title: Gut microbiota-dependent trimethylamine N-oxide in acute coronary syndromes: a prognostic marker for incident cardiovascular events beyond traditional risk factors.
abstract: OBJECTIVE
  Systemic levels of trimethylamine N-oxide (TMAO), a pro-atherogenic and pro-thrombotic metabolite produced from gut microbiota metabolism of dietary trimethylamine (TMA)-containing nutrients such as choline or carnitine, predict incident cardiovascular event risks in stable primary and secondary prevention subjects. However, the prognostic value of TMAO in the setting of acute coronary syndromes (ACS) remains unknown.
  
  
  RESULTS
  We investigated the relationship of TMAO levels with incident cardiovascular risks among sequential patients presenting with ACS in two independent cohorts. In the Cleveland Cohort, comprised of sequential subjects (n = 530) presenting to the Emergency Department (ED) with chest pain of suspected cardiac origin, an elevated plasma TMAO level at presentation was independently associated with risk of major adverse cardiac events (MACE, including myocardial infarction, stroke, need for revascularization, or death) over the ensuing 30-day (4th quartile (Q4) adjusted odds ratio (OR) 6.30, 95% confidence interval (CI), 1.89-21.0, P < 0.01) and 6-month (Q4 adjusted OR 5.65, 95%CI, 1.91-16.7; P < 0.01) intervals. TMAO levels were also a significant predictor of the long term (7-year) mortality (Q4 adjusted HR 1.81, 95%CI, 1.04-3.15; P < 0.05). Interestingly, TMAO level at initial presentation predicted risk of incident MACE over the near-term (30 days and 6 months) even among subjects who were initially negative for troponin T (< 0.1 ng/mL) (30 days, Q4 adjusted OR 5.83, 95%CI, 1.79-19.03; P < 0.01). The prognostic value of TMAO was also assessed in an independent multicentre Swiss Cohort of ACS patients (n = 1683) who underwent coronary angiography. Trimethylamine N-oxide again predicted enhanced MACE risk (1-year) (adjusted Q4 hazard ratios: 1.57, 95% CI, 1.03-2.41; P <0.05).
  
  
  CONCLUSIONS
  Plasma TMAO levels among patients presenting with chest pain predict both near- and long-term risks of incident cardiovascular events, and may thus provide clinical utility in risk stratification among subjects presenting with suspected ACS.
authors.affiliation: Department of Cellular & Molecular Medicine, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA.
authors.forename: Xinmin S
authors.initials: XS
authors.lastname: Li
authors.affiliation: Department of Cardiology, University Heart Center, University Hospital Zurich, Switzerland.
authors.forename: Slayman
authors.initials: S
authors.lastname: Obeid
authors.affiliation: Department of Cardiology, University Heart Center, University Hospital Zurich, Switzerland.
authors.forename: Roland
authors.initials: R
authors.lastname: Klingenberg
authors.affiliation: Department of Cardiology, Cardiovascular Center, University Hospital Geneva, Switzerland.
authors.forename: Baris
authors.initials: B
authors.lastname: Gencer
authors.affiliation: Department of Cardiology, Cardiovascular Center, University Hospital Geneva, Switzerland.
authors.forename: François
authors.initials: F
authors.lastname: Mach
authors.affiliation: Department of Cardiology, Cardiovascular Center, University Hospital Bern, Switzerland.
authors.forename: Lorenz
authors.initials: L
authors.lastname: Räber
authors.affiliation: Department of Cardiology, Cardiovascular Center, University Hospital Bern, Switzerland.
authors.forename: Stephan
authors.initials: S
authors.lastname: Windecker
authors.affiliation: Department of General Internal Medicine, University Hospital Bern, Switzerland.|Institute of Primary Health Care (BIHAM), University of Bern, Switzerland.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Rodondi
authors.affiliation: Department of Ambulatory Care and Community Medicine, Lausanne University, Lausanne, Switzerland.
authors.forename: David
authors.initials: D
authors.lastname: Nanchen
authors.affiliation: Department of Cardiology, Cardiovascular Center, University Hospital Lausanne, Switzerland.
authors.forename: Olivier
authors.initials: O
authors.lastname: Muller
authors.affiliation: Center for Molecular Cardiology, University of Zurich, Switzerland.
authors.forename: Melroy X
authors.initials: MX
authors.lastname: Miranda
authors.affiliation: Department of Cardiology, University Heart Center, University Hospital Zurich, Switzerland.
authors.forename: Christian M
authors.initials: CM
authors.lastname: Matter
authors.affiliation: Department of Mathematics, Cleveland State University, 2121 Euclid Avenue, Cleveland, OH 44115, USA.
authors.forename: Yuping
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of Cellular & Molecular Medicine, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Cellular & Molecular Medicine, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA.
authors.forename: Zeneng
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Cellular & Molecular Medicine, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA.|Department of Chemistry, Cleveland State University, 2121 Euclid Avenue, Cleveland, OH 44115, USA.
authors.forename: Hassan S
authors.initials: HS
authors.lastname: Alamri
authors.affiliation: Department of Cellular & Molecular Medicine, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA.|Department of Chemistry, Cleveland State University, 2121 Euclid Avenue, Cleveland, OH 44115, USA.
authors.forename: Valentin
authors.initials: V
authors.lastname: Gogonea
authors.affiliation: Department of Cellular & Molecular Medicine, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA.
authors.forename: Yoon-Mi
authors.initials: YM
authors.lastname: Chung
authors.affiliation: Department of Cellular & Molecular Medicine, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA.|Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA.
authors.forename: W H Wilson
authors.initials: WH
authors.lastname: Tang
authors.affiliation: Department of Cellular & Molecular Medicine, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA.|Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA.
authors.forename: Stanley L
authors.initials: SL
authors.lastname: Hazen
authors.affiliation: Department of Cardiology, University Heart Center, University Hospital Zurich, Switzerland.
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Lüscher
mesh_terms: D054058:Acute Coronary Syndrome / Q000188:drug therapy / Q000378:metabolism / Q000401:mortality*; D015415:Biomarkers / Q000378:metabolism; D002316:Cardiotonic Agents / Q000627:therapeutic use; D016022:Case-Control Studies; D005260:Female; D000069196:Gastrointestinal Microbiome / Q000502:physiology*; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008744:Methylamines / Q000378:metabolism; D008875:Middle Aged; D009203:Myocardial Infarction / Q000209:etiology / Q000401:mortality; D011379:Prognosis; D018570:Risk Assessment; D020521:Stroke / Q000209:etiology / Q000401:mortality
chemical_list: D015415:Biomarkers; D002316:Cardiotonic Agents; D008744:Methylamines; C005855:trimethyloxamine
keywords: Acute coronary syndrome; All-cause mortality; Choline; Gut microbiota; Incident major adverse cardiac events; Risk stratification; Trimethylamine N-oxide