title: Increased Trimethylamine N-Oxide Portends High Mortality Risk Independent of Glycemic Control in Patients with Type 2 Diabetes Mellitus.
abstract: BACKGROUND
  Recent studies show a mechanistic link between intestinal microbial metabolism of dietary phosphatidylcholine and coronary artery disease pathogenesis. Concentrations of a proatherogenic gut microbe-generated metabolite, trimethylamine N-oxide (TMAO), predict increased incident cardiovascular disease risks in multiple cohorts. TMAO concentrations are increased in patients with type 2 diabetes mellitus (T2DM), but their prognostic value and relation to glycemic control are unclear.
  
  
  METHODS
  We examined the relationship between fasting TMAO and 2 of its nutrient precursors, choline and betaine, vs 3-year major adverse cardiac events and 5-year mortality in 1216 stable patients with T2DM who underwent elective diagnostic coronary angiography.
  
  
  RESULTS
  TMAO [4.4 μmol/L (interquartile range 2.8-7.7 μmol/L) vs 3.6 (2.3-5.7 μmol/L); P < 0.001] and choline concentrations were higher in individuals with T2DM vs healthy controls. Within T2DM patients, higher plasma TMAO was associated with a significant 3.0-fold increased 3-year major adverse cardiac event risk (P < 0.001) and a 3.6-fold increased 5-year mortality risk (P < 0.001). Following adjustments for traditional risk factors and high-sensitivity C-reactive protein, glycohemoglobin, and estimated glomerular filtration rate, increased TMAO concentrations remained predictive of both major adverse cardiac events and mortality risks in T2DM patients [e.g., quartiles 4 vs 1, hazard ratio 2.05 (95% CI, 1.31-3.20), P < 0.001; and 2.07 (95% CI, 1.37-3.14), P < 0.001, respectively].
  
  
  CONCLUSIONS
  Fasting plasma concentrations of the proatherogenic gut microbe-generated metabolite TMAO are higher in diabetic patients and portend higher major adverse cardiac events and mortality risks independent of traditional risk factors, renal function, and relationship to glycemic control.
authors.affiliation: Center for Cardiovascular Diagnostics & Prevention, Department of Cellular & Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH.|Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic, Cleveland, OH.
authors.forename: W H Wilson
authors.initials: WH
authors.lastname: Tang
authors.affiliation: Center for Cardiovascular Diagnostics & Prevention, Department of Cellular & Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH.
authors.forename: Zeneng
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Center for Cardiovascular Diagnostics & Prevention, Department of Cellular & Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH.
authors.forename: Xinmin S
authors.initials: XS
authors.lastname: Li
authors.affiliation: Department of Mathematics, Cleveland State University, Cleveland, OH.
authors.forename: Yiying
authors.initials: Y
authors.lastname: Fan
authors.affiliation: Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Li
authors.affiliation: Department of Mathematics, Cleveland State University, Cleveland, OH.
authors.forename: Yuping
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Center for Cardiovascular Diagnostics & Prevention, Department of Cellular & Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH; hazens@ccf.org.|Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic, Cleveland, OH.
authors.forename: Stanley L
authors.initials: SL
authors.lastname: Hazen
mesh_terms: D000368:Aged; D001622:Betaine / Q000097:blood / Q000378:metabolism; D001786:Blood Glucose / Q000032:analysis* / Q000378:metabolism; D002794:Choline / Q000097:blood / Q000378:metabolism; D015331:Cohort Studies; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000175:diagnosis / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D008744:Methylamines / Q000097:blood* / Q000378:metabolism; D008875:Middle Aged; D011446:Prospective Studies; D012307:Risk Factors; D015996:Survival Rate
chemical_list: D001786:Blood Glucose; D008744:Methylamines; D001622:Betaine; C005855:trimethyloxamine; D002794:Choline