Faculty of Population Health Sciences, University College London, United Kingdom (F.W.A.).
authors.forename: Erik
authors.initials: E
authors.lastname: Lipsic
authors.affiliation: From the Department of Cardiology (R.N.E., E.L., D.J.v.V., P.v.d.H.), Department of Endocrinology (R.P.F.D.), Department of Critical Care (I.C.C.v.d.H.), University of Groningen, University Medical Center Groningen, The Netherlands; Division of Heart and Lungs, Department of Cardiology (D.K., F.W.A.), Julius Center for Health Sciences and Primary Care (G.W.D.), University Medical Center Utrecht, The Netherlands; Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, Utrecht (F.W.A., P.v.d.H.); and Institute of Cardiovascular Science, Faculty of Population Health Sciences, University College London, United Kingdom (F.W.A.).
authors.forename: Dirk J
authors.initials: DJ
authors.lastname: van Veldhuisen
authors.affiliation: From the Department of Cardiology (R.N.E., E.L., D.J.v.V., P.v.d.H.), Department of Endocrinology (R.P.F.D.), Department of Critical Care (I.C.C.v.d.H.), University of Groningen, University Medical Center Groningen, The Netherlands; Division of Heart and Lungs, Department of Cardiology (D.K., F.W.A.), Julius Center for Health Sciences and Primary Care (G.W.D.), University Medical Center Utrecht, The Netherlands; Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, Utrecht (F.W.A., P.v.d.H.); and Institute of Cardiovascular Science, Faculty of Population Health Sciences, University College London, United Kingdom (F.W.A.).
authors.forename: Iwan C C
authors.initials: IC
authors.lastname: van der Horst
authors.affiliation: From the Department of Cardiology (R.N.E., E.L., D.J.v.V., P.v.d.H.), Department of Endocrinology (R.P.F.D.), Department of Critical Care (I.C.C.v.d.H.), University of Groningen, University Medical Center Groningen, The Netherlands; Division of Heart and Lungs, Department of Cardiology (D.K., F.W.A.), Julius Center for Health Sciences and Primary Care (G.W.D.), University Medical Center Utrecht, The Netherlands; Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, Utrecht (F.W.A., P.v.d.H.); and Institute of Cardiovascular Science, Faculty of Population Health Sciences, University College London, United Kingdom (F.W.A.). p.van.der.harst@umcg.nl f.w.asselbergs@umcutrecht.nl.
authors.forename: Folkert W
authors.initials: FW
authors.lastname: Asselbergs
authors.affiliation: From the Department of Cardiology (R.N.E., E.L., D.J.v.V., P.v.d.H.), Department of Endocrinology (R.P.F.D.), Department of Critical Care (I.C.C.v.d.H.), University of Groningen, University Medical Center Groningen, The Netherlands; Division of Heart and Lungs, Department of Cardiology (D.K., F.W.A.), Julius Center for Health Sciences and Primary Care (G.W.D.), University Medical Center Utrecht, The Netherlands; Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, Utrecht (F.W.A., P.v.d.H.); and Institute of Cardiovascular Science, Faculty of Population Health Sciences, University College London, United Kingdom (F.W.A.). p.van.der.harst@umcg.nl f.w.asselbergs@umcutrecht.nl.
authors.forename: Pim
authors.initials: P
authors.lastname: van der Harst
mesh_terms: D000409:Alanine / Q000097:blood; D015415:Biomarkers / Q000097:blood; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D008075:Lipoproteins, HDL / Q000097:blood; D009682:Magnetic Resonance Spectroscopy; D055432:Metabolomics / Q000379:methods; D008687:Metformin / Q000627:therapeutic use*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D009426:Netherlands; D010743:Phospholipids / Q000097:blood; D020127:Recovery of Function; D000072657:ST Elevation Myocardial Infarction / Q000097:blood / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000503:physiopathology; D013318:Stroke Volume / Q000187:drug effects*; D013997:Time Factors; D016896:Treatment Outcome; D014280:Triglycerides / Q000097:blood; D018487:Ventricular Dysfunction, Left / Q000097:blood / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000503:physiopathology; D016277:Ventricular Function, Left / Q000187:drug effects*
chemical_list: D015415:Biomarkers; C034396:HDL-triglyceride; D007004:Hypoglycemic Agents; D008075:Lipoproteins, HDL; D010743:Phospholipids; D014280:Triglycerides; D008687:Metformin; D000409:Alanine
keywords: lipoproteins, HDL; metabolomics; metformin; prognosis; triglycerides