title: Prognostic value of elevated levels of intestinal microbe-generated metabolite trimethylamine-N-oxide in patients with heart failure: refining the gut hypothesis.
abstract: BACKGROUND
  Altered intestinal function is prevalent in patients with heart failure (HF), but its role in adverse outcomes is unclear.
  
  
  OBJECTIVE
  This study investigated the potential pathophysiological contributions of intestinal microbiota in HF.
  
  
  METHODS
  We examined the relationship between fasting plasma trimethylamine-N-oxide (TMAO) and all-cause mortality over a 5-year follow-up in 720 patients with stable HF.
  
  
  RESULTS
  The median TMAO level was 5.0 μM, which was higher than in subjects without HF (3.5 μM; p < 0.001). There was modest but significant correlation between TMAO concentrations and B-type natriuretic peptide (BNP) levels (r = 0.23; p < 0.001). Higher plasma TMAO levels were associated with a 3.4-fold increased mortality risk. Following adjustments for traditional risk factors and BNP levels, elevated TMAO levels remained predictive of 5-year mortality risk (hazard ratio [HR]: 2.2; 95% CI: 1.42 to 3.43; p < 0.001), as well as following the addition of estimated glomerular filtration rate to the model (HR: 1.75; 95% CI: 1.07 to 2.86; p < 0.001).
  
  
  CONCLUSIONS
  High TMAO levels were observed in patients with HF, and elevated TMAO levels portended higher long-term mortality risk independent of traditional risk factors and cardiorenal indexes.
authors.affiliation: Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio; Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic, Cleveland, Ohio. Electronic address: tangw@ccf.org.
authors.forename: W H Wilson
authors.initials: WH
authors.lastname: Tang
authors.affiliation: Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Zeneng
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Mathematics, Cleveland State University, Cleveland, Ohio.
authors.forename: Yiying
authors.initials: Y
authors.lastname: Fan
authors.affiliation: Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Bruce
authors.initials: B
authors.lastname: Levison
authors.affiliation: Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Jennie E
authors.initials: JE
authors.lastname: Hazen
authors.affiliation: Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Lillian M
authors.initials: LM
authors.lastname: Donahue
authors.affiliation: Department of Mathematics, Cleveland State University, Cleveland, Ohio.
authors.forename: Yuping
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio; Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Stanley L
authors.initials: SL
authors.lastname: Hazen
mesh_terms: D000368:Aged; D015415:Biomarkers / Q000097:blood; D005260:Female; D005500:Follow-Up Studies; D006333:Heart Failure / Q000097:blood / Q000401:mortality*; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000382:microbiology; D053208:Kaplan-Meier Estimate; D008297:Male; D013058:Mass Spectrometry; D008744:Methylamines / Q000097:blood*; D064307:Microbiota; D008875:Middle Aged; D009820:Ohio / Q000453:epidemiology; D011379:Prognosis; D011446:Prospective Studies; D018570:Risk Assessment / Q000379:methods*; D015996:Survival Rate / Q000639:trends; D013997:Time Factors
chemical_list: D015415:Biomarkers; D008744:Methylamines; C005855:trimethyloxamine
keywords: C-reactive protein; TMAO; cardiorenal; intestinal microbiota; mortality