Prognostic value of elevated levels of intestinal microbe-generated metabolite trimethylamine-N-oxide in patients with heart failure: refining the gut hypothesis

J Am Coll Cardiol. 2014 Nov 4;64(18):1908-14. doi: 10.1016/j.jacc.2014.02.617. Epub 2014 Oct 27.


Background: Altered intestinal function is prevalent in patients with heart failure (HF), but its role in adverse outcomes is unclear.

Objectives: 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.

Keywords: C-reactive protein; TMAO; cardiorenal; intestinal microbiota; mortality.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Biomarkers / blood
  • Female
  • Follow-Up Studies
  • Heart Failure / blood
  • Heart Failure / mortality*
  • Humans
  • Intestinal Mucosa / metabolism*
  • Intestines / microbiology
  • Kaplan-Meier Estimate
  • Male
  • Mass Spectrometry
  • Methylamines / blood*
  • Microbiota*
  • Middle Aged
  • Ohio / epidemiology
  • Prognosis
  • Prospective Studies
  • Risk Assessment / methods*
  • Survival Rate / trends
  • Time Factors


  • Biomarkers
  • Methylamines
  • trimethyloxamine